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

• Published in: Nature Reviews: Immunology 2007-08, Vol.7 (8), p.633-643
• Main Authors: Cambier, John C, Gauld, Stephen B, Merrell, Kevin T, Vilen, Barbara J
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Autoimmune diseases; Autoimmunity - immunology; B cells; B-Lymphocytes - immunology; Biomedical and Life Sciences; Biomedicine; Cell interaction; Clonal Anergy - immunology; Epitopes; Heterogeneity; Humans; Immunology; Mice; Mice, Transgenic; Models, Animal; Physiological aspects; Receptors, Antigen, B-Cell - immunology; review-article; Signal Transduction
• ISSN: 1474-1733; 1474-1741; 1365-2567
• DOI: 10.1038/nri2133

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. How self-reactive B cells can exist in the periphery yet be unresponsive to antigen stimulation is unclear. John Cambier and colleagues describe the mouse models that have been used to study B-cell anergy and the possible mechanisms that explain this phenomenon. 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.