Abstract
Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) regulates a panoply of leukocyte signaling pathways. A single nucleotide polymorphism (SNP) in PTPN22, rs2476601, is associated with increased risk of Type 1 Diabetes (T1D) and other autoimmune diseases. Over the past decade PTPN22 has been studied intensely in T cell receptor (TCR) and B cell receptor (BCR) signaling. However, the effect of the minor allele on PTPN22 function in TCR signaling is controversial with some reports concluding it has enhanced function and blunts TCR signaling and others reporting it has reduced function and increases TCR signaling. More recently, the core function of PTPN22 as well as functional derangements imparted by the autoimmunity-associated variant allele of PTPN22 have been examined in monocytes, macrophages, dendritic cells, and neutrophils. In this review we will discuss the known functions of PTPN22 in human cells, and we will elaborate on how autoimmunity-associated variants influence these functions across the panoply of immune cells that express PTPN22. Further, we consider currently unresolved questions that require clarification on the role of PTPN22 in immune cell function.
Highlights
Almost 1.6 million Americans have Type 1 Diabetes (T1D), an autoimmune disease that results in destruction of the insulin producing b cells in the pancreas and eventually requires exogenous insulin (1)
We propose that the T1D-associated risk allotype of PTPN22 permits excessive innate and adaptive immune signaling in response to aseptic and/or septic stress/danger signals, in turn, driving a type IV delayed hypersensitivity response against pancreatic b cell antigens
The combination of increased BAFFR, CD40, and SLAMF6 surface levels and the increased expression of IL4R, IL13R, IL17R, IL21R, as well as genes belonging to the CD40, Toll-like receptor (TLR), and B cell receptor (BCR) activation pathways may explain the enhanced CpG-induced expansion of IgM+ memory B cells and IgM- Plasma cells in Peripheral blood mononuclear cells (PBMC) seen in PTPN22620R/W and PTPN22620W/W donors compared to PTPN22620R/R donors
Summary
Almost 1.6 million Americans have Type 1 Diabetes (T1D), an autoimmune disease that results in destruction of the insulin producing b cells in the pancreas and eventually requires exogenous insulin (1). The enhanced LFA-1induced signaling and motility, and the reduced capacity of aTregs to suppress IFNg secretion from conventional T cells seen in PTPN22620R/W and PTPN22620W/W humans could help explain why rs2476601 is associated with increased overall risk of T1D development. The combination of increased BAFFR, CD40, and SLAMF6 surface levels and the increased expression of IL4R, IL13R, IL17R, IL21R, as well as genes belonging to the CD40, TLR, and BCR activation pathways may explain the enhanced CpG-induced expansion of IgM+ memory B cells and IgM- Plasma cells in PBMCs seen in PTPN22620R/W and PTPN22620W/W donors compared to PTPN22620R/R donors. Taken together we see that PTPN22 and PEP affect expression of costimulatory molecules in B cells of both humans and mice the effects of the R to W conversion are not consistent when comparing humans to mice
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