Autoimmunity risk alleles: hotspots in regulatory signaling pathways

John C. Cambier

J Clin Invest. 2013;123(5):1928-1931. https://doi.org/10.1172/JCI69289.

Commentary

Autoimmunity is the consequence of the combination of genetic predisposition and environmental effects, such as infection, injury, and constitution of the gut microbiome. In this edition of the JCI, Dai et al. describe the use of knockin technology to test the mechanism of action of a polymorphism in the tyrosine phosphatase nonreceptor 22 (PTPN22) (LYP) that is associated with susceptibility to multiple autoimmune diseases. The function of this allele, and that of a disproportionate number of autoimmune disease risk alleles, suggests that inhibitory signaling pathways that maintain B lymphocyte immune tolerance may represent an Achilles’ heel in the prevention of autoimmunity.

Find the latest version: https://jci.me/69289/pdf commentaries Autoimmunity risk alleles: hotspots in B cell regulatory signaling pathways John C. Cambier

Integrated Department of Immunology, University of Colorado School of Medicine and National Jewish Health, Denver, Colorado, USA.

Autoimmunity is the consequence of the combination of genetic predispo- . The authors characterized the effect sition and environmental effects, such as infection, injury, and constitution of the mutation on lymphocyte signaling of the gut microbiome. In this edition of the JCI, Dai et al. describe the use and various immunological parameters. of knockin technology to test the mechanism of action of a polymorphism The results provide important new insight in the protein tyrosine phosphatase nonreceptor 22 (PTPN22) (LYP) that is regarding the role of PTPN22 in regulation associated with susceptibility to multiple autoimmune diseases. The func- of by recep- tion of this allele, and that of a disproportionate number of autoimmune tors and thus in maintenance of immune disease risk alleles, suggests that inhibitory signaling pathways that main- tolerance. Dai et al. found that the R619W tain B lymphocyte immune tolerance may represent an Achilles’ heel in the variance did not affect protein half-life prevention of autoimmunity. of PTPN22 as previously suggested (13), but rather altered -mediated pro- Of immunologic tolerance, B cells, ics as well as personal experience, such as tein tyrosine phosphorylation and caused and autoimmunity history of infection and injury. As recently hypersensitivity to antigen receptor stim- The is charged with pro- as 2008, only a handful of genetic polymor- ulation. Furthermore, B cell expression of tecting us from the myriad pathogens in phisms that confer risk of SLE were recog- the variant was sufficient to promote auto- our environment and has the added chore nized, and these had been identified based immunity. Thus, PTPN22 is among the of recognizing and eliminating rogue cells on candidate gene approaches. With the SLE risk alleles defined thus far that result that threaten to cause cancer. Competence development of high-throughput genome- in compromised control of intracellular to generate immune responses is depen- wide analysis of SNPs has come a torrent BCR signaling, leading to loss of B cell tol- dent in part on continued generation of of new information that has the potential erance and autoimmunity (2–7). It may be new lymphocytes, T cells and B cells, each to provide a much more comprehensive telling that encoding molecules that expressing receptors with unique specific- view of disease-associated variants. In cir- enforce B cell tolerance are disproportion- ity for antigen. Indeed, we each produce cumsta