Snail silences suppressor

2 JEM Vol. 206, No. 1, 2009 Learning to tolerate ourselves On age 139, Duty et al. find self-reactive B cells in healthy adults that might harm their own body if given the chance. Checkpoints during B cell development ensure that immune cells won’t confuse the self for an intruder. At birth, many B cells express self-reactive receptors. Most of these potentially harmful cells are either set straight by rearranging new receptors or are eliminated before leaving the bone marrow. Yet a minority manages to escape, slipping into the periphery as mature B cells with a propensity for self-attack. In healthy mice, autoimmunity is avoided because most self-reactive escapees, which classically express high levels of IgD and reduced IgM, are arrested in an anergic state. But until now, a similar population of anergic, autoreactive B cells hadn’t been found in humans. Duty et al. have now spotted these cells in the blood of healthy adults, where they accounted for 2.5% of peripheral B cells. These cells turned out to be mature and autoreactive, bearing no signs of antigen encounter in vivo. The cells were also anergic, as they had faulty signaling in response to BCR ligation. These defects were overcome, however, when the authors gave cells a strong enough signal. Autoreactive B cells are common in patients with autoimmune diseases, such as lupus or rheumatoid arthritis (RA). And the authors suspect that the new population may contain the precursors of these troublemaking cells. Lapses in early steps of self-tolerance have been shown to contribute to disease in patients with lupus or RA. Alternatively, suggests author Patrick Wilson, anergy may fail in these patients, allowing self-sabotaging cells to run free. Why the body silences these potentially mutinous cells after they escape rather than putting them to death is unclear. Perhaps, suggests Wilson, a limited amount of autoimmunity isn’t such a bad thing, as long as it’s not chronic. For example, anergic cells might help attack pathogens disguised as self-antigens.