An R620W polymorphism in the phosphatase PTPN22 is associated with several human autoimmune diseases. In the Journal of Clinical Investigation, Meffre and colleagues determine how this variant can affect the clearance of autoreactive B cells. They find more autoreactive B cells in otherwise healthy homozygous and heterozygous carriers of the PTPN22 variant. Notably, autoreactive antibodies are present in these carriers without signs of any overt autoinflammatory disease. Healthy carriers of this PTPN22 variant also have frequencies of autoreactive B cell clones equivalent to those of patients with type 1 diabetes or rheumatoid arthritis. Microarray analysis of B cells from healthy donors carrying the variant PTPN22 shows generalized upregulation of genes associated with B cell survival, activation and proliferation, including those encoding costimulatory molecules, Toll-like receptors and cytokine receptors. Finally, B cells from carriers of the PTPN22 variant show greater responsiveness to stimulation with the costimulatory molecule CD40.

J. Clin. Invest. 121, 3635–3644 (2011)