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

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cellular response

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-lymphocytescytotoxic T lymphocytes (killer T cells).

Tables  Fc receptors  Immune Cytokines  Immunoglobulins

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killer T cells

Cytotoxic, CTLs, or killer T cells (CD8+) release lysis-inducing lymphotoxins.

Apo_1 : apoptosis : C9 : CD8+ : CD95 : caspases : class I MHC : CIK cells : CTLs : cytotoxic T lymphocytes : epitope : Fas-FasL : granzymes : LAK cells : LAK anti-tumor Tx : membrane attack complex : MHC class I : natural killer cells : NK cells : NK receptors : perforin : perforin gene : perforin pore : serine protease : Tc : TIL cells : TNFR

TcCTL , some CTL → CIK
natural killer cells (NK)
laboratory: leukocyte + IL-2LAK
▼ anti-tumor Tx TIL, LAK

Tc cells express CD8 plus an antigen-specific T cell receptor (TCR) that ligates antigens presented by MHC class I, and are derived from a common lymphoid progenitor matured in the thymus. These Tc cells, once activated and matured into cytotoxic T lymphocytes (CTLs), recognize and destroy infected/altered self-cells.

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells lyse target cells. CTLs recognize a specific epitope peptide presented by major histocompatibility complex (MHC) class I molecules on the target cells. NK cells recognize targets that express no class I MHC molecules I or low levels of MHC I molecules, enabling NK cells to target cells that have evaded CTLs.

Evidence suggests that both NK cells and CTLs exclusively employ perforin-dependent cytolysis. Perforin is a 534 aa glycoprotein with sequence homology to the membrane attack component of complement C9. As a cytolytic mediator, 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 permitting cytolytic cell death. The cell-type-specific expression of the perforin gene is determined by the promoter and upstream region, and there is evidence of transcriptional repression of the perforin gene in non-killer cells by two novel regulatory elements, one of which that is exclusively expressed by non-killer cells appears to be an Ets family member.[p]

Perforin pores in the plasma membrane of targetted cells permit entry of serine-protease granzymes, which cleave caspase precursors and trigger apoptosis. Perforin-dependent cytolysis plays an important role in immune response to bacterial and viral infections, in tumour surveillance, in immunopathology, and in autoimmunity.

A second cytolytic mechanism is mediated by the interaction of activated T cell surface FasL with TNFR family Fas receptors (TNFRSF6, Apo_1, CD95) expressed on the surface of the target cell. Fas and TNFR1 share a a conserved extracellular region and a cytoplasmic domain, crucial for the induction of apoptosis. Targets that express Fas can be lysed upon interaction with FasL on the surface of an effector cell (usually an activated T cell) or upon cross-linking by anti-Fas antibodies. A deficiency of functional Fas—FasL interactions results in lymphoproliferation, abnormal constitution of the peripheral T cell pool, and autoimmunity. [pdf]

Cytokine-induced killer (CIK) cells are a unique population of cytotoxic T lymphocytes (CTL) with the characteristic CD3+CD56+ phenotype. CIK cells also express CD94, part of the NK receptor comprising of CD94-NKG2 heterodimer. CIKs have demonstrated higher proliferative and cytolytic activities in comparison to the reported CD3-CD56+ lymphokine activated killer (LAK) cells that are essentially activated natural killer (NK) cells. CIK cells are non-MHC-restricted in target cell recognition and killing.

Lymphokine-activated killer cells (LAKs) are leukocytes stimulated in the laboratory to kill tumor cells. LAKs are generated by culturing spleen or peripheral blood leukocytes in presence of high concentrations of IL-2. LAKs are T-like cells that express CD3 or CD8. They lyse targets non-specifically, and with a target range hierarchy different than that of NK cells. LAK cells respond chemotactically and accumulate at sites of viral infection.

Natural killer (NK) cells are very important components of the innate immune system, are distinct from CTLs. 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.

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 (KIR) belonging to the immunoglobulin superfamily. 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
-- ● killer lectin like receptor (KLR) CD94/NKG2 heterodimer, which employs MHC as ligand
-- ● natural cytotoxic receptors (NCR) which do not associate with MHC.

Lymphokine-activated killer (LAK) and tumor-infiltrating lymphocytes (TIL) have been employed therapeutically since the '70s mainly in end-stage patients with solid tumors. TIL are more specific and potent cytotoxic effectors than LAK, but their clinical use be considered potentially useful only in a few patients, chiefly those with solid tumors such as melanoma and glioblastoma.[r]

TcCTL , some CTL → CIK
natural killer cells (NK)
laboratory: leukocyte + IL-2LAK
▲ anti-tumor TIL, LAK

▲ ф antibodies ф antigen : Apo_1 : apoptosisapoptosis ф B cells : C9 ф C9: CD8+ : CD95 ф CD : caspases : class I MHC ф complement system ф classes of MHC : CTLs ф cytolysis : cytotoxic T lymphocytes : epitope : Fas-FasL ф granulocytes : granzymes : membrane attack complex ф membrane attack complex ф MHC : MHC class I : natural killer cells ф : NK cells ф NK cells : perforin : perforin gene : perforin pore ф C9 pore ф receptors : serine protease ф serine proteases ф surface receptors : Tc : TNFR

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T cells

T cells or T lymphocytes are specialized lymphocytes distinguished by their TCR surface receptors.

activation T reg : APC : apoptosis : B7-1 : B7-2 : CD8 + : CD28 : CD80 : CD86 : costimulation : CTL : cytotoxic T lymphocytes : Fas-FasL : γδ T cells : granulysin : granzyme : helper T cell : IL-2 : interleukin-2 : natural killer T cells : NKT : perforin : pore : self-protection : serine protease : Tc : Th : Treg : Treg activation/action : T cell types : VDJ recombination

'T' lymphocytes initially develop in the thymus, and differentiate peripherally into several functional subsets of cells:
cytotoxic T cellsCTL, TcCD8 +
helper T cells, effector T cells – ThCD4 +
regulatory T cellsTreg (formerly termed 'suppressor' T cells)
natural killer T cellsNKT (different than NK cells)
γδ T cells

Cytotoxic T lymphocytes (CTLs) or killer T cells express antigen-specific, VDJ recombination-generated TCRs plus glycoprotein CD8 on their surfaces. The TCR recognizes specific antigenic proteins that are fragmented into peptides and then are presented in complex with MHC class I molecules (MHC-peptide complex - red).

APCs provide synergistic signaling by costimulatory molecules. APC signaling is necessary to sustain and integrate TCR signaling and to stimulate optimal T cell proliferation and differentiation.

The binding of TCR•antigen•CD8•MHC-I holds the activated CTL (Tc) in proximity to the damaged/infected target cell. Once activated, the Tc cell undergoes clonal expansion with the assistance of a cytokine, interleukin-2 (IL-2) that acts as a growth and differentiation factor for T cells. (Table  Immune Cytokines)

CD28 binds the CD80 (B7-1) and CD86 (B7-2) ligands that are expressed on antigen presenting cells (APCs). When exposed to infected/dysfunctional somatic cells, Tc cells release perforin, which form pores in the target cell's plasma membrane. Also released from Tcs are granulysin and the serine protease granzyme, which transit the perforin pore and induce apoptosis of the target cell.

A second cytolytic mechanism is mediated by the interaction of activated T cell surface FasL with TNFR family Fas receptors (TNFRSF6, Apo_1, CD95) expressed on the surface of the target cell.

Helper T cells (Th), or 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). Th cells direct antibody class switching in B lymphocytes.

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

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.

Regulatory cells (Treg)
Regulatory T cells were formerly called suppressor T cells because they suppress immune responses. Negative regulatory functions have been ascribed to several T cell types:
CD4+CD25+
CD4+CD25–
interleukin-10-producing TR1 cells
transforming growth factor-ß-secreting TH3 'regulatory' cells
[v]

Treg cells express the αβ TCR chains and are activated only when the TCR binds to its cognate peptide-class II MHC molecule and receives costimulation from B7 molecules (CD80, CD86) on the antigen-presenting cell. Once activated, Treg secrete interleukin 9 (IL-9), interleukin 10 (IL-10), +/- transforming growth factor-beta (TGF-β), and these lymphokines inhibit Th1 assistance of cell-mediated immunity and inflammation, and
Th2 assistance of antibody production, and may inhibit the action of CD8+ CTLs.

Because the antigenic peptides recognized by Treg TCRs are typically self-peptides, the chief function of Treg cells is provision of self-protection by preventing other T cells from attacking self components, thus protecting against autoimmunity.

CD25, or IL-2 receptor alpha chain, or IL-2R, or Tac antigen is a 55kDa glycoprotein whose transcription is regulated by Stat5, Elf-1, HGG-I(Y), GATA, and Tax from HTLV-1. CD25 is expressed on PHA-stimulated T cells, B cells stimulated with anti-IgM antibody, monocytes/macrophages stimulated with LPS, and highly expressed on HTLV-I-transformed T cell lines. NCBI LocusLink Record: 3559

Natural killer T cells – NKT cells are activated by group 2, CD1d molecules to secrete interferon-γ (IFNγ) and IL-4, which act as Th1 and Th2 cytokines.

γδ T cells carry TCRs encoded by different gene segments than those of αβ T cells. CD27 is cell-surface marker for T-cell progenitors that are beginning to undergo commitment to the αβ or γδ T-cell lineages, and newly emerging αβ and γδ T-lineage cells display early differences in dependence on Notch–Delta signaling and display distinct patterns of gene expression.[npg]

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, which comprise the predominant mammalian T cell population. Thus, γδ T cells function to bridge the innate and adaptive immune responses.

γδ T cells can form unique memory subsets with distinct adhesion and chemotactic capabilities, determining the tissue homing capabilities of cells. γδ T cells are enriched in areas of inflammation. Human γδ T cells express ligands for E- and P-selectins, so they display specialized homing to epithelial surfaces. The memory γδ T cells express chemokine family receptors not expressed by αβ T cells.

Human γδ T cells that express Vγ2Vδ2 TCRs can recognize nonpeptide antigens and Non-Hodgkin's B cell lymphomas. In particular, recognition of prenyl pyrophosphates is performed by this extracellular presentation pathway, which is distinct from MHC and CD1 presentation, and which is important in many different bacterial and parasitic infections. However, γδ T cells of the major tissue subset recognize self and foreign nonpeptide antigens presented by CD1. These nonpeptide antigens are lipids and glycolipids presented by CD1 proteins, which are MHC-like-molecules specialized for the presentation of lipids.[s].


▲ф ф antibodies ф antigen : APC ф APCs : apoptosisapoptosis : B7-1 : B7-2 ф CD : CD8 + : CD28 : CD80 : CD86cell growthcell membranescellular fate : costimulation ф costimulation : CTL ~ cytokines ф cytolysis : cytotoxic T lymphocytesdifferentiation : Fas-FasL : γδ T cells : granulysin § granulysin : granzyme : helper T cell ф helper T cell : IL-2 ~ immunoglobulins : interleukin-2 ф immune cytokines  Immune Cytokines : killer T cells ф killer T cells ф lymphocytes ф lymphokines ф MHC : natural killer T cells : NKT : perforin : pore ф receptors : serine protease ф signaling ф surface receptors: Tc : Th : Treg : T cell types ф thymus : VDJ recombination ф VDJ recombination ▲ф

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