autoimmunity

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



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tags [Immunology][autoimmunity]

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immune tolerance

Immune tolerance permits the immune response to distinguish between self and other, avoiding the problems inherent in autoimmune disorders. Tolerance is either natural or induced.

▼ acquired tolerance : clonal anergy : clonal deletion : hypotheses : idiotype network : induced tolerance : mechanisms : natural tolerance : negative selection : peripheral tolerance : receptor editing : regulatory T, Treg : suppressor population : theories : tolerance in B cells : tolerance in T cells ▼

Several hypotheses have been proposed to explain mechanisms of immunological tolerance:
● Clonal Deletion theory – proposal that self-reactive lymphoid cells are destroyed during the development of the immune system in the 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.

Induced, or acquired tolerance results from medical manipulations aimed at attenuating the immune or allergic response.
● hyposensitizing, "allergy shots"
● immune suppressant medications to prevent graft rejection
● anti-inflammatory medication to reduce damage wrought by autoimmune disorders

Because some T cells act as helper cells for B cells, it is more efficaceous to induce tolerance in T cell populations. Within the thymus, those maturing T cell precursors that bind self-derived epitope molecules are eliminated by apoptosis. Those comparatively safe T cells that have not been eliminated by this negative selection are released from the thymus to circulate throughout the lymphoid system. Should any T cells with potentially self-attacking TCRs escape thymic control, several back-up mechanisms exist to defuse them:
● lack of a costimulatory signal from "self"-cells
● death signal delivered to T cell by FasL on "self"-cells
● suppression of T cells by suppressor, regulatory T cells (Treg)
● sequestered antigens on tissues beyond circulatory barriers

As B cells mature in the bone marrow, tolerance is induced by the process of receptor editing – apoptosis of B thymocytes with BCRs directed at self-peptides. Peripheral tolerance is induced in any potential auto-reactive B cells that leave the bone marrow when they fail to receive costimulatory assistance from Th cells.

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Immunology
tags [Immunology] [immune tolerance] [immunosuppressants] [hyposensitization]

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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 cells – CTL, Tc – CD8 +
● helper T cells, effector T cells – Th – CD4 +
● regulatory T cells –Treg (formerly termed 'suppressor' T cells)
● natural killer T cells – NKT (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 : apoptosis סּ apoptosis : B7-1 : B7-2 ф CD : CD8 + : CD28 : CD80 : CD86 סּ cell growth סּ cell membranes ₪ cellular fate : costimulation ф costimulation : CTL ~ cytokines ф cytolysis : cytotoxic T lymphocytes ₪ differentiation : 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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