B-cell anergy: from transgenic models to naturally occurring anergic B cells? - PubMed (original) (raw)

Review

B-cell anergy: from transgenic models to naturally occurring anergic B cells?

John C Cambier et al. Nat Rev Immunol. 2007 Aug.

Abstract

Anergy, a condition in which cells persist in the periphery but are unresponsive to antigen, is responsible for silencing many self-reactive B cells. Loss of anergy is known to contribute to the development of autoimmune diseases, including systemic lupus erythematosus and type 1 diabetes. Multiple transgenic mouse models have enabled the dissection of mechanisms that underlie anergy, and recently, anergic B cells have been identified in the periphery of wild-type mice. Heterogeneity of mechanistic concepts developed using model systems has complicated our understanding of anergy and its biological features. In this Review, we compare and contrast the salient features of anergic B cells with a view to developing unifying mechanistic hypotheses that explain their lifestyles.

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Figures

Figure 1

Figure 1. Stages of B-cell development

B-cell development occurs in both the bone marrow and peripheral lymphoid tissues such as the spleen. In the bone marrow, development progresses through the pro-B-cell, pre-B-cell and immature-B-cell stages. During this differentiation, rearrangements at the immunoglobulin locus result in the generation and surface expression of the pre-B-cell receptor (pre-BCR, which is comprised of an Igµ heavy chain and surrogate light chains (VpreB or Vλ5)) and finally a mature BCR (comprised of rearranged heavy- and light-chain genes) that is capable of binding antigen. At this immature stage of development, B cells undergo a selection process to prevent any further development of self-reactive cells. Both receptor editing and clonal deletion have a role at this stage. Cells successfully completing this checkpoint leave the bone marrow as transitional B cells, eventually maturing into mature follicular B cells (or marginal-zone B cells). Following an immune response, antigen-specific B cells develop into either plasma (antibody-secreting) cells or memory B cells. Transitional 3 (T3) B cells, once thought to be part of the linear development from immature to mature B cells, are now thought to represent primarily self-reactive anergic B cells (also known as An1 B cells).

Figure 2

Figure 2. B-cell signalling in response to acute or chronic antigen stimulation

a | The normal B-cell receptor (BCR) response to acute antigen stimulation involves the phosphorylation of two tyrosine residues in the ITAMs (immunoreceptor tyrosine-based activation motifs) of Igα and Igβ by LYN or other SRC-family kinases. This results in the recruitment and activation of SYK (spleen tyrosine kinase), which in turn phosphorylates key downstream substrates such as BLNK (B-cell linker) and BTK (Bruton’s tyrosine kinase), resulting in productive BCR signalling, activation and productive interactions with helper T cells. b | In anergic B cells, chronic binding of self antigen is thought to favour monophosphorylation of ITAM tyrosines. This limits the recruitment and activation of SYK, yet allows efficient LYN activity, which enhances the phosphorylation and activation of an inhibitory complex containing SHIP1 (SRC-homology-2-domain-containing inositol-5-phosphatase 1) and DOK (docking protein). These proteins act to dampen any productive BCR-mediated signalling in a manner that is analogous to FcγRIIb (an inhibitory Fc receptor for IgG that is expressed by B cells). This inhibitory complex may also act in trans to inhibit signalling by other receptors, including CXC-chemokine receptor 4 (CXCR4) and possibly the receptor for B-cell-activating factor (BAFFR). DAG, diacylglycerol; ERK, extracellular-signal-regulated kinase; GRB2, growth-factor-receptor-bound protein 2; InsP3, inositol-1,4,5-trisphosphate; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PLCγ, phospholipase Cγ; PtdIns(3,4,5)P3, phosphatidylinositol-3,4,5-trisphosphate; PtdIns(4,5)P2, phosphatidylinositol-4,5-bisphosphate; SOS, son-of-sevenless homologue.

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