PTPN22 inhibition resets defective human central B cell tolerance

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.

Impaired B‐cell tolerance checkpoints promote the development of autoimmune diseases and pathogenic autoantibodies

“…In agreement with this hypothesis, we demonstrated that a lentiviral-driven expression of 620W PTPN22 variant in human B cells that developed in humanized mice was sufficient to abrogate central B-cell tolerance, whereas the expression of the common 620R PTPN22 had no impact on the functionality of this tolerance checkpoint 52. In agreement with this hypothesis, we demonstrated that a lentiviral-driven expression of 620W PTPN22 variant in human B cells that developed in humanized mice was sufficient to abrogate central B-cell tolerance, whereas the expression of the common 620R PTPN22 had no impact on the functionality of this tolerance checkpoint 52.…”

HSC extrinsic sex-related and intrinsic autoimmune disease–related human B-cell variation is recapitulated in humanized mice

“…Both the HC donor and the HC NSG mouse contained only 10% autoreactive B cells in their spleens, consistent with previous results. 37 For the RA donor, this defect was confirmed by the high percentage (50%) of B-cell clones making human epithelial type 2-binding antibodies in the RA donor and respective PI mouse compared with the HC patient ( Figure 5B). …”

Mechanisms of central tolerance for B cells

“…Consistent with this possibility, mice carrying a mutation in Ptpn22 (R619W) analogous to the disease-associated human PTPN22 allele (R620W) had a B cell-autonomous defect that could promote autoimmunity and was associated with the protection of immature B cells from apoptosis 131 . Moreover, in mice engrafted with human haematopoietic stem cells, intrinsic expression of the R620W allele was sufficient to impair B cell central tolerance 132 .…”