Immunology

Immunology Overview

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

Labels: , , , , , , , , , , ,

| 0 Guide-Glossary

anergy

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

Labels: , , , , , , , , , , , , , , , , ,

| 0 Guide-Glossary

receptors

The functionality of cells of the immune system is particularly dependent on signal pathways, and the various lymphoid cell types sport an array of receptors.

antigenic determinant : APC costimulation : BCR: complement receptors : cytokines : epitope : FcR : Ig-Fc : IgG : opsonins : pathogen associated molecular patterns : pattern recognition receptors : phagocyte receptors : respiratory burst complement : respiratory burst Fc : : scavenger receptors : TCR : TLR : Toll-like receptors : VDJ recombination

Phagocytes

Phagocytic cells detect infectious agents that bind to a variety of receptors on the phagocytes cell membranes, including:

Fc receptors (FcR, Ig-Fc) – the constant region (Fc) of IgG on bacterial surfaces can bind to the Fc receptor on phagocytes. Such binding to the Fc receptor requires prior antibody-antigen interaction. The binding of IgG-coated bacteria to phagocytic Fc receptors stimulates both metabolic activity in the phagocytes (respiratory burst) and phagocytic activity. Fc receptors include the clusters of differentiation, CD16 (Fcγ RIII), CD32 (Fcγ RII-A, Fcγ RII-B2, Fcγ RII-B1), and CD64 (Fcγ RI), Fcε RI, and Fcα RI. All FcR are stimulatory except inhibitory Fcγ RII-B1 and B2, which contain immunoreceptor tyrosine based inhibition motifs (ITIMs) in their cytoplasmic tail. Table  Fc receptors

Complement receptors – Phagocytic cells possess a receptor for the C3b complement opsonins, and binding of C3b-coated bacteria to this receptor stimulates enhanced phagocytosis and the respiratory burst. Table  Complement Receptors.

Scavenger receptors bind a variety of polyanions on bacterial surfaces, stimulating phagocytosis of the polyanion-coated bacteria. 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. Table  Scavenger Receptors

Toll-like receptors are a variety of pattern recognition receptors (PRR) that recognize pathogen associated molecular patterns (PAMP) on infectious agents. Binding of the infectious agents to Toll-like receptors stimulates phagocytosis and the release of inflammatory cytokines (IL-1, TNF-α, IL-6) from the phagocytes. Table  Toll-like Receptors

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

Lymphocytes

The surfaces of B cells and T cells are coated with thousands of identical copies of different integral membrane receptors (BCRs, TCRs), each capable of binding with a different antigen.

Receptor characteristics
● thousands of copies of integral membrane proteins with unique antigen binding sites
● encoded by genes assembled by VDJ recombination produced without antigen encounter
● the antigen binding site recognizes an antigenic determinant or epitope on the antigen
● binding, by non-covalent forces, is based on complementarity of the surface of the receptor and the surface of the epitope

Binding of receptor to epitope, when accompanied by APC-costimulation, leads to:
stimulation of the B or T cell to leave the G0 phase and enter the cell cycle
● repeated mitosis generates a clone of cells of identical specificity, each coated with an identical antigen receptor.

Cytokine receptors:
Hematopoietin family receptors are 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. Examples are receptors for IL-2 through IL-7 and GM-CSF.
___Colony-stimulating factors (CSFs) are glycoprotein molecules that support growth of hematopoietic colonies. Examples are receptors for interleukin 3 (IL-3), G-CSF, GM-CSF, M-CSF.

Interferon family receptors
Interferons are immune cytokines that are classified, as type I, II, or III, according to the receptors through which they signal. Interferon (INF) family receptors have conserved cysteine residues and include the receptors for IFNα, IFNβ, and IFNγ.

Tumor Necrosis Factor family receptors possess four extracellular domains. Examples are receptors for TNFα, TNFβ (lymphotoxin β, LT), CD40, CD27, CD30, and Fas.

Chemokine family receptors have seven transmembrane helices (serpentine, GRCRs) and interact with G protein. This family includes receptors for IL-8, MIP-1, MCP (monocyte chemoattractant protein), and RANTES (regulated upon activation normal T cell expressed and secreted). Chemokine receptors CCR5 and CXCR4 are used by HIV to preferentially enter either macrophages or T cells.

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

▲ф ф antibodies ф antigen : antigenic determinant ф APCs : APC costimulation : BCR ф BCR ф B cells ф CD ф cellular response ф clonal selection ф complement system : complement receptors ф complement system ф costimulation : cytokines ~ cytokines ф dendritic cells : epitope : FcR  Fc receptors ф granulocytes ф helper T cell ф hematopoiesis ф humoral immunity : Ig-Fc : IgG  Immune Cytokines  Immunoglobulins □□ Immunology ~ immunoglobulins ф inflammatory response ф immune cytokines ф immune response ф lymphocytes ф lymphoid system ф macrophages ф MHC : opsonins ф pathogens : pathogen associated molecular patterns (PAMP) : pattern recognition receptors (PRR) ф pattern-recognition receptors : phagocyte receptors ф phagocyte ф plasma cells : respiratory burst complement ››› respiratory burst : respiratory burst Fc : scavenger receptors ф signaling ф surface receptors : TCR ф TCR ф T cells : TLR : Toll-like receptors : VDJ recombination ▲ф

Top

Labels: , , , , , , , , , ,

| 0 Guide-Glossary

. . . since 10/06/06
Google