Influence of PTPN22 Allotypes on Innate and Adaptive Immune Function in Health and Disease

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.

Neglected Facts on Mycobacterium Avium Subspecies Paratuberculosis and Type 1 Diabetes

“…A single nucleotide polymorphism in PTPN22, rs2476601, is associated with increased risk of T1D, reduced age at onset, and reduced residual β-cell function at diagnosis. It affects T-cell receptor and B-cell receptor signaling as well as other adaptive and innate immune cell processes [ 83 ]. Sharp et al [ 80 ] demonstrated that single nucleotide polymorphisms in PTPN2/22 are found significantly in patients with Crohn’s disease and lead to an increase in T-cell proliferation due to loss of negative regulation, an increase of pro-inflammatory cytokines such as IFN-γ, and an increase of susceptibility to mycobacterial infections.…”

Genetic basis of defects in immune tolerance underlying the development of autoimmunity

“…The rs2476601 variant in the coding region of the protein tyrosine phosphatase non-receptor type 22 ( PTPN22) gene is one of the most strongly associated risk variants shared across autoimmune diseases including RA, T1D, and SLE ( 37 ). PTPN22 is notable for its role across multiple immune cell types including lymphocytes, natural killer (NK) cells, neutrophils, monocytes, macrophages, and DCs ( 37 ). In T and B cells, PTPN22 regulates antigen receptor signaling ( 38 ), making it a major focus of studies investigating its role in autoimmunity risk.…”

“…Human studies have also shown that the rs2476601 variant influences T cell maturation including increased CD4 memory T cells ( 43 ) and an increase in Th1 cells ( 44 ). In addition, this variant impacts TCR signaling, although the jury is still out as to whether it is a gain- or loss-of-function mutation, and this is likely dependent on context ( 37 ). This PTPN22 variant has also been recently implicated in cDC2 homeostasis because expression of the orthologous polymorphism in mice lead to expansion of cDC2 ( 45 ).…”

Functional Impact of Risk Gene Variants on the Autoimmune Responses in Type 1 Diabetes

“…The molecular consequences of the PTPN22 mutation and the impact on T1D risk have been discussed extensively before ( 92 , 93 ). The debate regarding the impact of the T1D risk variant on T cells remains as the results support both gain-of-function and loss-of-function as a mechanism ( 94 ).…”

“…In myeloid cells, PTPN22 is involved in the downstream signaling of TLR4, TLR7/8, NOD2 and cytokine receptors (reviewed in ( 92 )). In this case, LYP does not work as a phosphatase but promotes TRAF3 ubiquitination and TLR-induced upregulation of type I interferons (IFNs).…”