Immunology

antigen

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 ¤ cancercell-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 receptorsregulation 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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clonal selection

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

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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

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