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

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B cells

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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humoral immunity

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

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immune response

The immune response is mounted by cells of the immune system in response to invasion by pathogens. Immune responses are classifed as passive or active, innate or adaptive, and cellular or humoral.

activation B : activation T : active/passive : adaptive immune response : anergy : autoimmune : blood : cells : cellular immune response : cellular participants : classification : costimulation : danger hypothesis : humoral immune response : humoral participants : innate immune response : pattern recognition receptors : phagocytes : molecular participants : self-other : surface receptors

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)
● 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)

Anergy toward self-targets operates as one self-tolerance mechanism to control the autoreactive cells found in disease-causing autoimmunity. Immune responses ideally distinguish between self and other. In 1994, Polly Matzinger proposed an alternative to the widely established concept that the immune system primarily discriminates self from non-self. This alternative hypothesis suggested that the immune system is mainly adapted to recognize and respond to signals generated in a 'dangerous' situation that involves cell damage (Matzinger, 1994). This model, which became known as the 'danger' hypothesis, is based on the idea that the crucial signals for the initiation of immune responses are endogenous, not exogenous (Matzinger, 2001). According to this hypothesis, the power lies with the tissues: the activation state of APCs would depend on the health of cells in their neighbourhood. Accumulating evidence suggests that both exogenous and endogenous adjuvants contribute to the initiation of immune responses by activating APCs (Rock et al, 2005).[s=fft]

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

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 adaptive 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, 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.

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).
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) that already possesses VDJ recombination-generated affinity for the antigen.

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. 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 response to a repeated exposure of the priming antigen.[]diagram B[]

T lymphocytes participate in the cellular immune response, and are (first signal) activated by engagement of their surface receptor (TCR), which ensures antigen specificity and MHC restriction of the response. Delivery of first signal (TCR engagement) in the absence of costimulation by second signaling results in apoptosis or anergy. Synergistic signaling by (second signal) costimulatory molecules is also necessary to sustain and integrate TCR signaling to stimulate optimal T cell proliferation and differentiation. []diagram T[]

In addition to antibodies produced by plasma cells, a number of molecule types participate in the humoral response, including:
complement cascadeanaphylatoxins and opsonins
fibronectin
coagulation factors
interferon
● lysozyme, phospholipase
interleukin-1 (IL-1), inflammatory kinins
● iron-binding lactoferrin and transferrin
TNF-α

▲ф activation B : activation T (activation B : activation T : activation complement cascade ) : active/passive : adaptive immune response : anergy ф anergy ф antibodies ф antigen ф APCs ф autoimmunity : autoimmune ф B cells ф basophils : blood ф blood ф CD : cells : cellular immune response : cellular participants ф cellular response : classification ф CD ф cellular response ф clonal selection ф complement system ф costimulation : costimulation ф cytolysis ф cytotoxicity : danger hypothesis ф dendritic cells ф eosinophils ф granulocytes ф helper T cell ф hematopoiesis ф humoral immunity ф HIV/AIDs : humoral immune response : humoral participants ф immune cytokines ф immune response ф immune tolerance ф inflammatory response : innate immune response ф killer T cells ф leukocytes ф leukocyte adhesion cascade ф lymphocytes ф lymphokines ф lymphoid system ф macrophages ф MHC ф migration : pattern recognition receptors : phagocytes ф phagocyte ф plasma cells ф receptors ф signaling ф surface receptors : molecular participants : self-other : surface receptors ф surface receptorsT ф T cells ф thymus V ф vaccines ф VDJ recombination▲ф

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

Toll, A New Piece in the Puzzle of Innate Immunity. Wright SD. [Free Full Text Article] J Exp Med. 1999 Feb 15;189(4):605-9.

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isotype switching

Isotype switching is a characteristic feature of the humoral immune response, in which a switch from IgM to other Ig isotypes follows first exposure to an antigen. Affinity maturation ensures that repeated exposures to the same antigen will provoke greater antibody ligating affinity of the antibody secreted by successive generations of plasma cells.

Isotype switching is regulated by T cell-produced immune cytokines, such as interleukin-4 (IL-4), interferon-γ (IFN-γ), and TGF-β, which direct B cells to switch to specific Ig classes.

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