affinity maturation

Affinity maturation is a process of affinity-selected differentiation of activated B cells. Repeated exposures to the same antigen provokes greater antibody ligating affinity in the antibody secreted by successive generations of plasma cells.

The mechanisms by which affinity maturation is achieved are somatic hypermutation and clonal selection. Somatic hypermutation (SHM) is a diversity generating, regulated cellular mechanism through which antibodies are produced against an enormous variety of different potential antigens. The binding affinities of the variable regions of immunoglobulins are altered by AID-enzyme-promoted mutations during antigen-stimulated proliferation of B cells. These somatic hypermutations are transcribed and translated into thousands of slightly different immunoglobulins coded by the hypermutated V regions. The complementarity determining regions of these antibodies possess different affinities for the encountered antigen, and clonal selection will favor cells equipped with highest affinity antibodies because these B cells are favoured in terms of activation and co-operation with T cells.

Clonal selection is the phenomenon whereby a previously unencountered cognate antigen (epitope) can stimulate naïve B lymphocytes to proliferate and differentiate into clones of memory B cells and plasma cells that produce antibodies with the highest affinity for the antigen. Those B cells that have highest affinity BCR against the encountered antigen will be selected for proliferation, antibody production, and committment to an antigen-specific memory lineage.

Thus, SHM prepares a spectrum of antibodies with different affinities for the antigen, while clonal selection ensures that the immune system will react increasingly effectively (highest affinity) to an encountered antigen and will be ready for rapid response to subsequent encounters with the antigen.

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tags [Immunology] [affinity maturation]

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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.

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tags [Immunology] [anergy]

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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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plasma cells

Plasma cells are B lymphocytes that have been activated to differentiate and mature by CD4+ helper T lymphocytes. Activated B cells become either memory B cells or plasma cells, which secrete copious amounts of monoclonal antibodies against the original antigen that triggered the antigen presenting cells.

Affinity maturation is a process of affinity-selected differentiation and maturation of activated B cells. Repeated exposures to the same antigen provokes greater antibody ligating affinity in the antibody secreted by successive generations of plasma cells. Isotype switching, in response to signaling by specific cytokines, provides for a switch of production from IgM to other Ig isotypes following first exposure to an antigen. T cell-produced immune cytokines, such as interleukin-4 (IL-4), interferon-γ (IFN-γ), and TGF-β effect isotype switching.

Plasma cells are predominantly located in the bone marrow (0.2% to 2.8% of leukocytes) and are rarely found in the peripheral blood.(description of morphology)

Plasma cells are seen in abnormal numbers in multiple myeloma, plasma cell leukemia, Waldenström's macroglobulinemia, and MGUS (monoclonal gammopathy of uncertain significance).

[] tem plasma cell [] micrograph macrophage surrounded by normal plasma cells [] micrograph macrophage & plasma cells []

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