Immunology

Immunology Overview

2010-12-31T23:58:00.000-08:00

Immunology is the study of the immune system, which defends the body against foreign intrusion by pathogens. (right - colorized scanning electron micrograph of red blood cells - erythrocyte, platelet, leukocyte)

The immune system is intimately connected with the hematologic system since white blood cells (leukocytes, including B- and T-lymphocytes) are key players in the lymphoid system. Cellular participants in the immune and inflammatory responses include :
● phagocytic cells (dendritic cells, monocytes and macrophages, and granulocytes)
● antigen presenting cells (dendritic cells, macrophages, B lymphocytes, helper T cells)
● antibody producing cells (plasma cells)
● cytotoxic cells (CTL, NK, NKT)
● regulatory cells (APCs, helper T cells, regulatory T cells)
● cells-in-waiting (memory B cells, monocytes, naïve B cells, Tc)
● chemical releasing cells (basophils, eosinophils, neutrophils; mast cells - histamine, cytokines; hepatocytes - complement proteins)

An antigen is any molecule that stimulates an immune response. Most antigens are proteins or polysaccharides, though small molecules coupled to carrier proteins (haptens) can also be antigenic. The segment of an antigenic molecule to which its cognate antibody binds is termed an epitope or antigenic determinant. Immune responses ideally distinguish between self and other. Anergy toward self-targets operates as one self-tolerance mechanism to control the autoreactive cells found in disease-causing autoimmunity.

Immune responses are classifed as passive or active, innate or adaptive, and cellular or humoral.

These categories are not mutually exclusive. For example, both innate and adaptive immune responses employ cellular responses. Similarly, humoral and cellular responses intersect rather than being mutually independent (e.g., helper T cells assist in activation of B cells, opsonization). Unfortunately, some terminology employed in immunology predates understanding of mechanisms, so some commonly used names do not immediately reflect the distinction between cell types (NK cells versus NKT cells) or origins (lymphoid versus myeloid origins of dendritic cells). Similarly revision of chemical terminology has resulted in misleading terminology of biochemical components (e.g., complement C4b•2b was formerly termed C4b•2a).

Passive measures to prevent pathogenic incursions are provided by physical barriers to invasion – the skin, secretions, and ciliary action. Should pathogens pass beyond the physical barricade, then active innate and acquired immune reactions mount a defense.

Innate immune responses employ phagocytic cells that are circulating or tissue emplaced – granulocytes, monocytes, dendritic cells, macrophages, and B lymphocytes. The early, innate response also employs chemical responses – chemical-mediated inflammation; the complement cascade; antimicrobial peptides; and, pattern-recognition receptors (PRR), including Toll-like receptors. The innate system is considered to constitute an evolutionarily older defense strategy, and it is the predominant immune system exhibited by plants, fungi, insects, and primitive metazoa.

An induced, acquired, adaptive response begins when foreign or pathogenic substances (antigens) are 'recognized' by cells of the lymphoid system, stimulating a co-ordinated cellular/humoral response depending upon the nature of the pathogen. Antigen recognition relies on a random and highly diversified repertoire of receptors for antigens (TCR, BCR) and antigen stimulation is followed by clonal selection and expansion of cells expressing receptors with relevant specificities, accounting for immunological memory. Adaptive immune responses are typically delayed for 4 to 7 days because specific clones must expand and differentiate into effector cells before participating in host defense.

Surfaces of cells of the immune system are coated with proteins and receptors that participate in cellular signal transduction, enabling regulatory interaction:
● clusters of differentiation – a defined subset of cellular surface receptors (epitopes) on B and T lymphocytes that identify cell type and stage of differentiation, and which are recognized by antibodies.
● B cell receptors (BCR) comprising one of thousands of distinct immunoglobulin superfamily molecules generated through VDJ recombination.
● T cell receptors (TCR) with heterodimers of α and β chains or γ and δ chains with Ig-like domains. Each TCR originates in a single allele and binding with a single specificity (CDR3 for antigens and CDR1-2 for MHCs).
● pattern-recognition receptors, including Toll-like receptors, which participate in the innate immune response by responding to pathogen-associated molecular patterns (PAMP) and endogenous stress signals termed danger-associated molecular patterns (DAMP).
● major histocompatibility complex (MHC) molecules of classes I, II, and III, participate in lymphocyte recognition and antigen presentation.

B lymphocytes perform the humoral immune response, and are activated when naïve B cells encounter their specific, cognate antigen. Secreted cytokines promote the proliferation of single clones of B cells that express that immunoglobulin surface receptor (BCR) which already possesses VDJ recombination-generated affinity for the antigen. Assisted by costimulation from helper T cells, B cells may undergo differentiation into plasma cells, which secrete copious quantities of the monoclonal antibody, or into memory B cells, which are primed for rapid, amplified secondary response to a repeated exposure of the priming antigen.

T lymphocytes participate in the cellular immune response, and are activated by engagement of their surface receptor (TCR), which ensures antigen specificity and MHC restriction of the response. As for B cells, costimulatory, synergistic second signaling by costimulatory molecules is also necessary to sustain and integrate TCR signaling in order to stimulate optimal T cell proliferation and differentiation. T cells include cytotoxic T cells, helper T cells, regulatory T cells, natural killer T cells, and γδ T cells.

A ф activation ф affinity maturation ф anergy ф antibodies ф antigen ф APCs ф autoimmunity B ф B cells ф basophils ф blood C ф cancer and immune system ф cancers of immune system ф CD ф cellular response ф class-switch recombination ф clonal selection ф complement system ф costimulation ф cytolysis ф cytotoxicity D ф dendritic cells E ф eosinophils ф evolution of immune and coagulation systems G ф gene conversion ф granulocytes H ф helper T cell ф hematopoiesis ф humoral immunity ф HIV/AIDs I ф immune cytokines ф immune response ф immune tolerance ф inflammatory response ф interferons ф isotype switching K ф killer T cells L ф leukocytes ф leukocyte adhesion cascade ф lymphocytes ф lymphokines ф lymphoid system M ф macrophages ф MHC ф migration ф monocytes N ф neutrophils P ф pathogens ф pattern-recognition receptors ф phagocyte ф plasma cells R ф receptors S ф secondary antibody diversification ф signaling ф somatic hypermutation, somatic mutation ф surface receptors T ф T cells ф thymus ф (tolerance) V ф vaccines ф VDJ recombination

Tables Complement Receptors Fc receptors Immune Cytokines Immunoglobulins Interferons Scavenger Receptors Toll-like Receptors Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers

tags [Immunology] [Overview]

activation

2010-12-24T21:04:00.000-08:00

Activation of cells of the immune system variably induces proliferation, differentiation, production, and maturation. Some activated cells of the immune system are involved in activation (costimulation) of other cell types. Likewise, some activated cells express molecules involved in activation.

▼activating agents : B cell activation : costimulatory agents : costimulatory cells : complement activation pathways : dendritic cell activation : granulocyte activation : lymphocyte activation : macrophage alternative : macrophage classical : markers : mediators : monocyte-macrophage : pDC : phagocyte activation : precursor dendritic cells : signaling/receptors : T cell activation : Tc activation : Th activation▼

Activating agents
_ ● antigen
___ ● pathogens
___ ● pathogen-associated molecular patterns (PAMP)
___ ● danger-associated molecular patterns (DAMP)

Markers
___ ● major histocompatibility complex (MHC) molecules

Costimulatory agents
___ ● CD28
___ ● SLAM (signaling lymphocytic activation molecule), a 70-kDa costimulatory molecule belonging to the Ig superfamily
___ ● ICOS (inducible costimulator) molecules
___ ● TNFR: CD40, CD30, CD27, OX-40, 4-1BB
___ ● negative regulators of costimulation: CTLA-4, PD-1

Costimulatory cells
● helper T cells (Th) for activation of B cells, and APCs for activation of T cells
_ ●Antigen presenting cells display epitope proteins – exogenous antigen or fragmented angtigen from phagocytosed cells – on their surfaces. APCs include:
___ ● phagocytic cells – dendritic cells, macrophages
___ ● B cells (B lymphocytes)

Signaling / receptors
_ ● pattern recognition receptors
_____ ● complement receptors (table)
_____ ● Fc receptors (table)
_____ ● scavenger receptors (table)
_____ ● Toll-like receptors (table)
_ ● TNFR
_ ● B cell receptors (BCR)
___ ● immunoglobulin - antibodies (table)
_ ● T cell receptors (TCR)
_____ ● clusters of differentiation
_____ ● major histocompatibility complex (MHC) molecules

Mediators
_ ● immune cytokines (table)

Phagocytes

Dendritic cells
Dendritic cells and their immature counterparts, Langerhans cells (LC), are highly specialized, professional antigen-presenting cells (APC). Immature dendritic cells are called 'veiled cells' because they display large cytoplasmic 'veils' rather than the long dendritic projections of mature cells. As key regulators of immune responses, dendritic cells (DC) stimulate lymphocytes to perform cell-mediated and humoral immune responses against pathogens and tumor cells.

Immature, precursor dendritic cells (pDC) circulate throughout the body, migrating to lymphocyte rich tissues (such as spleen and lymph nodes) upon stimulating encounter with antigen. The dendritic cells internalize the antigen then externalize (fragmented) antigen that they present to lymphocytes in MHC-peptide complexes, expressing markers that stimulate lymphocyte activation.

Monocyte → macrophage activation
Production of the macrophage lineage from progenitors in the bone marrow is typically controlled by M-CSF, which is constitutively expressed by many cell types. Serum levels of M-CSF and GM-CSF increase in response to invasive stimuli and inflammation, and monocyte numbers increase dramatically. M-CSF-derived macrophages are larger, and have a higher phagocytic capacity, while GM-CSF-derived macrophages are more cytotoxic against TNF-α-resistant tumour targets, express more MHC class II antigen, and constitutively secrete more PGE-2.

Classically activated macrophages are associated with chronic inflammation and tissue injury wherein classically activated macrophages exhibit a Th1-like phenotype, promoting inflammation, destruction of the extracellular matrix (ECM), and apoptosis. Classical macrophage activation proceeds in two stages.
1. IFN-γ-primed stage in which macrophages exhibit enhanced MHC class II expression, antigen presentation, but reduced proliferative capacity. (IFN-α, IFN-β, IL-3, M-CSF, GM-CSF and TNF-α can also prime macrophages for selected functions.)
2. Secondary stimuli operated to fully activate primed macrophages. Diverse agents provide secondary signals (including LPS (CD14), bacteria, yeast glucans, GM-CSF and phorbol esters). Macrophages stimulated for tumoricidal activity secrete IL-1, display decreased MHC class II gene transcription, and are generally poor antigen presenters of antigen.[r]

Alternatively activated macrophages typically resolve inflammation and facilitate wound healing wherein they display a Th2-like phenotype, promoting construction of ECM, cell proliferation, and angiogenesis. Alternative macrophage activation does not require a priming stage and IL-42 and/or IL-1326 can act as sufficient stimuli.[r2]

Granulocyte activation
The hematopoietic cytokines, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have pleiotropic activating effects on mature leukocytes, which can improve leukocyte function, facilitating eradication of microbial infections. G-CSF activates neutrophils, while GM-CSF activates neutrophils, eosinophils, and monocyte/macrophages.

Lymphocytes
B cell activation: naïve B cells → plasma cells
Activation of naïve B cells occurs when a BCR (antibody) encounters and ligates its cognate antigen. B cells are coated in immunoglobulin receptors and are able to recognize intact antigen, which they engulf, digest, and subsequently present in complex with surface MHC class II molecules. The MHC-peptide complex binds CD4 + helper T cells (Th), inducing secretion of cytokines that stimulate B cell proliferation and their differentiation into plasma cells, which secrete specific antibodies that bind with the cognate antigen. These antigen-antibody complexes are subsequently cleared by liver and spleen cells and the classical complement cascade.

T cell activation:
Activation of T cells requires a first signal of TCR engagement, which ensures antigen specificity and MHC restriction of the response. The second signal comprises synergistic costimulatory signaling by professional antigen presenting cells. The costimulatory second signal is necessary to sustain and integrate TCR signaling to stimulate optimal T cell proliferation and differentiation. The level of activation of T cells is closely related to their state of differentiation.

Activation of the resting Tc cell involves two steps: 1) TCR on the CD8+ cell interacts with antigen-class I MHC complex on the surface of a target cell. 2) CD8+ Tc cell is stimulated by cytokines, particularly IL-2, which have been secreted predominantly by activated Th cells. Resting Tc do not express IL-2 receptors until antigen stimulation increases the expression of Tc IL-2 receptors, ensuring that activation is confined to Tc cells that ligate cognate antigen. Activated Tc cells become CTLs.

The first signal for helper T cell (Th) activation is interaction of the TcR-CD3 complex with antigen-MHC class II molecules on the surface of an antigen presenting cell. Stimulation is aided by the CD4 molecule on Th cells, with or without assistance from other accessory molecules, such as CD45, CD28 and CD2. Increased IL-2 secretion by the T cell and an increase in IL-2 receptors on the T cell surface trigger a cascade of biochemical events.

Three pathways are involved in complement activation:
● classical pathway (binding of an antibody to its cognate antigen)
● alternative pathway (relies upon spontaneous conversion of C3 to C3b)
● mannose-binding lectin pathway (MBL -MAPS) (homologous to the classical pathway, but utilizes opsonin, mannan-binding lectin (MBL) and ficolins rather than C1q)

▲ф A activating agents § adaptor protein ~ adhesion molecules ф affinity maturation ♦ AID ф anergy ф antibodies ф antigen ф APCs סּ apoptosis ф autoimmunity B : B cell activation ф B cells ọ blood ọ bone marrow C סּ caspases ф CD סּ cell-cycle control ₪ cellular fate ф cellular response סּ cellular signal transduction סּ chemotaxis ф class-switch recombination ф clonal selection ф complement system : complement activation pathways : costimulatory agents : costimulatory cells ~ cytokines ~ cytokine receptors D סּ death receptor : dendritic cell activation ф dendritic cells ₪ differentiation E סּ ECM F ♦ Fyn G ф gene conversion ọ germinal centers : granulocyte activation ф granulocytes H ф helper T cell ф hematopoiesis ф humoral immunity I ф immune cytokines ф immune response ф immune tolerance ~ immunoglobulins § immunoglobulin isotypes ф inflammatory response ф interferons ф isotype switching L ф leukocytes ф leukocyte adhesion cascade : lymphocyte activation ф lymphocytes ọ lymphoid system ф lymphokines ф lymphoid system M : macrophage alternative : macrophage classical ф macrophages ф MHC ф migration ¤ mitogens ф monocytes : markers : mediators : monocyte-macrophage N § NF-κB P ф pathogens ф pattern-recognition receptors : pDC : phagocyte activation ф phagocyte ф plasma cells : precursor dendritic cells ¤ proliferation R ф receptors S ф secondary antibody diversification ф signaling ¤ signaling molecules : signaling/receptors סּ signal transduction ф somatic hypermutation, somatic mutation ф surface receptors T : T cell activation ф T cells : Tc activation : Th activation ф thymus ọ thymus ф (tolerance) ▲ф

Complement Receptors Fc receptors Immune Cytokines Immunoglobulins Interferons Scavenger Receptors Toll-like Receptors

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tags [Immunology] [activation]

affinity maturation

2010-12-24T18:35:00.000-08:00

Affinity maturation is a process of affinity-selected differentiation of activated B cells. Repeated exposures to the same antigen provokes greater antibody ligating affinity in the antibody secreted by successive generations of plasma cells.

The mechanisms by which affinity maturation is achieved are somatic hypermutation and clonal selection. Somatic hypermutation (SHM) is a diversity generating, regulated cellular mechanism through which antibodies are produced against an enormous variety of different potential antigens. The binding affinities of the variable regions of immunoglobulins are altered by AID-enzyme-promoted mutations during antigen-stimulated proliferation of B cells. These somatic hypermutations are transcribed and translated into thousands of slightly different immunoglobulins coded by the hypermutated V regions. The complementarity determining regions of these antibodies possess different affinities for the encountered antigen, and clonal selection will favor cells equipped with highest affinity antibodies because these B cells are favoured in terms of activation and co-operation with T cells.

Clonal selection is the phenomenon whereby a previously unencountered cognate antigen (epitope) can stimulate naïve B lymphocytes to proliferate and differentiate into clones of memory B cells and plasma cells that produce antibodies with the highest affinity for the antigen. Those B cells that have highest affinity BCR against the encountered antigen will be selected for proliferation, antibody production, and committment to an antigen-specific memory lineage.

Thus, SHM prepares a spectrum of antibodies with different affinities for the antigen, while clonal selection ensures that the immune system will react increasingly effectively (highest affinity) to an encountered antigen and will be ready for rapid response to subsequent encounters with the antigen.

Tables Complement Receptors Cytokines Fc receptors Immune Cytokines Immunoglobulins Interferons Scavenger Receptors Toll-like Receptors

tags [Immunology] [affinity maturation]

anergy

2010-12-24T10:36:00.000-08:00

Anergy (immunologic tolerance) refers to the failure to mount a full immune response against a target.

Anergy toward self-targets operates as one self-tolerance mechanism to control the autoreactive cells found in autoimmunity. Clonal deletion in which lymphocytes are killed if they recognize a self-antigen during their maturation in the thymus gland or bone marrow is a major mechanism for the prevention of autoimmunity. However, not all human self-antigens are expressed in the central lymphoid organs where the lymphocytes are developing. Thus, self-tolerance to an individual's own antigens must also depend on mechanisms such as clonal anergy. Theoretically, recognition of a self-antigen eliminates the proliferative capacity of autoreactive lymphocytes in the peripheral immune system. Another process, immunoregulation, utilizes regulatory T cells that weaken harmful or inappropriate lymphocyte responses.

In B cell anergy, self-reactive B cells persist in the periphery yet remain unresponsive to immunogen. Research findings indicate that continuous binding of antigen and subsequent receptor signaling are essential for the maintenance of anergy.[n]

T cell anergy is induced when TCR stimulation "freezes" T cell responses until they receive an adequate subsequent antigenic signal from an antigen-presenting cell. Such APC signals can rescue T cells from anergy, stimulating them to produce the lymphokines necessary for the growth of additional T cells.

During a productive immune response, CD4+ T cells respond to effective signals by producing interleukin 2 (IL-2) and by proliferating. Effective signals stimulate require both ligation of TCRs with cognate antigens presented by class II MHC molecules on the surface of APCs and activation of costimulatory receptors, such as CD28, which recognize ligands such as B7 proteins expressed on the surface of APCs.

When T cells receive stimulus only TCR signals in the absence of engagement of costimulatory receptors, they enter a state of anergic unresponsiveness characterized by an inability to produce IL-2 or to proliferate upon re-stimulation. Such anergic T cells show a profound block in Ras/MAPK pathway that prevents activation of the AP-1 family of transcription factors (Fos/Jun).

GRAIL (gene related to anergy in lymphocytes) is GRAIL is an E3 ubiquitin ligase that is necessary for the induction of CD4+ T cell anergy in vivo. It is upregulated in naturally occurring (thymically derived) CD4+ and CD25+ cells [a] and anergized T cells [1]. Both GRAIL and Foxp3 are genotypic marker for CD25+ Treg cells. T cell activation appears to be controlled by Foxp3 through transcriptional regulation of early growth response (Egr) genes Egr-2 and Egr-3, and E3 ubiquitin (Ub) ligase genes Cblb [?], Itch [?] and GRAIL, subsequently affecting degradation of two key signaling proteins, PLCgamma1 and PKC-theta. [a]

It is believed that GRAIL could induce anergy through ubiquitylation of membrane-associated targets required for T-cell activation. It has been demonstrated that two isoforms of otubain-1, in conjunction with the deubiquitylating enzyme USP8, produce opposing effects on the expression and function of GRAIL in the induction of anergy.[2] GRAIL is differentially expressed in naturally occurring and peripherally induced CD25+ Treg cells where the expression of GRAIL has been suggested is linked to their functional "regulatory" activity.

Tables Complement Receptors Cytokines Fc receptors Immune Cytokines Immunoglobulins Interferons Scavenger Receptors Toll-like Receptors

tags [Immunology] [anergy]

antibodies

2010-12-24T10:04:00.000-08:00

Antibodies are glycoproteins of the immunoglobulin superfamily, and are adhesion-signaling molecules that recognize (bind to) specific antigens. Antibodies are synthesized by B cell-derived plasma cells.

▼: adhesion molecules : antigen binding site : C : CH1-4 : cellular adhesion molecules : complement fixation : complementarity determining regions : constant domains : domains : evolution of immunoglobulins : Fab : Fc : heavy chain : hinge region : Ig supergene family : isotypes : kinase activation : light chain : location of Ig classes : membrane-bound Igs : multimeric structures : tissue location : V : VDJ recombination : VH, VL : variable domains :▼

Immunoglobulins (left - click to enlarge) comprise two heavy (h) and two light-chain (l) protein subunits, each of which folds into domains (4 on heavy, 2 on light). These adhesion sites or domains contain one or more folds of 60 to 100 amino acids.

Depending upon the character of the heavy chain, immunoglobulins are divided into five classes – IgG, IgD, IgE, IgA, IgM – that are expressed in different tissues. The classes are further subdivided into isotypes, which have different properties in terms of complement fixation and binding to immunoglobulin (Ig) receptors.

Members of the immunoglobulin supergene family are found as:
● membrane-bound surface receptors of immune-system cells,
● cellular adhesion molecules, or
● soluble antibodies (γ-globulins) synthesized by activated B cells.

Membrane-bound Igs have a transmembrane segment and a cytoplasmic C-terminal tail. The 2 β- chains are stabilized into sandwiched β sheets that are adherent by virtue of hydrophobic interactions between disulphide bonds. Igs assume a Y-shaped structure "topped" at the extracellular N-terminals by variable domains (red), with a variable domain at the tip of the heavy chain (1) and the light chain (2), between which lies an antigen binding site (3). The variable regions are coded by pluripotential DNA sequences that can generate thousands of polypeptide sequences capable of adhering to millions of different ligands. Binding is homophilic or heterophilic, including binding to different Igs and to integrins. Both light and heavy chains contain constant domains (white, 4).

Right - click to enlarge - the heavy chains of IgA, IgD and IgG each have four domains, where those at the N-terminal are variable (VH) and the other three are constant (CH1-3). IgE and IgM have one variable and four constant domains (CH1-4) on the heavy chain. The variable domains are termed Fab, while the constant domains are termed Fc.

The light chains have two domains, one variable domain (VL) at the N-terminal, and one constant (CL) domain.

The antigen binding site lies between VH and VL (shaded lavendar). Most variability is found in three superficial-loop forming regions in the VH and VL domains, which are the complementarity determining regions or CDRs. CDR3 binds antigens and CDR1-2 bind MHCs. CDR3 shows more variation that do either CDR1 or 2.

The domains have related amino acid sequences that possess a common secondary and tertiary structure. This conserved structure is found frequently in proteins involved in cell-cell interactions and is particularly important in immunology. The constant (Fc) regions have complement fixing and Ig receptor binding activity. The hinge region, in IgG, IgA and IgD, is an important sequence of 10-60 amino acids between CH1 and CH2 that confers flexibility on the molecule.

animations Џ B cell selection Џ ELISA test +ve, -ve Џ IgG rotating x- y- axes Џ Rotating mouse IgG2a Molecule (y-axis) Џ somatic recombination of Ig gene Џ spinning IgG1 Kol Џ unfolding (small) IgG . unfolding (large) IgG .

Immunoglobulins attain their enormous variability by splicing components (VDJ recombination) coded in widely scattered sequences of DNA that are located in two different chromosomes. Antigen binding takes place at the heavy chain, which displays enormous variation by virtue of combining 1 of 400 possible variable gene segments with 1 out of 15 diversity segments and 1 out of 4 joining segments. This alternative splicing generates 24,000 possible combinations for the DNA encoding the heavy chain alone. The variable coding segments are assembled together with those for the constant-C segments of the heavy-chain molecule.

Tissue location:
IgA – mucus – gut, respiratory tract
IgD – antigen receptor on B cells
IgE – mast cells – releases histamines in response to allergens
IgG – primary immunity against invading pathogens
IgM – early B cell-mediated response to invading pathogens

Some antibody classes form multimeric structures – pentamers (IgM) and dimers or trimers (IgA). These two isotypes also associate with a small protein called the joining (J) chain required for stabilisation of the complexes.

The immunoglobulin superfamily is evolutionarily ancient, is widely expressed, and is constitutive or long-term up-regulated. Immunoglobulin antibodies are released by activated B cells of the immune system, on which they also act as surface marker proteins. Adherence of immunoglobilins to foreign substances or to cellular invaders may be sufficient to disarm the invader, or the attached antibodies function as attack signal to macrophages and natural killer cells. Adhesion molecules of the immunoglobulin supergene family, activate specific kinases through phosphorylation, resulting in activation of transcription factors, increased cytokine production, increased cell membrane protein expression, production of reactive oxygen species, and cell proliferation.

▲: adhesion molecules ~ adhesion molecules ф antigen : antigen binding site ф APCs ф B cells : C : CH1-4 : cellular adhesion molecules : complement fixation ф complement system : complementarity determining regions : constant domains : domains : evolution of immunoglobulins : Fab : Fc : heavy chain : hinge region ф humoral immunity : Ig supergene family ~ immunoglobulins : isotypes : kinase activation ♦ kinases : light chain : location of Ig classes : membrane-bound Igs : multimeric structures ф receptors ф signaling ф surface receptors ф T cells : tissue location ~ tyrosine kinases : V : VDJ recombination ф VDJ recombination : VH, VL : variable domains :▲

Tables Fc receptors Immune Cytokines Immunoglobulins Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers

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tags [Immunology]
[antibodies]

antigen

2010-12-24T10:03:00.000-08:00

An antigen is any molecule that stimulates an immune response. Most antigens are proteins or polysaccharides, though small molecules coupled to carrier proteins (haptens) can also be antigenic. The segment of an antigenic molecule to which its cognate antibody binds is termed an epitope or antigenic determinant.

▼ allergen : allergic reactions : antigenic determinant : autoantigenic : autoimmune disorders : class I histocompatibility molecule (MHC I) : class II histocompatibility molecule (MHC II) : immunogen : endogenous : epitope : exogenous : lipid Ag : pathogen-associated molecular pattern (PAMP) : pattern-recognition receptor (PRR) : polysaccharide Ag : T-dependent : T-independent : tolerogen : Toll-like receptor (TLR) : tumor antigens : tumor-associated antigen (TAA) : tumor-specific antigen (TSA) ▼

Antigens are classified by immune activity as immunogens, tolerogens, or allergens according to whether the molecule in question activates the immune response, is tolerated by the immune system, or elicits an allergic response, respectively. Allergic reactions are exaggerated immune responses to molecules (allergens) that would otherwise not prove harmful. Antigens may also be classified according to their source as exogenous, endogenous, autoantigenic, or tumor antigens.

Exogenous antigens are foreign molecules that are ingested (endo-, phagocytosis) by antigen presenting cells on which the fragmented and extruded antigens are then carried on class II histocompatibility molecules (MHC II) for presentation to CD4+ Th cells. Pathogen-associated molecular patterns (PAMPs ) are small molecular sequences consistently found on pathogens that are recognized by Toll-like receptors (TLRs) and other pattern-recognition receptors (PRRs). Pattern recognition receptors (PRR) are a class of innate immune response-expressed protein receptors that respond to PAMPs.

Endogenous antigens are internally generated molecules that become presented on the cell surface in the complex with class I histocompatibility molecules (MHC I). Endogenous antigens may result from exogeneous viral or bacterial infections that have altered the host cell.

In autoimmune disorders, endogenous, self-molecules induce autimmune attack by CD8+ Tc/CTLs that have escaped negative selection in the thymus.

Tumor-specific antigens (TSAs) typically result from a tumor specific mutation and are targetted for non-self attack when displayed on class I histocompatibility molecules. Tumor-associated antigens (TAAs) are more common than TSAs, and are presented both by tumor cells and by normal cells. Tumor antigens may elicit targetting by CTLs before the tumor cells can successfully proliferate and metastasize. Unfortunately, tumors employ a variety of mechanisms to evade the immune system.

Protein antigens are T dependent in that they require T cell co-operation to induce antibody responses in B cells. Non-protein antigens, such as polysaccharides and lipids can elicit T-independent antibody responses. Such T-independent antigens are typically polymeric, so it is believed that they are able to cross-link BCR-surface-Ig sufficiently strongly to activate B cells without T cell costimulation. These T-independent polymeric antigens elicit IgM antibodies and do not demonstrate affinity maturation. However, a subclass of T cells are specialized to present lipid and glycolipid antigens – γδ T cells recognize foreign nonpeptide antigens presented by CD1 proteins, which are MHC-like-molecules specialized for the presentation of lipids.

ф activation ф anergy ф antibodies ф antigen presenting cells (APCs) ф autoimmunity ф basophils ¤ cancer סּ cell-cycle control ф class-switch recombination ф clonal selection ф dendritic cells o-o endogenous vs exogenous ф eosinophils ф granulocytes ~ growth factors ф immune cytokines ф immune response ф immune tolerance ф inflammatory response ф interferons ф isotype switching ф leukocytes ф lymphocytes ф lymphokines ф lymphoid system ф macrophages ф MHC ф monocytes ф pathogens ф pattern-recognition receptors ф phagocyte ф plasma cells ¤ proliferation ф receptors ₪ regulation of gene expression ф secondary antibody diversification ф signaling ф surface receptors ф vaccines

Tables Fc receptors Immune Cytokines Immunoglobulins Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers

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tags [Immunology] [antigen] [pathogen] [autoimmune]

APCs

2010-12-24T08:49:00.000-08:00

APCs are antigen presenting cells, which display epitope proteins – exogenous antigen or fragmented antigen from phagocytosed cells – on their surfaces.

▼ APC types : B cells : BCRs : CD1 family : CD1 proteins : CD4+ : class II MHC : dendritic cells : endocytosis : exocytosis : fragmented antigen peptides : histocompatibility molecules : γδ T cells : intact antigen : lipid antigen : macrophages : mycobacterial cell wall components : peptide antigen : phagocytic presenting cells : T cells and fragmented peptides, T cells and lipid antigens ▼

Antigen presenting cells include:
● phagocytic cells – dendritic cells, macrophages
● B cells (B lymphocytes)
● γδ T cells

Fragmented antigen – APCs engulf the antigen through endocytosis, then the endosome fuses with a lysosome where the antigen is digested into fragments such as short peptides. Following, exocytosis, a class II histocompatibility molecule holds the fragmented antigenic peptides at the surface of the cell, where they may be recognized by CD4+ T cells.

Intact antigen – dendritic cells can present intact antigen to B cells (not fragmented in lysosomes) by presenting the antigen on the cell surface. This antigen can bind to BCRs of the appropriate specificity, and can stimulate the B cells.

Presentation of peptide antigens for activation of naïve T cells does not reside solely in dendritic cells. A population of γδ T cells can efficiently present peptide antigens to αβT cells, and γδ T cells of the major tissue subset recognize self and foreign nonpeptide, lipid antigens presented by CD1 proteins. γδ T cells carry TCRs encoded by different gene segments than those of αβ T cells.

CD1 proteins are a family (CD1a-e) of cluster of differentiation glycoproteins related to the class I MHC molecules. CD1 are involved in the presentation of lipid and glycolipid antigens, particularly self, microbial, and mycobacterial cell wall components, to CD1-specific T cells.

The human CD1 family of transmembrane glycoproteins are encoded by five CD1 family genes organized in a cluster on chromosome 1. CD1 glycoproteins form heterodimers with beta-2-microglobulin. CD1 family members are considered to differ in cellular localization and specificity for particular lipid ligands. The CD1a protein (R4, T6, CD1, FCB6, HTA1) localizes to the plasma membrane and to recycling vesicles of the early endocytic system. Alternatively spliced transcript variants have been observed.[e]

ф activation ₪ alternative splicing ф antibodies ф antigen ф B cells cell membranes ф costimulation ф dendritic cells סּ endosomes סּ exosome ф helper T cell ф killer T cells סּ lysosome ф macrophages ф MHC ф pathogens ф pattern-recognition receptors ф phagocyte סּ phagocytosis סּ receptor-mediated endocytosis ф surface receptors ф γδ T cells ф T cells

Tables Fc receptors Immune Cytokines Immunoglobulins Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers

tags [Immunology][APC]

autoimmunity

2010-12-24T03:04:00.000-08:00

Autoimmune responses involve immune responses directed at self, and are operative in the development of immunological tolerance to self. Autoimmune diseases arise when the immune system targets the organism's tissues because of a failure of tolerance.

Several hypotheses have been proposed to explain mechanisms of immumological tolerance:
● Clonal Deletion theory – proposal that self-reactive lymphoid cells are destroyed during the development of the immune system in an individual.
● Clonal Anergy theory – proposal that self-reactive T- or B-cells become inactivated in the normal individual and cannot amplify the immune response.
● Idiotype Network theory – proposal that a network of antibodies capable of neutralising self-reactive antibodies exists naturally within the body.
● Suppressor population or Regulatory T cell theories – proposal that regulatory T-lymphocytes (commonly including CD4+FoxP3+ cells) function to prevent, downregulate, or limit autoaggressive immune responses.
● Clonal Ignorance theory – proposal that host immune responses are directed to ignore self-antigens

Tables Fc receptors Immune Cytokines Immunoglobulins Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers

tags [Immunology][autoimmunity]

basophils

2010-12-23T23:05:00.000-08:00

Basophils are granulocytes packed with granules that stain basic (purple with H&E). The nucleus is bilobed, and the metachromatic granules contain sulfated glycosaminoglycans as well as vasoactive compounds – histamine and proteoglycans. Lysosomal arylsulfatase is found in granules of developing basophils in bone marrow. Basophil granules are surrounded by a unit membrane and contain particles which are uniform in size across the same granule yet vary in size in different granules within the same cell. Some granules reveal a homogeneous texture and/or "myelin" figures. [s] Though basophils and mast cells share morphological features, the appearance of most basophil granules differs from the ultrastructure of human mast cell granules.

Activated basophils release proinflammatory histamine and proteoglycans from granules, and synthesize then secrete leukotrienes and cytokines (particularly IL-4). Histamine and IL-4, which is associated with production of IgE, are involved in allergic reactions.

Basophils are the least common granulocyte, representing about 0.5% to 1% of circulating leukocytes. A low basophil count combined with a low neutrophil count almost always portends leukemia.

Tables Fc receptors Immune Cytokines Immunoglobulins .

tags [Immunology][leukocytes]

B cells

2010-12-23T21:37:00.000-08:00

B cells are lymphocytes (WBCs) that participate in humoral immunity by producing antibodies in response to antigen stimulation.

▼ activation : B-1 : B-2 : BCRs : CDRs : granzymes : helper T cells : life-span B cells : lymphopoiesis : memory B : naïve B cells : NK cells : NK receptors : NK cells attack viral infected cells : perforin : plasma B : stimulation : surface-immunoglobulins : surface receptors : VDJ recombination ▼

Surface membrane-associated immunoglobulins (IgD and IgM) act as B cell receptors (BCRs), and the enormous variety of antigen recognition sites is attributable to VDJ recombination (alternative splicing) of peptide sequences encoded by V, D, and J genes. The variable region of immunoglobulins includes the recognition sites or complementarity determining regions (CDRs).
Lymphopoiesis, which takes place in the bone marrow of almost all mammals, produces small lymphocytes, large granular lymphocytes (NK) cells, B lymphocytes (precursors of plasma cells, T lymphocytes, and lymphoid dendritic cell. Recognition of self during lymphopoiesis permits anergy (suppression of self-attack).

Naïve B cells each have one of millions of distinct surface antigen-specific receptors, yet have not encountered their specific, cognate antigen. With a life-span of only a few days, many B cells die without ever encountering their cognate antigen. Naïve B cells are activated when the BCR binds to its cognate antigen. This antigen-Ig binding must be coupled with a signal from a helper T cell in order to activate the B cell.

Once activated, B lymphocytes:
● differentiate into one of the B cell types (directly or through intermediate, germinal center reactions)
● plasma cells produce antibodies against the antigenic stimulus, or memory cells are primed for subsequent activation by the antigen

Types of B cell:
● B-1
● B-2
● Plasma B cells
● Memory B cells

After newly formed B cells exit generative sites in fetal liver or adult bone marrow they undergo selection events that may involve interactions with self or with external antigens. Selective events can influence the phenotype and functional characteristics of B cells. B cell receptor-mediated events also influence lymphoid organs localization as marginal zone B cells in the spleen, as follicular (B-2 cells), as well as B-1 cells in the peritoneal and pleural cavities. [] fluorescence micrograph spleen, fm high power in which T cells form periarteriolar lymphocyte sheath (PALS) (red) and B-2 cell follicles (green) []

B-1 cells are the first B cells produced in the fetus, and in adults are located primarily in the peritoneal and pleural cavities. B1 cells are believed to operate in the innate response to infection by viruses and bacteria, and usually show preferential responses to T cell-independent antigens. The diversity of B-1 lymphocytes is attributed to their recombinatorial recombination, in which there is a preferential recombination between D-proximal VH gene segments. B-1 lymphocytes express (polyspecific) IgM in greater quantities than they express IgG, and the ability of B1 cells to respond to isotype switch commitment factors such as interleukin-4 may be secondary to their production of IgM. B-1 cells express CD5, which binds to CD72 to mediate B cell-B cell interactions.

B-2 cells are conventional B lymphocytes that are produced postnatally (unlike fetal B-1 cells) and are replaced from the bone marrow.

Plasma B lymphocytes are committed to production of copious amounts of monoclonal antibodies.

Memory B lymphocytes are long-lived, stimulated B lymphocytes that are primed for rapid response to a repeated exposure of the priming antigen. Memory B cells are generated in lymphoid tissue after B cell activation/proliferation and reside in the bone marrow, lymph nodes, and spleen. High affinity surface immunoglobulins enable their activation by lower levels of cognate antigen than are naïve B cells.

NK cells are differentiated from killer T cells. NK, natural killer cells constitute a corps of circulating lymphocytes that are constitutively specialized to attack cancerous cells and virus infected cells. Preprogramming for target recognition, coupled with the absense of need for backup by a clone of identical cells, renders NK cells capable of rapid (innate) response to pathogens. NK attack involves the exocytosis of cytoplasmic granules containing perforin and granzymes. Perforin forms pores in the plasma membrane of attacked cells through which serine-protease granzymes enter, cleaving caspase precursors and triggering apoptosis.

Individuals inherit multiple, polymorphic genes for NK receptors, so the assemblage of NK receptors differs between individuals. NK cells carry two forms of surface receptors:
● killer inhibitory receptors (KIRs) transmit an inhibitory signal when they encounter class I MHC molecules on a cell surface. (By contrast, T cells only recognize antigens that are presented by a MHC molecule.)
● activating receptors, which activate the NK cell upon binding to a target cell

Viral infection often causes suppression of MHC expresion, leading to a reduction of inhibition of NKs by its killer inhibitory receptors. This double negative renders the virus infected cell a target for killing by NK cells.

"About 85% of peripheral B cells are phenotypically mature and display first-order exponential kinetics defined by a half-life of 5-6 weeks, whilst the remainder are short-lived with a life span of several days."[s]

[] tem plasma cell [] micrograph macrophage surrounded by normal plasma cells [] micrograph macrophage & plasma cells []

▼ activation : BCRs : CDRs : helper T cells : life-span B cells : lymphopoiesis : naïve B cells : surface-immunoglobulins : surface receptors : VDJ recombination ▼

Tables Fc receptors Immune Cytokines Immunoglobulins Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers

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tags [Immunology][lymphocyte]

blood

2010-12-23T00:09:00.000-08:00

Blood is a highly specialized tissue produced in the bone marrow in a process called hematopoiesis. Blood contains red blood cells (erythrocytes) and white cells (leukocytes) circulating in plasma accompanied by platelets, plasma proteins, and other dissolved substances.

[] Hemopoiesis [] Hematopoiesis - high-resolution version (837 KB) [] tem basophil [] tem eosinophil [] tem eosinophil [] tem small lymphocyte [] tem monocyte [] tem neutrophil engulfing Candida []

tags [Immunology][hematology]

cancer and immune system

2010-12-22T23:16:00.000-08:00

The immune system plays a role in surveillance of neoplastic cells that have escaped controls on proliferation. In their turn, tumors employ a variety of mechanisms to evade the immune system.

Some tumors have tumor-specific antigens on their surfaces. These antigens are also called TSA, tumor-specific transplantation antigens, TSTA, or tumor rejection antigens, TRA. TSA are absent on non-tumor cells, and typically appear after an infecting virus has caused the cell to express viral antigens and to become immortal. Some TSAs are not induced by viruses, are are the idiotypes of BCR on B cell lymphomas or TCR on T cell lymphomas.

Tumor-associated antigens (TAA) are more common than TSA. These T antigens are found on tumor cells and on normal cells during fetal life (onco-fetal antigens), after birth in selected organs, or in many cells at a considerably lower concentration than on tumor cells. Because of the presence of these antigens on various normal cells, the immune responses to TAA may be suppressed because they are tolerated as "self".

Evasive mechanisms range from a passive failure to express major histocompatibility complexes (MHC) and co-stimulatory molecules 4,5 to active strategies such as the production of immunosuppressive cytokines and other factors 6,7 . Passive and active processes are also involved in the Fas counterattack.[s]

The Fas ligand (FasL, C95L) is expressed by cells of the lymphoid/myeloid series and by non-lymphoid cells, where it contributes to the 'immune privilege' of cancer cells by inducing apoptosis in infiltrating proinflammatory immunocytes 9,10 . Simultaneously, many cancer cells are relatively resistant to Fas-mediated apoptosis.

This resistance to Fas-mediated apoptosis might be a result of downregulation of Fas, or release of soluble Fas, or of abnormalities in the level of several signal transduction cascade proteins. Neoplastic Fas resistance might also result from downregulation of caspase 1, Bax or Bak, and upregulation of FLIP, FAP-1 or Bcl2. Further, some components of the pathway exhibit mutations, including Fas itself and caspase 8. Some mutations of oncogenes and tumor suppressor genes, which are commonly found in tumors, could impair Fas signaling (p53 and Ras) or could cooperate with Fas resistance (c-Myc) in certain tumor cells. Many cancer cells express FasL, so are able to counterattack and kill Fas-sensitive tumor- infiltrating lymphocytes (TILs).[s]

¤ carcinogenesis ¤ immune evasion ¤ malignant transformation ¤ metastasis ¤ oncogenes ¤ p53 ¤ proliferation ¤ proto-oncogenes ¤ Ras ¤ signaling molecules ¤

Malignant Transformation Oncogenes Proto-oncogenes Regulatory Proteins Sequences Apoptosis vs Necrosis Apoptosis Tables Fc receptors Immune Cytokines Immunoglobulins Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers

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tags [Immunology][cancer]

cancers of immune system

2010-12-22T23:10:00.000-08:00

Cancers of the hematologic/immune system most commonly include:
● Leukemias
● Lymphomas
● Multiple Myeloma
● Myeloproliferative Disorders and Myelodysplastic Syndrome

Disorders of the immune system include:
● autoimmune disorders
● immune deficiency disorders

Tables Fc receptors Immune Cytokines Immunoglobulins Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers

tags [Immunology][cancer]

CD

2010-12-22T20:59:00.000-08:00

CD stands for cluster of differentiation, which indicates a defined subset of cellular surface receptors (epitopes) that identify cell type and stage of differentiation, and which are recognized by antibodies.

There are more than 250 identified clusters, each a different molecule, coating the surface of B lymphocytes and T lymphocytes.

All T and B cells have about 10⁵ = 100,000 molecules on their surface. B cells are coated with CD21, CD35, CD40, and CD45 together with non-CD molecules, while T cells express CD2, CD3, CD4, CD8, CD28, CD45R, and other non-CD molecules. Many CDs are expressed on both B and T cells, including CD5, CD6, CD23, CD27, CD28, CD84. Dendritic cells also express CD4 and CD8.

▼ B lymphocyte CDs : B and T lymphocyte CDs : T lymphocyte CDs : TNFRs : CD1 : CD2 : CD3 : CD4 : CD5 : CD6 : CD8 : CD14 : CD23 : CD25 : CD27 : CD28 : CD30 : CD31 : CD36 : CD40 : CD45 : CD45 isoforms : CD55 : CD58 : CD72 : CD84 : complement CÆ : costimulatory : ITAMs : LFA : lymphocyte function associated antigen : glycoproteins : Ig superfamily : Macrophages/Monocytes : migration : pattern recognition receptors : platelets : scavenger receptors : SLAM (signaling lymphocyte activation molecule) : TNFR▼

T cell CDs:

CD2 family receptors are immunoglobulin (Ig) superfamily type I transmembrane, glycosylated proteins characterized by an N-terminal variable (V) domain that lacks disulfide bonds and a truncated Ig constant 2 (C2) domain that has two disulfide bonds in the extracellular region.

CD3 family receptors comprise three distinct chains – CD3γ, CD3δ and CD3ε in mammals – which are closely related proteins of the immunoglobulin superfamily, each containing a single extracellular immunoglobulin domain. The CD3 chains associate with TCRs and the ζ-chain to activate T lymphocytes. Together the TCR, ζ-chain, and CD3 molecules consitute the TCR complex.

The transmembrane region of the CD3 chains is negatively charged, enabling these chains to associate with the positively charged TCR chains (TCRα and TCRβ). The intracellular tails of the CD3 molecules contain a single conserved motif termed the immunoreceptor tyrosine-based activation motif (ITAM) that is essential for TCR signaling. Phosphorylation of CD3's ITAM enables the CD3 chain to bind Fyn, a membrane-associated protein tyrosine kinase important in the T cell's signaling cascade.

CD4 is notorious because of its importance in HIV/AIDs. It is an approximately 55 kDa type I membrane glycoprotein expressed predominantly on T cell precursors and a subset of mature T cells, providing the surface protein to which HIV attaches itself in order to invade the cell. CD4 is also found on the surface of monocytes, macrophages, Langerhans cells, astrocytes, keratinocytes and glial cells. The number of serum T4 cells is employed to measure the health of the immune system in people infected with HIV.[R&D]

CD8 (T8) is a protein embedded in the cell surface of 'suppressor' or regulatory T lymphocytes (Treg).

The CD31 adhesion molecule (PECAM-1) is expressed in large amounts at intercellular junctions of endothelial cells, subsets of T cells, platelets, and most other leukocytes including monocytes and neutrophils. CD31 is required for the trans-endothelial migration – extravasation – of leukocytes through intercellular junctions of vascular endothelial cells.

CD58 is also known as lymphocyte function-associated antigen (LFA-3). CD58 is a cell-bound immunoglobulin superfamily receptor with only one known ligand, which is CD2. CD58 is widely expressed on human hematopoietic and non-hematopoietic tissues, leukocytes, erythrocytes, endothelial and epithelial cells, and fibroblasts. The receptor-ligand pair, CD58 plus CD2, optimizes immune recognition and initiates T cell expansion and activation. Such contact activities can occur between helper T cells and antigen-presenting cells and between cytolytic effectors and target cells.

B and T cell CDs:

C5 is a 67 kDa surface glycoprotein of the scavenger receptor cysteine-rich (SRCR) superfamily that appears on thymocytes, mature T cells, and B cells. CD5 is important for the apoptosis of antigen-receptor induced B lymphocytes and for the maintenance of tolerance by anergic B cells. CD5 crosslinking induces extracellular mobilization of calcium ions, tyrosine phosphorylation of intracellular proteins, and production of diacylglycerol. Infection by EBV downregulates CD5 expression, while the glycoprotein is expressed in many T-cell leukemias and lymphomas.

CD6 is a member of the group B scavenger receptor cysteine-rich (SRCR) superfamily, which is expressed at low levels on immature thymocytes, at high levels on mature thymocytes, on the majority of peripheral blood T cells, a subset of B cells, and a subset of neuronal cells. Human and mouse CD6 proteins share 70% amino acid sequence identity over their full lengths.

CD23 is the receptor for the Fc portion of IgE.

CD27 Ligand/TNFSF7 is also known as CD70, and is a type II transmembrane glycoprotein belonging to the TNF superfamily (TNFSF). The expression of CD27 Ligand is induced by antigen-receptor activation in B cells. CD27/TNFRSF7 is a lymphocyte-specific member of the TNF receptor superfamily, which is expressed on a subset of human T cell precursors (thymocytes), on the majority of mature T cells, on natural killer (NK) cells, and subsets of B cells. CD27 ligation on NK cells induces proliferation and production of IFN-γ. CD27 binding (ligation) to T cells provides a co-stimulatory signal required for T cell proliferation, the promotion of effector T cell formation, and clonal expansion. The binding of CD27 to B cells inhibits the terminal differentiation of activated B cells into plasma cells and instead enhances commitment to memory B cell responses.

CD28 and CTLA-4, together with their ligands, B7-1 and B7-2, constitute one of the dominant B and T cell costimulatory pathways. CD28 and CTLA-4 are structurally homologous molecules of the immunoglobulin (Ig) gene superfamily. Mouse CD28 is expressed constitutively on almost all mouse T cells and on developing thymocytes.

CD45 is a protein tyrosine phosphatase (PTP) that regulates Src kinases required for T and B cell receptor signal transduction. CD45 dephosphorylates a negative regulatory residues on one or more of the protein tyrosine kinases that are involved in receptor-mediated second messenger formation. CD45 is located in all hematopoietic cells except erythrocytes and platelets, so it is also called the common leukocyte antigen.[]rotatable im[]

The CD45-regulated Src kinases are Lyn and Blk in B cells, and Lck and Fyn in T cells. ITAMs are immunocreceptor tyrosine bases motifs comprising two tyrosine residues separated by amino acids. RTK-phosphorylation of ITAMS enables them to bind to second family protein tyrosine kinases such as CD45, for which their SH2 domains have high binding affinity. In T cells, CD45 phosphorylates Csk, which is an inhibitory protein tyrosine kinase that controls tyrosine activity in lymphocytes. In B cells, calcium ions are transduced by the BCR, inducing CD45 expression. CD45RO, CD45RA, and CD45RB are isoforms of CD45.

CD84 is also known as Ly-9B, and is a member of the CD150/SLAM (signaling lymphocyte activation molecule) subfamily of the CD2 family (designated SLAMF5). CD84 is expressed on B cells, T cells, monocytes and platelets and acts as a self-ligand. Human and mouse CD84 share approximately 57% amino acid sequence identity.

B cell CDs:

CD40 is a type I transmembrane glycoprotein belonging to the TNF receptor superfamily. CD40 is expressed on B cells, follicular dendritic cells, dendritic cells, activated monocytes, macrophages, endothelial cells, vascular smooth muscle cells and several tumor cell lines. Human and mouse CD40s have 64% identity of amino acid sequence identity.

CD72 is a 39-43 kDa type II membrane glycoprotein of the C-type lectin family. CD72 is a pan-B cell marker that is expressed throughout the B lymphocytes differentiation (except plasma cells). CD72 is also present on follicular dendritic cells.

Monocytes/Macrophages

CD14 is a 55 kDa cell surface glycoprotein that is preferentially expressed on monocytes and macrophages. The amino acid sequence of human CD14 is approximately 65% identical to mouse CD14, and 82% identical to rat proteins.

Also: CD4, CD31 adhesion molecule (PECAM-1), CD40, CD84

Platelets:

CD36 is also known as scavenger receptor class B member 3 (SR-B3), GPIIIb, platelet membrane glycoprotein IV (GPIV), collagen receptor, thrombospondin receptor, and fatty acid translocase (FAT). CD36 is a broadly-expressed integral membrane glycoprotein with multiple physiological functions. As a member of the scavenger receptor family, CD36 is a multi-ligand pattern-recognition receptor that interacts with a large number of structurally dissimilar ligands. Upon ligand binding, CD36 transduces signals that mediate a wide range of pro-inflammatory cellular responses.

Complement CÆ activation family (RCA):

CD55, also known as decay-accelerating factor (DAF), is a 70 to 75 kDa member of the regulators of complement/CÆ activation (RCA) family of proteins. It is ubiquitously expressed on cells that are exposed to plasma complement proteins. Human CD55 is synthesized as a 381 amino acid precursor that comprises a 34 aa signal sequence, a 319 aa mature region and a 28 aa C-terminal prosegment.

Costimulatory:

CD28 and CTLA-4, together with their ligands, B7-1 and B7-2.

Pattern-recognition receptors :

CD36

Glycoproteins:

CD4, CD5, CD14, CD27, CD30, CD36, CD40, CD72

Immunoglobulin superfamily:

CD2, CD58, CD28 and CTLA-4,
CD23 is the receptor for the Fc portion of IgE.

LFA (lymphocyte function associated antigen):

CD58

migration:

CD31 adhesion molecule (PECAM-1)

Scavenger receptor (SRCR) family:

CD5, CD6, CD36

SLAM (signaling lymphocyte activation molecule) subfamily:

CD84 (Ly-9B), CD2 family (SLAMF5)

TNFRs :

CD30/TNFRSF8 is a type I transmembrane glycoprotein belonging to the TNF receptor superfamily, where the the ligand for CD30 is CD30L (CD153, TNFSF8), which is a member of the TNF superfamily. CD30 binding by CD30L mediates pleiotropic effects, including cellular proliferation, activation, differentiation, and apoptosis.

Other TNFRs are CD40 and CD27.

Miscellaneous CDs
CD9 is a member of the tetraspanin transmembrane receptor family. CD9 contains four putative transmembrane domains and two extracellular loops, and is thought to be involved in egg-sperm fusion. Several reports indicate that CD9 associates with integrins and affects cell behavior on fibronectin surfaces (ref).[s]

▲ B lymphocyte CDs : B and T lymphocyte CDs : T lymphocyte CDs : TNFRs : CD2 : CD3 : CD4 : CD5 : CD6 : CD8 : CD14 : CD23 : CD27 : CD28 : CD30 : CD31 : CD36 : CD40 : CD45 : CD45 isoforms : CD55 : CD58 : CD72 : CD84 : complement CÆ : costimulatory : ITAMs : LFA : lymphocyte function associated antigen : glycoproteins : Ig superfamily : Macrophages/Monocytes : migration : pattern recognition receptors : platelets : scavenger receptors : SLAM (signaling lymphocyte activation molecule) : TNFR ▲

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[C][CD5][CD72] Tables Fc receptors Immune Cytokines Immunoglobulins

tags [Immunology][cluster+differentiation][receptor]

cellular response

2010-12-22T19:12:00.000-08:00

Cellular responses to invading pathogens utilize phagocytic and cytotoxic cells of the innate and adaptive immune responses.

The immune system is intimately connected with the hematologic system since white blood cells (leukocytes, including B- and T-lymphocytes) are key players in the lymphoid system.
Cellular participants in the immune and inflammatory responses include :
● phagocytic cells (dendritic cells, monocytes and macrophages, and granulocytes)
● antigen presenting cells (dendritic cells, macrophages, B lymphocytes, helper T cells, γδ T cells)
● antibody producing cells (plasma cells)
● cytotoxic cells (CTL, NK)
● regulatory cells (APCs, helper T cells, regulatory T cells)
● cells-in-waiting (memory B cells, monocytes)
● chemical releasing cells (basophils, eosinophils, neutrophils; mast cells - histamine, cytokines; hepatocytes - complement proteins)

Innate responses solely comprise cellular immune responses employ phagocytic cells that are circulating or tissue emplaced – granulocytes, monocytes, dendritic cells, macrophages, natural killer T cells, and B lymphocytes. The innate response induces (triggers) the adaptive system, the cellular component of which relies upon activated macrophages, T-lymphocytes – cytotoxic T lymphocytes (killer T cells).

Tables Fc receptors Immune Cytokines Immunoglobulins

tags [Immunology][cellular+immunity]

class-switch recombination

2010-12-22T12:56:00.000-08:00

Class-switch recombination involves isotype switching between immunoglobulin classes and isotypes.

Small resting B lymphocytes initially producing IgM antibodies. The diverse antibody repertoire achieved early in B-lymphocyte development results from VDJ recombination of gene segments to produce unique heavy- and light-chain variable (V) Ig regions. The variable regions encode the antigen binding sites of antibody receptors expressed on the surface of naïve B lymphocytes and their clonal progeny. The low affinity of naïve VDJ generated antibodies is compensated for by the high affinity of secreted IgM, in which the prototypical four-chain Ig structure is combined into pentamers or hexamers. Following encounter with antigen, B cells become activated to isotype switch from IgM to other Ig classes, including high-affinity IgG and IgA antibodies required to inactivate toxins, neutralize viruses, and promote the clearance of microorganisms.

Ligation of antigen by cognate B lymphocytes accompanied by costimulation by helper T lymphocytes, activates B lymphocytes, which enter the germinal centers of peripheral lymphoid organs to become centroblast B cells. Within the germinal center, secondary antibody diversification is brought about through somatic hypermutation (SHM) and/or gene conversion (GC) of the V region to generate high-affinity antigen binding sites. (SHM is the predominant mechanism in mice and humans, whereas GC occurs in chickens and some other species.)

Within a particular centroblast B cell in the germinal center, the heavy-chain variable (V) regions encoding the antigen binding sites are rearranged down the chromosome through class-switch recombination (CSR). Then they can be expressed with one of the constant (C) region genes to perform many different effector functions having been released into the circulation.

This isotype class switch distributes a particular variable region to different constant immunoglobulin regions. Each constant region mediates a specialized effector function, and switching permits adaptive guidance of antibodies. Creating a new heavy chain requires loop-out and deletion of DNA between switch regions, employing transcription of the switch regions. Requisite switching factors include activation-induced cytidine deaminase and components of general DNA repair, including base excision repair (UNG2), mismatch repair, and double-strand break repair.[r1]

'Individuals, such as those with hyper-IgM syndrome (HIGM), who lack the ability to make such high-affinity IgG and IgA antibodies, are unable to combat bacterial and viral infections and usually die at a young age.[s]

Tables Fc receptors Immune Cytokines Immunoglobulins

[r1] DNA acrobats of the Ig class switch. Wang CL, Wabl M. J Immunol. 2004 May 15;172(10):5815-21. [Free Full Text Article]

[s] The generation of antibody diversity through somatic hypermutation and class switch recombination. Li Z, Woo CJ, Iglesias-Ussel MD, Ronai D, Scharff MD. Genes Dev. 2004 Jan 1;18(1):1-11. [Free Full Text Article]

tags [Immunology][recombination]

clonal selection

2010-12-22T12:09:00.000-08:00

Clonal selection is the phenomenon whereby the antigenic determinant (epitope) of a previously unencountered cognate antigen can stimulate naïve B lymphocytes to proliferate (clonal expansion) and differentiate into memory B cells and plasma cells that produce antibodies against the antigen (primary response). That is, the antigen itself determines (selects) the characteristics of clones of B cells that expand (multiply and specialize) after encounter with the antigen.

Should the epitope be encountered again, the memory B cell-conducted secondary response will be specific, more rapid, and elicit a greater production of antibodies than was the first-encounter, primary response. Vaccination takes advantage of immunological memory in that the individual is primed for efficient, rapid response to epitopes associated with disease producing organisms.

Tables Complement Receptors Cytokines Fc receptors Immune Cytokines Immunoglobulins Interferons Scavenger Receptors Toll-like Receptors

tags [Immunology] [clone]

complement system

2010-12-22T09:11:00.000-08:00

The complement system comprises an assembly of liver-manufactured, soluble and cell-bound proteins that participate in innate and adaptive immunity. Activation of the complement cascade by protease cleavage leads to chemotaxis (C5a), inflammation and increased capillary permeability (C3a, C5a), opsonization (C3b), and cytolysis.

▼activation : alternative pathway : amplification by C3 : anaphylatoxins C3a, C5a : antigen uptake : C1 : C2 : C3 : C4 : C5 : C6 : C7 : C8 : C9 : C1INH : CD59 : chemotaxis : classical pathway : complement cascade : complement control proteins : convertases C3, C3/C5, C5 : disorders : evolution : Factor B : Factor H : Factor I : ficolins : immunoglobulins and complement activation : inhibitory proteins : lectin pathway : MBL -MAPS : mannose-binding lectin pathway : membrane attack complex : opsonin : pathways : perforin : phagocytosis : pore : proteases : regulation : serine proteases : sialic acid ▼

Sequential activation of the protein components of the complement cascade upon cleavage by a protease, leads to each component's becoming, in its turn, a protease. Three pathways are involved in complement attack upon pathogens:
● classical pathway
● alternative pathway
● mannose-binding lectin pathway (MBL -MAPS)

The classical pathway utilizes C1, which is activated by binding of an antibody to its cognate antigen.

Inactive C1 circulates as a serum molecular complex comprising 6 C1q molecules, 2 C1r molecules, and 2 C1s molecules. Constant regions in some immunoglobulins specifically bind C1q, activating C1r and C1s. The mu chains of IgM and some gamma chains of IgG contain specific binding sites, though IgM is far more effective than IgG.

Activated C1s is a serine protease that cleaves C4 and C2 into small inactive fragments (C4a, C2a) and larger active fragments, C4b and C2b. The active component C4b binds to the sugar moieties of surface glycoproteins and binds noncovalently to C2b, forming another serine protease C4b•C2b, which is called C3 convertase because it cleaves C3, releasing an active C3b opsonin fragment.

Macrophages and neutrophils possess receptors for C3b, so cells coated with C3b are targetted for phagocytosis (opsonization). The small C3a fragment is released into solution where it can bind to basophils and mast cells, triggering histamine release and, as an anaphylatoxin, potentially participating in anaphylaxis.

C3 amplifies the humoral response because of its abundance and its ability to auto-activate (as a C3 convertase). Breakdown of C3b generates an antigen-binding C3d fragment that enhances antigen uptake by dendritic cells and B cells .

Binding of C3b to C5 induces an allosteric change that exposes C3b•C5 to cleavage by C4b•C2b, which is now acting as C3/C5 convertase. The alternative pathway possesses a distinct C5 convertase, so the two pathways converge through C5.

Cleavage of C5 by the C3/C5 convertase releases:
● anaphylotoxic C5a, which promotes chemotaxis of neutrophils
● C5b, which complexes with one molecule of each of C6, C7, and C8. The resultant C5b•6•7•8 complex assists polymerization of as many as 18 C9 molecules to form a cytolysis-promoting pore (membrane attack complex, tem) through the plasma membrane of the target cell, which then suffers osmosis-induced cytolysis.

Another cytolytic mediator utilized by CTLs and NK cells is perforin, which is a 534 aa glycoprotein with sequence homology to the membrane attack component of complement C9. Like C9, perforin integrates into the target cell membrane, forming polyprotein pores up to 20nm in diameter comprising 12—18 perforin monomers, which breach membrane integrity and permit cytolytic cell death.

The alternative pathway is not activated by antigen-antibody binding, but instead relies upon spontaneous conversion of C3 to C3b, which is rapidly inactivated by its binding to inhibitory proteins and sialic acid on the cell's surface. Because bacteria and other foreign materials lack these inhibitory proteins and sialic acid, the C3b is not inactivated and it forms the C3b•Bb complex with Factor B. The C3b.Bb complex acts as a C3 convertase, forming C3b•Bb•C3b, which acts as a C5 convertase that can ititiate assembly of the membrane attack complex. C3b•Bb, acting as a C3 convertase, provides a positive feedback loop that amplifies production of C3.

The lectin pathway (MBL - MASP) is homologous to the classical pathway, but utilizes opsonin, mannan-binding lectin (MBL, MBP) and ficolins rather than C1q. Binding of mannan-binding lectin to mannose residues on the pathogen surface activates the MBL-associated serine proteases, MASP-1, MASP-2, MASP-3, which cleave C4 into C4b and C2 into C2b. As in the classical pathway, C4b and C2b bind to form the C4b•C2b C3 convertase. Ficolins are homologous to MBL and function through MASPs. Diversified ficolins are of particular importance in invertebrates, which lack the adaptive immune response that evolved some 500 million years ago in jawed vertebrates.

Several complement control proteins regulate activity of the complement system, including:
● C1 inhibitor (C1INH), which eliminates the proteolytic activity of activated C1r and C1s. Following C1 activation by antigen-antibody complexes, C1INH permits only a brief interval during which activated C1 can cleave C4 and C2.
● Factor I, which inactivates C3b
● Factor H, which removes Bb, thus interrupting the C3 convertase feedback loop within the alternative pathway
● CD59, which inhibits C9 polymerization during assembly of the membrane attack complex.

Dysregulation of the complement system manifests variously as immune complex disorders (C2 deficiency), susceptibility to bacterial infections (C3 deficiency), the autoimmune disorder SLE (early component or C2 deficiency), hereditary angioneurotic edema (HANE) (C1INH deficiency).

▲ activation : alternative pathway : amplification by C3 : anaphylotoxins C3a, C5a ф antibodies ф antigen : antigen uptake : C1 : C2 : C3 : C4 : C5 : C6 : C7 : C8 : C9 : C1INH : CD59 : chemotaxis : classical pathway : complement cascade : complement control proteins : convertases C3, C3/C5, C5 : disorders : evolution : Factor B : Factor H : Factor I : ficolins : immunoglobulins and complement activation : inhibitory proteins : lectin pathway : MBL -MAPS : mannose-binding lectin pathway : membrane attack complex : opsonin : pathways : perforin : phagocytosis : pore : proteases : regulation : serine proteases : sialic acid ▲

Tables Fc receptors Immune Cytokines Immunoglobulins

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tags [Immunology][complement]

costimulation

2010-12-22T09:05:00.000-08:00

Costimulation involves ligand-receptor interactions at the surfaces of a responder lymphocyte and an "accessory" cell – APCs for activation of T cells, and helper T cells for activation of B cells.

▼activation B : activation T : anergy : CD28 receptor : CD28RE : CDC42 : costimulatory molecules : first/second signals : helper T cell : IL-2 : MAPK cascade : MHC class II : negative regulators : Rac : regulatory mechanisms : Rel-NFkB : Rho GTPases : TCR engagement : TCR threshold reduction : transcription factors : WASP ▼

Activation of B cells occurs when a BCR (antibody) encounters and ligates its cognate antigen. Naïve B cells each have one of millions of distinct surface antigen-specific receptors, yet have not encountered their specific, cognate antigen. With a life-span of only a few days, many B cells die without ever encountering their cognate antigen. In most cases, B-cell activation is dependent upon costimulation by an activated helper T cell that has itself been activated by the same antigen. (click images to enlarge)

Unlike T cells, B cells are coated in immunoglobulin receptors and are able to recognize intact antigen, which they engulf, digest, and subsequently present in complex with surface MHC class II molecules. The MHC-peptide complex binds CD4 + helper T cells (Th), inducing secretion of cytokines that stimulate B cell proliferation and their differentiation into plasma cells, which secrete specific antibodies that bind with the cognate antigen. These antigen-antibody complexes are subsequently cleared by liver and spleen cells and the classical complement cascade.

Activation of T cells requires (1) TCR engagement, which ensures antigen specificity and MHC restriction of the response. However, synergistic signaling by (2) costimulatory molecules is also necessary to sustain and integrate TCR signaling to stimulate optimal T cell proliferation and differentiation.

Delivery of first signal (TCR engagement) in the absence of costimulation by a second signal(s) results in apoptosis or anergy. Anergic T cells neither produce IL-2 nor proliferate upon restimulation. This requirement of naïve T cell activation for delivery of both antigen-specific and costimulatory signals implies that only professional antigen presenting cells can initiate T cell responses.

Activation-regulatory mechanisms:
● increasing TCR avidity (adhesion molecules)
● enhancing recruitment of tyrosine kinases to the TCR complex coreceptors (CD4 and CD8)
● costimulation involving reciprocal and sequential signals between cells

Negative regulators of costimulation include receptors that bind B7 family members:
● CTLA-4
● PD-1

Molecules involved in costimulation include:
1. Disulfide-linked homodimers that bind to distinct members of the B7 family of surface proteins
---● CD28 ↓
---● ICOS (inducible costimulator) molecules
2. Members of the TNF receptor (TNFR) family
---● CD40, the major B cell costimulatory molecule
---● CD30
---● CD27
---● OX-40
---● 4-1BB

The CD28 receptor is involved in the best characterized costimulatory pathway. CD28 is the primary costimulatory molecule for naïve T cells, although CD4+ helper T cells are more dependent than are CD8+ killer T cells on CD28 costimulation. CD28 binds the CD80 (B7-1) and CD86 (B7-2) ligands that are expressed on antigen presenting cells (APCs). CD28 costimulation increases T cell responses in naïve cells by increasing cytokine (mainly IL-2) production, which results from an increase in both cytokine gene transcription and mRNA stabilization.

CD28 signaling involves the activation of the small Rho family GTPases Rac and CDC42, which activate p21-activated kinase. This may link them to the mitogen-activated protein kinase cascades and the subsequent induction of IL-2 synthesis. Rac and CDC42 are also important in CD28-mediated cytoskeletal rearrangements, through the action of the Wiscott-Aldrich syndrome protein (WASP).

CD28 costimulation increases the activity of nuclear transcription factors of the Rel/NFkB family, whose members bind the CD28-responsive element (CD28RE) present in several cytokine gene promoters.

CD28 triggering reduces the number of engaged TCRs necessary to induce cytokine production and cell proliferation. This threshold reduction for T-cell activation is attributed to CD28-induced recruitment of lipid rafts to the immunological synapse, which promotes recruitment of raft-associated kinase and adapter molecules.

▲ activation B : activation T : anergy : CD28 receptor : CD28RE : CDC42 : costimulatory molecules : first/second signals : helper T cell : IL-2 : MHC class II : negative regulators : plasma cells : Rac : regulatory mechanisms : Rel-NFkB : Rho GTPases : TCR engagement : TCR threshold reduction : WASP ▲

Tables Fc receptors Immune Cytokines Immunoglobulins

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tags [Immunology][costimulation][activation]

cytolysis

2010-12-22T01:04:00.000-08:00

Cytolysis (cell lysis) results when the plasma membrane is ruptured, resulting in osmosis-induced swelling and cell death. (see cytotoxicity)

Cytotoxic lymphocytes (CTLs) are important agents of cytolysis. Cytotoxic cells are considered essential for the elimination of oncogenically or virally transformed cells, but they are detrimental when mediating autoimmune disease or graft rejection.

Tables Fc receptors Immune Cytokines Immunoglobulins

tags [Immunology][cytolysis][cell+death]

cytotoxicity

2010-12-22T01:03:00.000-08:00

Cytotoxic agents are toxic to cells:
● Cytotoxic physical agents
___ ● thermal (excessive heat or cold)
___ ● irradiation

● Cytotoxic drugs and chemicals have cytolytic, carcinogenic, mutagenic and/or teratogenic potential. Direct contact may cause tissue irritation, ulceration, and necrosis.
___ ● antineoplastic and immunosuppressive therapeutic agents
___ ● free radicals
___ ● strong acids and alkalis
___ ● secreted digestive enzymes and antimicrobials – lysozyme, phospholipase, defensins
___ ● secreted cytolytic molecules • FasL, granzymes, granulysin, perforin
___ ● phagocytosis-promoting opsonins – C3b of complement cascade, pulmonary surfactants

● Cytotoxic cellular immune responses
_ ● Antibody-dependent cell-mediated cytotoxicity (ADCC) is mediated by antibody-marking
_ ● Complement-dependent cytotoxicity (CDC) is mediated by the complement system (opsonin-induced phagocytosis performed by macrophages and neutrophils, anaphylatoxin induced histamine release by basophils and mast cells).
_ ● Lymphocyte-mediated cytotoxicity ('LMC') requires is independent of antibody-marking and the complement system

__ ● killer cells
___ ● non-specific 'attack' cells – eosinophils (IgE, CD67), macrophages (IgG, CD14), K cells (IgG), LAK cells (IL-2 activated cytolysis cells, lymphokine-activated killer cells), NK cells (CD16, CD56)
___ ● natural killers cells (NK) of innate immune system – have activating receptors and killer inhibitory receptors (KIR) – secrete cytolytic granzymes and perforin ('LMC')
___ ● natural killer T cells (NKT) – have αβ TCR plus some of the cell-surface molecules of NK cells – respond to glycolipid antigens presented by the cell-surface molecule CD1d (ADCC) – secrete IFN-γ (Th1 cytokine) plus IL-4 and IL-13 (Th2 cytokines)
___ ● cytotoxic T cells • (CD8 +) Tc matures into CTL (killer T cells) following activation (ADCC)
___ ● phagocytic cells engulf pathogens, often after pathogen coating by opsonins (CDC)

Tables Fc receptors Immune Cytokines Immunoglobulins

tags [Immunology] [cytotoxicity] [cell death]

dendritic cells

2010-12-21T19:10:00.000-08:00

Dendritic cells and their immature counterparts, Langerhans cells (LC), are highly specialized, professional antigen-presenting cells (APC) located in the skin, mucosa, and lymphoid tissues.

▼ adhesion : APC activities : clonal expansion B cells : cytokines : DC types : disorders : ectopic FDC-formation : follicular dendritic cells (FDC) : FDC networks : generating germinal centers : germinal centers : immature dendritic cells : immune regulators : immunological synapse : interferon producing cells : lymphoid dendritic cells : maturation : morphology : myeloid dendritic cells : pDC : plasmacytoid dendritic cells (PDC, IPC) : precursor dendritic cells : regulators : Th1 and Th2 stimulation : TLRs : types of DC : veiled cells ▼

Immune dendritic cells are named for their morphology (long surface projections), and bear no relationship to neurons. Immature dendritic cells are also called 'veiled cells' because they display large cytoplasmic 'veils' rather than dendrites. DC and LC play a key role in the induction phase of contact allergenicity.

As key regulators of immune responses, dendritic cells (DC) stimulate lymphocytes to perform cell-mediated and humoral immune responses against pathogens and tumor cells. DCs can also educate T cells to tolerate self-antigens, thereby minimizing autoimmune reactions.

Types of dendritic cell
● follicular dendritic cells (origin?) – FDC
● lymphoid dendritic cells (lymphopoiesis) –
● myeloid dendritic cells (monocytopoiesis) – MDC1, MDC2
● plasmacytoid dendritic cells – PDC, IPC – the major producers of type I interferon (IFN)

Immature, precursor dendritic cells (pDC) circulate throughout the body, migrating to lymphocyte rich tissues (such as spleen and lymph nodes) upon stimulating encounter with antigen. The dendritic cells internalize the antigen, then digest, and externalize the fragmented antigen that they present to lymphocytes in MHC-peptide complexes, expressing markers that stimulate lymphocyte activation. Dendritic cells are the most effective antigen presenting cells. Follicular dendritic cells stimulate differentiation of B cells, monocytopoietic lineages (pDC1) stimulate differentiation of Th1 cells, lymphopoietic dendritic cells (pDC2) induce differentiation of Th2 cells. Plasmacytoid cells produce type 1 interferon (IFN-α, β, Ω) and can mature into dendritic cells that link innate and adaptive immune responses.

A variety of factors operate in antigen recognition and processing by immature (precursor) dendritic cells and in the maturation of immature cells. Toll-like receptors on the surfaces of precurson dendritic cells recognize microbial components and induce the differentiation of dendritic cell precursors. GM-CSF and IL-4 stimulate the maturation of monocytopoietic pDC1, while IL-3 stimulates the differentiation of pDC2. The transition to mature dendritic cells down-regulates those factors that were involved in antigen internalization, while up-regulating the expression of MHC, costimulatory molecules that participate in lymphocyte activation, adhesion molecules, and specific cytokines and chemokines.

Adhesion molecules enhance direct interactions between T cells and dendritic cells (immunological synapse). Dendritic cell stimulation of formation of Th1 and Th2 cells appears to be regulated by negative feedback. Th1 production of interferon-γ blocks the further stimulation of Th1 differentiation by DC1 cells. Th2 production of IL-4 kills the dendritic cell precursors that contribute to Th2 cell creation. Thus, although IL-4 stimulates Th2 differentiation, the promotion of Th2 cell formation by DC2 cells does not appear to involve IL-4. Costimulatory receptors CD80 and CD86 expressed by mature dendritic cells activate T cells in concert with the recognition of antigen/MHC by the T cell receptor. The secretion of IL-12 by dendritic cells stimulates T cell responses, in particular the differentiation of Th1 cells, which produce interferon-γ and other inflammatory cytokines.

Follicular dendritic cells are stromal cells unique to primary and secondary lymphoid follicles. FDCs express all three types of complement receptors as well as Ig-Fc receptors, through which antigen-antibody immune complexes are retained. FDCs present native antigens to potential memory B cells, of which only those coated with high affinity B cell receptors (BCR) are able to bind.

Recirculating resting B cells migrate through the FDC networks. Antigen-activated B cells undergo clonal expansion within the FDC networks in a T cell-dependent fashion, generating germinal centers. Evidence suggests the presence of two types of dendritic cells within human germinal centers: (i) the classic FDCs that express DRC-1, KiM4, and 7D6 antigens represent stromal cells; and (ii) the newly identified CD3-CD4-CD11c- germinal center dendritic cells (GCDC) represent hematopoietic cells that may be analogous to antigen-transporting cells of mice.

Within germinal centers, B cells undergo somatic hypermutation, positive and negative clonal selection, isotype switching and differentiation into high-affinity plasma cells and memory B cells. Adhesion between FDCs and B cells is mediated by ICAM-1 (CD54)-LFA-1(CD11a) and VCAM-VLA-4. T cells may interact with FDCs in a CD40/CD40-ligand-dependent fashion.

Ectopic FDC-formation is found in a number of autoimmune diseases and/or chronic inflammatory situations, suggesting that FDC development is not restricted to secondary lymphoid organs, but rather that local conditions drives a precursor cell type into FDC-maturation. The precursor of FDCs has presently not been identified, but data suggests a close relation to fibroblast-like cells. [s] It was initially believed that all DCs were of myeloid origin until several recent studies demonstrated that some DCs could also be efficiently generated from lymphoid-restricted precursors. FDCs appear to be involved in the growth of follicular lymphomas and in the pathogenesis of HIV infection.[pm]

Lymphoid dendritic cells are of lymphopoietic origin, and IL-3 stimulates the differentiation of pDC2 cells into DC2 cells, which stimulates differentiation of Th2 cells, which secrete the lymphokine interleukins 4, 5, 10, and 13. (IL-4, IL-5, IL-10, IL-13)

Myeloid dendritic cells are of monocytopoietic origin, and the maturation of precursor cells (pDC1) is stimulated by GM-CSF, and IL-4. Mature DC1 cells secrete interleukin 12 (IL-12), which acts through the JAK-STAT pathway to induce Th1 cells to secrete TNF-β (lymphotoxin) and IFN-γ. MDC-1 is the more common subtype, and is a major stimulator of Th1 cell differentiation. MDC-2 is rare, and may function in response to wound infection.

Plasmacytoid dendritic cells (pDC=IPC) are the major producers of type I interferon (IFN) and exhibit the unique ability to link innate and adaptive immune responses, by differentiating into DC capable of stimulating naive T cells and modulating the adaptive immune response. Human plasmacytoid DCs (PDCs) can induce either Th1- or Th2-type immune responses upon exposure to viruses or IL-3, respectively.

Plasmacytoid dendritic cell precursors (pDC) are type 1 interferon-(α, β, Ω)-producing cells (IPCs) that comprise 0.2%-0.8% of peripheral blood mononuclear cells (humans, mice). IPCs display plasma cell morphology, selectively express Toll-like receptor (TLR)-7 and TLR9, and rapidly secrete massive amounts of type 1 interferon following viral stimulation. IPCs promote the function of natural killer cells, B cells, T cells, and myeloid DCs through type 1 interferons (IFN) during an antiviral immune response. Later in viral infection, IPCs differentiate into a unique type of mature dendritic cell, which directly regulates the function of T cells and thus links innate and adaptive immune responses. [s, ↓] [fft]

images [] sem dendritic cell and T cell [] micrograph Langerhans cells [] PKC bII signaling in dendritic cells [] micrograph gallery dendritic cells [] photomicrograph dendritic cells interacting with yeast (lilac) [] photomicrograph Human Dendritic cell (labelled with anti MHC class-I FITC) presenting Influenza antigens to T-lymphocytes.
videos Џ Nature video library index Q Џ

ф activation ф affinity maturation ф anergy ф antibodies ф antigen ф APCs ф autoimmunity ф B cells ф blood ọ bone marrow ф CD ф cellular response ф class-switch recombination ф clonal selection ф complement system ф costimulation ф helper T cell ф hematopoiesis ф humoral immunity ф immune cytokines ф immune response ф immune tolerance ф inflammatory response ф interferons ф isotype switching ф killer T cells ф lymphocytes ф lymphokines ф lymphoid system ф lymphopoiesis ф macrophages ф MHC ф monocytopoiesis ф pattern-recognition receptors ф phagocyte ф plasma cells ф receptors ф signaling ф somatic hypermutation ф surface receptors ф T cells ф thymus

Tables Complement Receptors Cytokines Fc receptors Immune Cytokines Immunoglobulins Interferons Scavenger Receptors Toll-like Receptors

IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. [Annu Rev Immunol. 2005]
Plasmacytoid dendritic cell precursors/type I interferon-producing cells sense viral infection by Toll-like receptor (TLR) 7 and TLR9. [Springer Semin Immunopathol. 2005] PMID: 15592841 [Free Full Text]
Natural type I interferon-producing cells as a link between innate and adaptive immunity. [Hum Immunol. 2002] PMID: 12480256
Thrombopoietin cooperates with FLT3-ligand in the generation of plasmacytoid dendritic cell precursors from human hematopoietic progenitors. [Blood. 2004] PMID: 14670916
Flexibility of mouse classical and plasmacytoid-derived dendritic cells in directing T helper type 1 and 2 cell development: dependency on antigen dose and differential toll-like receptor ligation. [J Exp Med. 2003] PMID: 12515817
Roles of toll-like receptors in natural interferon-producing cells as sensors in immune surveillance. [Hum Immunol. 2002]

tags [Immunology] [dendritic+cell] [APC] [cytokine] [Toll-like+receptor]

evolution of immune and coagulation systems

2010-12-20T15:09:00.000-08:00

Immune system
The innate immune system is ancient and displays roots roughly one billion years old, deep in the deuterostome branch of the bilaterians (pre-Cambrian). The lectin pathway (MBL - MASP) is homologous to the classical complement pathway, but utilizes opsonin, mannan-binding lectin (MBL, MBP) and ficolins rather than C1q. Diversified ficolins are of particular importance in invertebrates, which lack the adaptive immune response that evolved some 500 million years ago in jawed vertebrates.

Macrophage scavenger receptors appear to mediate important, conserved functions, so it was likely pattern-recognition receptors that arose early in the evolution of host-defense mechanisms. Eicosanoids play a prominent role in inflammatory/immune responses and the evolution of eicosanoid receptors has been analyzed on the basis of amino acid sequences. Eiconasoid receptors are located on a variety of cells, tissues, and organs and can be activated by either non-selective or selective ligands.

The more specific, versatile, memory-capable adaptive immune response evolved more recently, roughly 450 million years ago, and is found in the jawed vertebrates (gnathostomes) but not in invertebrates.

Although the B cells of higher vertebrates lack phagocytic capabilities, it has recently been demonstrated that B cells from teleost (bony) fish and amphibians display potent phagocytic activities. Particle uptake by B cells induced activation of 'downstream' degradative pathways, leading to 'phagolysosome' formation and intracellular killing of ingested microbes. It is most probable that the less-elaborated, restrictive adaptive immune response of fish and amphibians makes the preservation of phagocytosis an evolutionary advantage to B cells in their defence against pathogens. These findings support the idea that B cells evolved from an ancestral phagocytic cell type, providing an evolutionary framework for understanding the close relationship between mammalian B lymphocytes and macrophages.[a, n]

Mast cell degranulation releases histamine and other vasoactive mediators in response to allergens. Although this reaction is most often encountered in allergic reactions, it apparently evolved as a defense system against intestinal parasitism, such as tapeworm infestations.

The versatile immunoglobulin superfamily is evolutionarily ancient, is widely expressed, and is constitutive or long-term up-regulated. Immunoglobulin antibodies are released by activated B cells of the immune system, on which they also act as surface marker proteins. The enormous diversity of antibodies is attributable to the alternative splicing of VDJ recombination.

RAG1 and RAG2, the proteins that mediate VDJ recombination, are closely related to transposases, and it is believed that evolution of the vertebrate genome includes their entry as part of a Transib superfamily transposon.

Blood coagulation employs the same fundamental mechanism in all vertebrates, from the early diverging jawless fishes to mammals.[1]. It has been amply demonstrated that all groups of fish generate thrombin through pathways that:
● utilize vitamin K-dependent factors
● exhibit factor XIII-dependent fibrin cross-linking, and
● manifest a fibrinolysis inhibited by the same antifibrinolytic agents as mammals (1–3).

(Thrombin-generated fibrin coagulation has not been observed in nonvertebrate chordates or in other invertebrate animals.)

Such a convoluted pathway as the clotting cascade could not have evolved as a single event. Proponents of "intelligent design theory" attempted to monopolize on this fact in order to promote their claims that an intelligent designer (God) must be responsible for the so-called "irreducible complexity" of the coagulation cascade. (Behe is a little more cautious in his wording, but the implied argument is as stated above.) Just as for the claims of irreducible complexity for evolution of the eye and the bacterial flagellum, the argument has been both logically and scientifically refuted.

Scientists realized some time ago that a series of gene duplications must be responsible for the complex set of interactions observed in mammalian clotting. Sequence comparisons of serine proteases led to the suggestion that the contact system of clotting factors ( factors XI and XII, and prekallikrein) must have evolved more recently than some of the other clotting factors and thus would likely be absent in lower vertebrates (4).

The genome sequences (5) for the puffer fish, Fugu rubripes, along with that for the urochordate (sea squirt) Ciona intes (6) have enabled a direct comparison of two early diverging chordates. The genomes confirm that the main lines of the vertebrate clotting pathway were evolved during the less than a hundred million years between the last common ancestor of these two creatures. It is currently believed that 50–100 million years separate the appearances of urochordates (including the sea squirt) and vertebrates. During this interval, the machinery for thrombin-catalyzed fibrin formation was presumably 'concocted by gene duplication and the shuffling about of key modular domains'.[adapted from article]

Talk Origins Evolving Immunity . Evolution of the Immune System, Spring 2005 .

Sequence comparisons of the three homologous polypeptide chains that compose vertebrate fibrinogens (acute phase proteins) imply that the molecule evolved before the divergence of vertebrates and invertebrates. Computer comparisons of various fibrinogen-related sequences indicate that the sea cucumber proteins diverged before the beta-gamma gene duplication.
Presence of a vertebrate fibrinogen-like sequence in an echinoderm. [Proc Natl Acad Sci U S A. 1990]

Coelomocytes increased expression of ferritin mRNA after stimulation. In vertebrates, cytokines can cause changes in iron levels in macrophages. Similarly, echinoderm macrokines produced decreases in iron levels in coelomocyte supernatant fluids. These results suggest that echinoderm ferritin is an acute phase protein and suggest that sequestration of iron is an ancient host defense response in animals.
Evolution of the acute phase response: iron release by echinoderm (Asterias forbesi) coelomocytes, and cloning of an echinoderm ferritin molecule.[Dev Comp Immunol. 2002 Jan;26(1):11-26.]

tags [Immunology] [evolution] [immune system] [coagulation cascade] ["irreducible complexity"]

eosinophils

2010-12-20T09:05:00.000-08:00

Eosinophils (acidophils) are granulocytes packed with granules that stain acidic (red with H&E). Eosinophils combat parasitic infection, and have diverse immune responsibilities.

Eosinophils play roles in:
● combatting viral infections (RNAses)
● allergic response
● fibrinolysis (following inflammation).
● pathogenesis of asthma
● combatting helminthic colonization, other parasites.

The acidophilic granules contain proteolytic enzymes that are toxic to parasite and elicit allergic symptoms in the host. The enzymes include histaminase, peroxidase, RNase, DNases, lipase, plasminogen, and Major Basic Protein. Eosinophils also secrete IL-5.

Eosinophils normally comprises about 2.3% of leukocytes, and elevations (eosinophilia) are associated with parasitic infestation, collagen vascular diseases (such as rheumatoid arthritis), malignancies such as Hodgkin's lymphoma, allergic skin conditions (such as exfoliative dermatitis), Addison's Disease, and hypersensitivity to drugs such as penicillin.

Tables Fc receptors Immune Cytokines Immunoglobulins

tags [Immunology] [leukocyte]

gene-conversion

2010-12-18T19:10:00.000-08:00

Gene conversion involves nonreciprocal transfer of genetic information (during meiosis) in which gene sequences are copied across into a homologous DNA sequence during recombination. Holliday suggested that gene conversion may be explained by repair of heteroduplex DNA.

Whereas somatic hypermutation generates single nucleotide polymorphisms (SNP), a somatic gene conversion-like mechanisms diversify antibodies by switching part of its antigen-binding region for a replacement gene segment. Inter- and intraspecies variations occur in preference for hypermutation versus a somatic gene conversion-like mechanism. The B-cells in chickens employ a somatic gene conversion-like mechanisms until adolescence, at which time the cells move from the hindgut bursa of Fabricus to the spleen and somatic hypermutation predominates.

graft rejection

2010-12-18T06:58:00.000-08:00

Graft rejection, transplant rejection, or allograft rejection is a normal process in which the functional immune system of a transplant recipient attacks the transplanted organ or tissue. Immunosuppressive drugs are administered to recipients in order to minimize the risk of rejection. Rarely, the donor stem cells of an allogeneic stem cell transplant will not survive because of their attack by the recipient's lymphocytes. Conditioning of patients with cytotoxic therapy prior to transplantation is intended to suppress the recipient's immune system sufficiently to avoid graft rejection. In occasional recipients, a graft may be unsuccessful because too few donor cells have been infused.

An emerging body of evidence suggests that innate immunity, providing the first line of host defence against invading pathogens or their components (PAMPs), also plays a critical role in acute and chronic allograft rejection. Donor organ injury induces an inflammatory milieu in the allograft, and this appears to be the initial key event for activation of the innate immune system. Injury-induced generation of putative endogenous molecular ligand, in terms of damage/danger-associated molecular patterns (DAMPs) such as heat shock proteins, are recognized by toll-like receptors (TLRs). Acute allograft injury such as oxidative stress during donor brain-death condition and post-ischemic reperfusion injury in the recipient could induce DAMPs, which may activate innate TLR-bearing dendritic cells, which could initiate the recipient´s adaptive alloimmune response by way of direct allo-recognition through donor-derived DCs and indirect allo-recognition through recipient-derived DCs, leading to acute allograft rejection. Chronic injurious events in the allograft induce the generation of DAMPs, which may interact with and activate innate TLR-bearing vascular cells (endothelial cells, smooth muscle cells), contributing to the development of atherosclerosis of donor organ vessels and promoting chronic allograft rejection.[from]

granulocytes

2010-12-18T06:56:00.000-08:00

Granulocytes are granulated leukocytes generated by granulopoiesis in the bone marrow. Because their nuclei vary in shape (usually 3-lobed) granulocytes are also termed polymorphonuclear leukocytes (PMN, PML). Usually, the term polymorphonuclear leukocyte is used to designate neutrophil granulocytes, which are the most abundant of the granulocytes.

The granules are named according to their staining characteristics with hematoxylin and eosin (H&E) :
● Basophil granules stain purple
● Eosinophil granules stain red
● Neutrophil granules stain a neutral pink

Mast cells contain metachromatic granules that store inflammatory mediators, including rich in histamine and heparin. Mast cells react to allergens and other degranulating agents with sequential exocytosis (description). Mast cells function in wound healing, in autoimmune disorders, and in the inflammatory and immune responses, including allergic reactions and anaphylaxis. (image at left - click to enlarge).

Mast cells are morphologically similar to basophils and both express CD34, though they may have different bone marrow precursors. Unlike basophils, masts cell circulate in an immature form, maturing only in tissue sites where they are resident. Mast cells are found in connective tissue of most organs, and in mucosal tissue.

Mast cells can be activated when an allergen binds to the IgE that is already coating the cell. Allergens are typically proteins or polysaccharides that bind to the Fab segment of the cognate IgE coating the mast cell surface. Crosslinking of two or more IgE molecules is required to activate the mast cell when steric changes disturb the cell membrane structure, triggering an intracellular cascade that activates the mast cell. Although this reaction is most often encountered in allergic reactions, it apparently evolved as a defense system against intestinal parasitism, such as tapeworm infestations.

Mast cells express pattern-recognition receptors plus high-affinity receptor (FcεRI) for IgE, which ligates specific IgE molecules irreversibly.
On activation, mast cells degranulate, releasing preformed mediators into the interstitium:
● histamine
● proteoglycans, mainly heparin (anticoagulant)
● serine proteases
● freshly synthesized lipid mediators (eicosanoids) Eicosanoid Actions :
_ ● prostaglandin D2 (PGD2)
_ ● leukotriene C4 (LTC4)
● cytokines

Complement Receptors Cytokines Eicosanoid Actions Fc receptors Immune Cytokines Immunoglobulins Interferons Scavenger Receptors Toll-like Receptors

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tags [Immunology] [WBC] [granulocyte]

helper T cell

2010-12-17T19:12:00.000-08:00

Helper T cells, T helper cells (Th), effector T cells circulate throughout the body where they interface with MHC class II protein on other cells, determining whether the MHC class II is presenting 'self' or 'non-self protein' (antigen). MHC class II receptors are located on the surface of professional antigen presenting cells (APCs), which display epitope proteins – exogenous antigen or fragmented angtigen from phagocytosed cells – on their surfaces.

When a helper T cell is activated by contact with antigen, it enters the cell cycle in addition to producing lymphokines and chemokines. Th cells direct antibody class switching in B lymphocytes, orchestrate activation and growth of cytotoxic T cells, and maximize the bactericidal activity of phagocytes (macrophages).

Naïve B lymphocytes each have one of millions of distinct surface antigen-specific surface receptors, yet have not encountered their specific, cognate antigen. With a life-span of only a few days, many B cells die without ever encountering their cognate antigen. Naïve B cells are stimulated when the BCR binds to its cognate antigen. This antigen-Ig binding must be coupled with a signal from a helper T cell in order to activate the B cell.

Helper T cells mostly carry the CD4 surface protein, though a few carry CD8. The CD4 receptor triggers targetting by HIV, which determines the crippling effect of HIV on the immune system.
Subsets of Th cells are defined by the class of cytokine that they secrete upon activation:
Th1 – produce copious amounts of IL-2 and IFN-γ.
Th2 – particularly effective at stimulating B cells through secretion of IL-4, IL-5, and IL-6.
Th3 – produce cytokine transforming growth factor-beta (TGF-β) and IL-10.

Th1 cells are the more effective antiviral agents by virtue of their secretion of interferons (IFN-γ). Immune Cytokines Interferons

The cytokines produced by the two Th subsets perform cross-regulatory role. An activated Th2 cell secreting IL-4,-5,and 6 downregulates local Th1 cells in the neighborhood, whereas Th1 cytokines downregulate Th2 responses.

Tables Fc receptors Immune Cytokines Immunoglobulins

[] diagram - helper T cells and phagocytic response to tumor cells [] diagram - HIV binding via CD4 receptors [] micrograph germinal center with helper T cells [] tem - helper T & B cell []

hematopoiesis

2010-12-17T19:11:00.000-08:00

Hematopoiesis is the production of blood cells, a developmental process located in the (red) bone marrow, though some cells mature elsewhere. For example, T lymphocytes are so named because they mature in the thymus, and antigenic stimulation of B lymphocytes to become plasma cells typically takes place in the periphery.

▼ B lymphocyte development : common lymphoid progenitor : common myeloid progenitor : E2A : EBF : early B lineage : erythropoiesis : granulopoiesis : hematopoietic growth factors : lymphopoiesis : monocytopoiesis : Pax-5 : pluripotential stem cell : precursors : progenitors : regulatory transcription factors : stages : stem cells : thrombopoiesis : transcriptional regulatory proteins▼

The process of haematopoiesis occurs in several stages, and is controlled by at least 11 hematopoietic growth factors (including the colony-stimulating factors, IL-2 through IL-7, G-CSF, GM-CSF, and M-CSF). The first stage involves the differentiation of a pluripotential stem cell into a committed progenitor, which is followed by maturation of committed progenitors in distinct pathways, in which precursors are partially developed, 'adolescent' cells en route to maturity.

stem → progenitor → precursor → adult → mature

[] labeled photomicrograph of bone marrow, diagram of adult stem cell plasticity, diagram of stem cell versus progenitor cell

Stem cell stage:

pluripotential hematopoietic stem cell

↓ --------------------↓

common myeloid progenitor----or----common lymphoid progenitor

The common myeloid progenitor can generate:

● proerythroblasts (pronormoblasts) → erythropoiesis

● myeloblasts → granulopoiesis

● monoblasts → monocytopoiesis

● megakaryoblasts → thrombopoiesis

The common lympoid progenitor can generate:

● lymphoblasts → lymphopoiesis

Committed progenitor stage to mature cell : granulopoiesis

common myeloid progenitor

↓

myeloblast

↓

B/E/N promyelocyte

↓---↓---↓

B/E/N myelocyte

↓---↓---↓

B/E/N metamyelocyte

↓---↓---↓

B/E/N band

↓---↓---↓

basophil, eosinophil, neutrophil

↓ -----------------------

mast cell -----------------------

Committed progenitor stage to mature cell : lymphopoiesis

common lymphoid progenitor

↓

lymphoblast

----------------------------------------↓ rearrangements H: D-J → H: V-DJ

prolymphocyte

-----------------↓ rearrangements L: V-J --------------------------↓

small lymphocyte------or----- natural killer cell (large granular lymphocyte)

------------↓ IgM→IgD ---------↓------------------------------------ ↓

------B lymphocyte--or-- T lymphocyte

------------↓----------------------------------------------------------- ↓

--------plasma cell------------------------------------------lymphoid dendritic cell

Development of mature B lymphocytes from multipotent progenitors requires the coordinated activities of a number of transcriptional regulatory proteins, including EBF, Pax-5, and E2A.

During B cell-development from the precursor stage, differentiation involves rearrangement of the heavy chain gene segments. The functional integrity of the rearranged gene is tested: Precursor-B cells express two single domain Ig-like proteins of invariant sequence that substitute for the light chain. Formation of a complex comprising the μ (mu) heavy chain with the surrogate light chains instructs the cell to discontinue rearrangement of the heavy chain locus and to commence rearrangement of the k (kappa) locus. If successful light chain rearrangement is achieved such that the light and heavy chains form a complete antibody, then this complex instructs the cell to discontinue rearrangement of light chains, ensuring that only a single specificity is produced (allelic exclusion). Џ B cell maturation - animation Џ

Those developing B cell clones that fail to generate a productive rearrangement at both one of their heavy chain alleles and a light chain locus will undergo apoptosis. Immune tolerance mechanisms also exist to ensure the death of any newly produced B cells that express an antibody that reacts strongly with self proteins on the surface of host cells.

E2A proteins function in early B lineage development to regulate B lineage-specific gene expression as well as B cell survival. E2A-encoded proteins are involved in the differentiation of a number of cell types, and they are especially important in lymphocyte development.

The E2A gene encodes E47 and E12, which are basic-helix-loop-helix (bHLH) transcription factors that bind DNA either as homodimers or as heterodimers with other bHLH proteins. Such bHLH DNA binding activity in the B-lineage comprises E47 homodimers. Development of thymocytes mainly involves heterodimers of E47 and a related bHLH protein, HEB. Thymocytic E2A protein expression is required to initiate T-cell differentiation. During the development of thymoctyes, E-proteins and their antagonists, Id2 and Id3, regulate T-lineage specific gene expression and TCR rearrangement. E2A and Id proteins block thymocytic maturation in the absence of pre-TCR expression, and pre-TCR signaling acts to promote development in part by inhibiting E2A activity. [l]

Committed progenitor stage to mature cell : monocytopoiesis

common myeloid progenitor

↓

monoblast

↓

promonocyte

↓

monocyte

↓ ----↓

macrophage or myeloid dendritic cell

Committed progenitor stage to mature cell : erythropoiesis

common myeloid progenitor

↓

proerythroblast

↓

basophilic erythroblast

↓

polychromatic erythroblast

↓

polychromatic erythrocyte (reticulocyte)

↓

erythrocyte (RBC)

Committed progenitor stage to mature cell : thrombopoiesis

common myeloid progenitor

↓

megakaryoblast

↓

promegakaryocyte

↓

megakaryocyte

↓

thrombocytes (platelets)

[] Hematopoiesis - high-resolution version (837 KB) [] micrograph erythroid island central macrophage []

Tables Complement Receptors Cytokines Fc receptors Immune Cytokines Immunoglobulins Interferons Scavenger Receptors Toll-like Receptors

▲ Top ▲

tags [Immunology] [hematopoiesis]

humoral immunity

2010-12-17T03:11:00.000-08:00

The humoral immune response employs antibodies secreted by B lymphocytes, and is a component of the adaptive immune response. In addition to antibody production, the immune system secretes chemical mediators.

Elements of the humoral response include:
● secretion of antibodies
___● neutralization of pathogens and toxins
___● activation of classical complement pathway
___● opsonin production
● stimulation of cellular responses
___● formation of germinal centers
___● activation of helper T cells (Th2)
___● production of memory B lymphocytes
___● opsonin-directed phagocytosis and elimination of pathogens
● chemi-genetic responses
___● isotype switching between immunoglobulin types
___● affinity maturation (combining somatic hypermutation and affinity based clonal selection)
___● production of immune cytokines
___● C9 complement membrane attack complex
___● production of acute phase-inflammatory response mediators

Tables Complement Receptors Cytokines Fc receptors Immune Cytokines Immunoglobulins Interferons Scavenger Receptors Toll-like Receptors

tags [Immunology] [antibodies] [cytokine] [helper T]

HIV/AIDs

2010-12-17T03:03:00.000-08:00

[] Binding of HIV to CD4 helper T-cell lymphocyte [] Life cycle and drug targets for HIV []

Tables Fc receptors Immune Cytokines Immunoglobulins

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immune cytokines

2010-12-16T11:11:00.000-08:00

Cytokines are small proteins that regulate and mediate immunity, inflammation, and hematopoiesis. They are secreted de novo in response to immune stimuli, and usually act briefly, locally, at very low concentrations (the exception being endocrine action at distant cells). All cytokines possess four conserved cysteine residues, and are divided into two families based upon the contiguity (CC) or separation of cysteine residues (CXC).

The orchestration and regulation of cytokine production during inflammatory responses constitutes a key determinant of both the resolution of challenge and the limitation of host tissue damage. Cytokines bind to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter cellular activity (gene expression). Cytokines are often produced in cascades.

Tables Immune Cytokines Fc receptors Immunoglobulins Interferons

▼ actions : chemokine : chemokine family receptors : classification of cytokines : colony-stimulating factors (CSF) : cytokine cascade : cytokine effects : cytokine receptors : cytokine secreting cells : distance of cytokine action : granulocyte colony-stimulating factor (G-CSF) : granulocyte-macrophage colony-stimulating factor (GM-CSF) : hematopoietin family receptors : interleukins, interleukins as largest group : interferon family receptors (IFNR) : largest group of cytokines : lymphokine : lymphotoxins : macrophage colony-stimulating factor (M-CSF) : mechanism of cytokine action : monokine : receptors : search for novel cytokines : target cells : tumor necrosis family receptors
(TNFR) ▼

Actions of cytokines include:
a) up- or down-regulation of the expression of membrane proteins (including cytokine receptors),
b) secretion of effector molecules: histamine release; antibody secretion - IgA, IgG1, and IgE synthesis; IL-1 synthesis; cytokine production; MHC Class II; and CAM expression
c) cellular proliferation
d) chemotaxis of neutrophils, monocytes, and T cells
e) cellular differentiation
f) inflammation
g) phagocytosis
h) death of tumor cells
i) elimination of pathogens

Cytokines are classified according to the cells that produce them:
a) Lymphokines - produced by lymphocytes
b) Monokines - produced by monocytes,
c) Chemokines - chemotactic activities
d) Interleukins - manufactured by one leukocyte to act on other leukocytes.

The cells that produce cytokines include B cells, T cells, dendritic cells, NK, Tc, Th, Th1, Th2, endothelial cells, mast cells, plasma cells, progenitor, marrow stroma, thymus stroma, and tumor cells, along with fibroblasts, leukocytes, monocytes, and macrophages.

Cytokine function may be targetted at:
a) The cells that secrete them (autocrine action),
b) Local cells (paracrine action),
c) Distant cells (endocrine action).

Target cells include: B cells, T cells, NK, Tc, Th, Th2, stem, mast cells, plasma cells, progenitor, tumor cells, phagocytes, neutrophils, monocytes, and macrophages.

Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine secreted by several cell types, including mononuclear cells of the immune system and pituitary cells in the brain. Functional promoter polymorphisms in the MIF gene affect the clinical presentation of systemic sclerosis (SSc, scleroderma) and confer susceptibility to systemic lupus erythematosis (SLE). MIF counteracts cortisol-induced inhibition of inflammatory cytokine secretion, and employs the CD74 receptor.

Cytokines bind to specific membrane receptors:
a) Hematopoietin family receptors - dimers or trimers with conserved cysteines in their extracellular domains and a conserved Trp-Ser-X-Trp-Ser sequence.
The two subunits are i) cytokine-specific, and ii) signal transducing.
Cytokine binding promotes dimerization of the alpha and beta subunits, which then associate with cytoplasmic tyrosine kinases to phosphorylate proteins and activate mRNA transcription. Examples - receptors for IL-2 through IL-7 and GM-CSF.

Colony-stimulating factors (CSFs) are glycoprotein molecules that support growth of hematopoietic colonies. Interleukin 3 (IL-3) exhibits broad activity in the proliferation and differentiation of erythroid, megakaryocytic, and myeloid lineage progenitor cells.

Macrophage colony-stimulating factor (M-CSF, CSF1) acts selectively on the macrophage lineage, while granulocyte colony-stimulating factor (G-CSF) acts selectively on cells of the granulocyte lineage.

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have pleiotropic activating effects on mature leukocytes, which can improve leukocyte function, facilitating eradication of microbial infections. G-CSF activates neutrophils, while GM-CSF activates neutrophils, eosinophils, and monocyte/macrophages.

G-CSF is a 19.6 kDA glycoprotein that exists in two forms, comprising either 174 or 180 amino-acids. It is produced in a number of different tissues and stimulates granulopoietic proliferation and differentiation in the bone marrow. GM-CSF is a 14.6 kDa globular protein of 128 amino acids that contains two intramolecular disulfide bonds and two potential N-linked glycosylation sites. It is produced by endothelial cells, monocytes, fibroblasts and T-lymphocytes. GM-CSF is a hematopoietic growth factor that stimulates the development of macrophages and neutrophils, and inhibits neutrophil migration while enhancing the functional activity of the mature end-cells. It also promotes the proliferation and development of early erythroid megakaryocytic and eosinophilic progenitor cells.

b) Interferon (IFN) family receptors have the conserved cysteine residues but not the Trp-Ser-X-Trp-Ser sequence, and include the receptors for IFNα, IFNb, and IFNγ.

c) Tumor Necrosis Factor family receptors possess four extracellular domains, and include receptors for soluble TNFα and TNFβ as well as membrane-bound CD40 (important for B cell activation and macrophage activation) and Fas (which signals the cell to undergo apoptosis). TNFα is lymphotoxin β (LT), where the lymphotoxins occur either as homotrimers of LT-α (LT-α3) or as heterotrimers of one LT-α subunit plus two LT-β subunits (LT-α,β2).[s]

d) Chemokine family receptors have seven transmembrane helices and interact with G protein. This family includes receptors for IL-8, MIP-1 and RANTES. Chemokine receptors CCR5 and CXCR4 are used by HIV to preferentially enter either macrophages or T cells.

Cytokines are often produced in cascades, as one cytokine stimulates its target cells to produce additional cytokines. Cytokines are redundant in their activity, in that different cytokines can stimulated similar functions. Different cell types may secrete the same cytokine, or for a single cytokine may act on several different cell types (pleiotropy). Cytokines can also act synergistically with two or more cytokines acting together, or antagonistically with cytokines causing opposing activities.

Interleukins comprise the largest group of cytokines, stimulating proliferation and differentiation of immune cells. The group includes Interleukin 1 (IL-1), which activates T cells; IL-2, which stimulates proliferation of antigen-activated T and B cells; IL-4, IL-5, and IL-6, which stimulate proliferation and differentiation of B cells; Interferon gamma (IFNγ), which activates macrophages; and IL-3, IL-7 and Granulocyte Monocyte Colony-Stimulating Factor (GM-CSF), which stimulate hematopoiesis.

Short half lives, low plasma concentrations, pleiotropy, and redundancy combine to make the isolation and characterization of cytokines difficult. Search for novel cytokines is often conducted at the DNA level, identifying genes that are similar to known cytokine genes.

▲ actions : chemokine : chemokine family receptors : classification of cytokines : colony-stimulating factors (CSF) : cytokine cascade : cytokine effects : cytokine receptors : cytokine secreting cells : distance of cytokine action : granulocyte colony-stimulating factor (G-CSF) : granulocyte-macrophage colony-stimulating factor (GM-CSF) : hematopoietin family receptors : interleukins, interleukins as largest group : interferon family receptors (IFNR) : largest group of cytokines : lymphokine : lymphotoxins : macrophage colony-stimulating factor (M-CSF) : mechanism of cytokine action : monokine : receptors : search for novel cytokines : target cells : tumor necrosis family receptors (TNFR) ▲

Tables Immune Cytokines Cell signaling Receptor Tyrosine Kinases(RTK) Second Messengers Phosphate-handling Enzymes Cell Adhesion Molecules (CAM) .

· adenylyl (adenylate) cyclase ф antibodies ф antigen ф B cells · cadherins · calcium ions · cAMP-dependent protein kinase · CDKs ф cellular response · chemotaxis ф class-switch recombination ф clonal selection ф complement system ф costimulation · cyclin-dependent kinases · cytokine receptors · DAG ф dendritic cells · diacylglycerol · DNA ligases · ERKs · GPCRs · GPCR families ф granulocytes · guanylate cyclases · guanyl cyclase ф helper T cell ф hematopoiesis ф humoral immunity · Ig superfamily ф immune response ф inflammatory response · inositol triphosphate · integrins · IP3 ф leukocytes ф leukocyte adhesion cascade ф lymphokines ф macrophages · MAP kinases ф macrophages ф MHC ф migration · mitogen activated protein kinases ф monocytes ф neutrophils ф pathogens ф pattern-recognition receptors ф phagocyte · phosphatases · phosphodiesterases ф plasma cells · phospolipases · phosphorylation · PKA · PKC · phospholipase C-gamma · protein kinase A · protein kinase C · protein tyrosine kinases (PTKs) ф receptors · receptor tyrosine kinases · second messengers · second messenger cAMP · second messenger cGMP · selectins ф signaling · signal transduction ф surface receptors ф T cells · TNFs · two-component systems ·

Tables Fc receptors Immune Cytokines Immunoglobulins Interferons Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers