The PTPN22 genetic variant 1858T, encoding Lyp620W, is associated with multiple autoimmune disorders for which the production of autoantibodies is a common feature, suggesting a loss of B cell tolerance. Lyp620W results in blunted BCR signaling in memory B cells. Because BCR signal strength is tightly coupled to central and peripheral tolerance, we examined whether Lyp620W impacts peripheral B cell homeostasis in healthy individuals heterozygous for the PTPN221858T variant. We found that these subjects display alterations in the composition of the B cell pool that include specific expansion of the transitional and anergic IgD+ IgM− CD27− B cell subsets. The PTPN22 1858T variant was further associated with significantly diminished BCR signaling and a resistance to apoptosis in both transitional and naive B cells. Strikingly, parallel changes in both BCR signaling and composition of B cell compartment were observed in type 1 diabetic subjects, irrespective of PTPN22 genotype, revealing a novel immune phenotype and likely shared mechanisms leading to a loss of B cell tolerance. Our combined findings suggest that Lyp620W-mediated effects, due in part to the altered BCR signaling threshold, contribute to breakdown of peripheral tolerance and the entry of autoreactive B cells into the naive B cell compartment.

Human autoimmune diseases are genetically complex, arising from the combined impact of environmental factors and multiple polymorphic alleles with varying disease risk (1). Among the genetic variants associated with autoimmunity, the PTPN22 1858C/T variant stands out because of its association with multiple autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), Graves disease, and myasthenia gravis (2, 3). PTPN22 encodes the lymphoid tyrosine phosphatase (Lyp) expressed in multiple hematopoietic cell types. The disease-associated single-nucleotide polymorphism is a missense mutation at position 1858 (C→ T; Arg620→ Trp), which results in a gain-of-function manifest by blunting of TCR and BCR signaling (3, 4). In previous studies, we demonstrated that healthy individuals who carry the PTPN22 1858T allele exhibit alterations in BCR signal transduction characterized by diminished phosphorylation of proximal-signaling effectors, impaired BCR-driven proliferation, and a decrease in the size of the memory B cell compartment (5, 6).