Living with the Enemy!

ReseaRch highlights

b CELLS Living with the enemy!

Self-reactive antibodies are inevitable In mouse models, anergic B cells somatic mutations and that no two

by-products of the random process tend to express BCRs of the IgD BND cells have the same VDJ junc-

of V(D)J recombination. Indeed, isotype and low levels of surface IgM. tions. This suggests that BND cells are previous studies estimate that up to So, the authors tested the specificity naturally autoreactive and have not 20% of circulating B cells in healthy of antibodies isolated from single undergone class-switch recombina- + – humans are potentially autoreactive. IgD IgM B cells (referred to as BND tion and clonal expansion, as occurs It is thought that some newly gener- cells), which were typically found to during an immune response. ated B cells that express potentially make up 1–10% of naive B cells in Evidence from mouse models autoreactive B-cell receptors (BCRs) healthy adult donors. Consistent with indicates that BCR signalling enter the periphery if they fail to the hypothesis that this population is in anergic B cells is attenuated.

undergo appropriate receptor editing equivalent to the autoreactive anergic Similarly, human BND cells showed and escape elimination by clonal B cells found in mouse models, the reduced mobilization of intracellular

deletion. Extensive investigation in antibodies from BND cells showed calcium and decreased levels of transgenic mouse models suggests fourfold higher anti-DNA reactivity phosphorylation of key signalling that these ‘escapees’ are kept in check (a feature of autoantibodies in sys- proteins after BCR cross-linking by a functional attenuation known as temic lupus erythematosus and other compared with naive B cells. As anergy. Now, for the first time, Duty autoimmune diseases) than those reported for anergic B cells in mice, + + – et al. identify a subset of mature B cells from naive IgD IgM CD27 B cells. basal calcium levels in BND cells were in humans that are naturally auto- Moreover, 75% of the antibodies higher than in naive B cells, which is

reactive and exist in an from BND cells showed reactivity probably a consequence of constant anergic state. to HEp-2 cells, a commonly used exposure to self antigen. indicator of antinuclear antibodies. Finally, the finding that the func-

Further characterization of the tion of BND cells could be rescued by

phenotype of BND cells revealed that the provision of appropriate T-cell fac- they are mature B cells: they were tors, such as interleukin-4 and CD40 found to express markers that are ligand, suggests that these cells could only found on mature B cells, includ- be a source of precursors for patho- ing CD22, CD23, CD40 and CD44, logical autoantibody-secreting cells in and only expressed low levels of the autoimmune disease and therefore a immature B-cell markers CD5, potential therapeutic target.

CD24 and CD38. In addition, BND Lucy Bird cells showed no signs of ongoing ORIGINAL RESEARCH PAPER Duty, J. A. et al. receptor editing, such as tran- Functional anergy in a subpopulation of naive scripts for the surrogate light B cells from healthy humans that express chain, or of proliferation. autoreactive immunoglobulin receptors. J. Exp. Med. 22 Dec 2008 (doi:10.1084/jem.20080611) Sequence analysis of the FuRtHER REAdING Cambier, J. C. et al. B-cell antibody variable regions anergy: from transgenic models to naturally in B cells indicated that occurring anergic B cells? Nature Rev. Immunol. ND 7, 633–643 (2007) these cells do not have