Summary

* In humoral immune responses, B lymphocytes are activated by antigen and secrete antibodies that act to eliminate the antigen. Both protein and nonprotein antigens can stimulate antibody responses. B cell responses to protein antigens require the contribution of CD4+ helper T cells specific for the antigen.

* Helper T cell-dependent B cell responses to protein antigens require initial activation of naive T cells y y y in the T cell zones and of B cells in lymphoid follicles in lymphoid organs. The activated lymphocytes migrate toward one another and interact at the edges of follicles, where the B cells present the antigen to helper T cells.

Activated helper T cells express CD40L, which engages CD40 on the B cells, and the T cells secrete cytokines that bind to cytokine receptors on the B cells. The combination of CD40 and cytokine signals stimulates initial B cell proliferation and differentiation.

Stimulation of activated B cells at extrafollicular sites by helper T cells leads to the formation of extrafollicular foci where some isotype switching occurs and short-lived plasma cells are generated. Some activated helper T cells differentiate into specialized TFH cells that express high levels of ICOS and CXCR5 and secrete IL-21. TFH cells and activated B cells migrate into the follicle, and TFH cells activate these specific B cells to initiate the formation of germinal centers. The late events in T cell-dependent antibody responses, including extensive isotype switching, somatic mutation, affinity maturation, generation of memory B cells, and induction of long-lived plasma cells, take place within germinal centers.

* Helper T cell-derived signals, including CD40L and cytokines, induce isotype switching in B cells by a process of switch recombination, leading to the production of various Ig isotypes. Isotype switching requires the induction of AID, a cytidine deam-inase that converts cytosine to uracil in single-stranded DNA, and different cytokines allow AID to access distinct downstream heavy chain loci.

* Affinity maturation occurs in germinal centers and leads to increased affinity of antibodies during the course of a T cell-dependent humoral response. Affinity maturation is a result of somatic mutation of Ig heavy and light chain genes induced by AID, followed by selective survival of the B cells that produce the high-affinity antibodies and bind to antigen displayed by FDCs in the germinal centers. Tfh cells also participate in selection of high-affinity B cells.

* Some of the progeny of germinal center B cells differentiate into antibody-secreting plasma cells that migrate to the bone marrow. Other progeny become memory B cells that live for long periods, recirculate between lymph nodes and spleen, and respond rapidly to subsequent exposures to antigen by differentiating into high-affinity antibody secre-tors. The differentiation of activated B cells into plasma cells or memory cells is controlled by the expression of various transcription factors.

* TI antigens are generally nonprotein antigens that induce humoral immune responses without the involvement of helper T cells. Many TI antigens, including polysaccharides, membrane glycolipids, and nucleic acids, are multivalent, can cross-link multiple membrane Ig molecules on a B cell, and activate complement, thereby activating the B cells without T cell help. TLR activation on B cells by microbial products facilitates T-independent B cell activation. TI antigens stimulate antibody responses in which there is limited heavy chain class switching, affinity maturation, or memory B cell generation because these features are largely dependent on helper T cells, which are not activated by nonprotein antigens. However, some T-independent isotype switching can be induced by TLR stimulation by microbes, which may lead to the production of cytokines of the TNF family that activate B cells to induce AID.

* Antibody feedback is a mechanism by which humoral immune responses are downregulated when enough antibody has been produced and soluble antibody-antigen complexes are present. B cell membrane Ig and the receptor on B cells for the Fc portions of IgG, called FcyRIIB, are clustered together by antibody-antigen complexes. This activates an inhibitory signaling cascade through the cytoplasmic tail of FcyRIIB that terminates the activation of the B cell.

selected readings

B Cell Subsets and B Cell Activation

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Hardy RR. B-1 B cell development. Journal of Immunology 176:2749-2754, 2006.

Harwood NE, and FD Batista. New insights into the early molecular events underlying B cell activation. Immunity 28:609619, 2008.

Martin F, and AC Chan. B cell immunobiology in disease: evolving concept from the clinic. Annual Review of Immunology 24:467-496, 2006.

T Follicular Helper Cells and the Germinal

Center Reaction

Crotty S. Follicular helper CD4 T cells. Annual Review of Immunology vol. 29, 2011.

Crotty S, RJ Johnston, and SP Schoenberger. Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nature Immunology 11:114-120, 2010.

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Radbruch A, G Muehlinghaus, EO Luger, A Inamine, KG Smith, T Dörner, and F Hiepe. Competence and competition: the challenge of becoming a long-lived plasma cell. Nature Reviews Immunology 6:741-750, 2006.

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AID, Class Switching, and Somatic Mutation

Cerutti A. The regulation of IgA class switching. Nature Reviews Immunology 8:421-434, 2008.

Delker RK, S Fugmann, and FN Papavasiliou. A coming-of-age story: activation-induced cytidine deaminase turns 10. Nature Immunology 10:1147-1153, 2009.

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Neuberger MS. Antibody diversification by somatic mutation: from Burnet onwards. Immunology and Cell Biology 86:124132, 2008.

Peled JU, FL Kuang, MD Iglesias-Ussel, S Roa, SL Kalis, MF Goodman, and MD Scharff. The biochemistry of somatic hypermutation. Annual Review of Immunology 26:481-511, 2008.

Stavnezer J, JE Guikema, and CE Schrader. Mechanism and regulation of class switch recombination. Annual Review of Immunology 26:261-292, 2008.

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