Research ArticleAUTOIMMUNITY

PTPN22 inhibition resets defective human central B cell tolerance

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Science Immunology  22 Jul 2016:
Vol. 1, Issue 1, pp. aaf7153
DOI: 10.1126/sciimmunol.aaf7153

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Restoring tolerance

Therapies that target and eliminate B cells have had some success in patients with autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis. However, restoring tolerance in self-reactive B cells that lead to disease remains an unmet goal. The 1858T allele of protein tyrosine phosphatase nonreceptor type 22 (PTPN22 T) has been associated with autoreactive B cells in autoimmune disease in humans. Now, Schickel et al. report that this allele interferes with the development of central B cell tolerance in a humanized mouse model of autoimmunity and that blocking PTPN22 can restore this defect. If these observations hold true in humans, targeting PTPN22 may be able to restore B cell tolerance in patients with autoimmune disease.

Abstract

The 1858T protein tyrosine phosphatase nonreceptor type 22 (PTPN22 T) allele is one of the main risk factors associated with many autoimmune diseases and correlates with a defective removal of developing autoreactive B cells in humans. To determine whether inhibiting PTPN22 favors the elimination of autoreactive B cells, we first demonstrated that the PTPN22 T allele interfered with the establishment of central B cell tolerance using NOD-scid-common γ chain knockout (NSG) mice engrafted with human hematopoietic stem cells expressing this allele. In contrast, the inhibition of either PTPN22 enzymatic activity or its expression by RNA interference restored defective central B cell tolerance in this model. Thus, PTPN22 blockade may represent a therapeutic strategy for the prevention or treatment of autoimmunity.

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