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

Nature Reviews Immunology volume 7, pages 633–643 (2007)Cite this article

Key Points

  • Normal B-cell development results in the generation of self-reactive B cells. The regulation of these potentially pathogenic B cells is essential in the prevention of autoimmune disease.

  • Three mechanisms regulate these cells: deletion by apoptosis, the generation of antigen receptors with new specificity by receptor editing, and anergy. Anergy refers to a state in which self-reactive B cells exist in the periphery but are quiescent and unresponsive to antigen stimulation.

  • Numerous transgenic mouse models have been used to study B-cell anergy, each with advantages and disadvantages. Anergic B cells have also been identified in non-transgenic mice (An1 B cells) and share features with anergic B cells from mouse models of anergy.

  • Anergic B cells do not respond to in vivo antigen stimulation by secreting antibody. Many anergic B cells also exhibit attenuated B-cell-receptor signalling in response to either antigen or Toll-like-receptor stimulation in vitro .

  • Many anergic B cells also have a shortened lifespan and altered anatomical localization compared with naive, non-self-reactive B cells.

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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Figure 1: Stages of B-cell development.
Figure 2: B-cell signalling in response to acute or chronic antigen stimulation.

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Acknowledgements

We would like to thank S. H. Clarke, J. M. Thomas and L. J. Wysocki for their help and input.

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  1. Department of Immunology, University of Colorado Health Science Center and National Jewish Medical Research Center, 1400 Jackson Street, Denver, 80206, Colorado, USA

    John C. Cambier, Stephen B. Gauld & Kevin T. Merrell

  2. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    Barbara J. Vilen

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Glossary

Receptor editing

A molecular process that involves secondary rearrangements (mostly of the light chains) that replace existing immunoglobulin molecules and generate a new antigen receptor with altered specificity.

Central tolerance

Self-tolerance that is created at the level of the central lymphoid organs. Developing T cells in the thymus, and B cells in the bone marrow, that strongly recognize self antigen face deletion or marked suppression.

Anergy

A state of non-responsiveness to antigen. Anergic T or B cells cannot respond to their cognate antigens under optimal conditions of stimulation.

Systemic lupus erythematosus

(SLE). An autoimmune disease in which autoantibodies specific for DNA, RNA or proteins associated with nucleic acids form immune complexes. These complexes damage small blood vessels, especially in the kidneys. Patients with SLE generally have abnormal B- and T-cell function.

MRL.Faslpr/lpr mice

A mouse strain that spontaneously develops glomerulonephritis and other symptoms of systemic lupus erythematosus. The lpr mutation causes a defect in FAS (also known as CD95), preventing the apoptosis of activated lymphocytes; the MRL strain contributes disease-associated mutations that have yet to be identified.

Small nuclear ribonucleoprotein

(snRNP). A nuclear particle that consists of a short RNA (<300 nucleotides) and one or more tightly bound proteins. They are involved in pre-mRNA processing and tRNA biogenesis.

Non-obese diabetic mice

(NOD mice). A strain of mice that normally develop idiopathic autoimmune diabetes that closely resembles type 1 diabetes in humans. The main component of susceptibility is the unique MHC haplotype H2g7.

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Cambier, J., Gauld, S., Merrell, K. et al. B-cell anergy: from transgenic models to naturally occurring anergic B cells?. Nat Rev Immunol 7, 633–643 (2007). https://doi.org/10.1038/nri2133

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