Autoimmunity risk alleles: hotspots in B cell regulatory signaling pathways

Abstract

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 protein 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.

Figure 1. Proximal activating and regulatory signal transduction by B lymphocyte antigen receptors.

Antigen aggregation of receptors composed of membrane Ig (mIg) and transducers CD79a and CD79b leads to tyrosine phosphorylation of CD79 immunoreceptor tyrosine-based activation motifs (ITAMs) (green) by Lyn/Fyn Src family tyrosine kinases. Participation of Src family kinases in this signaling pathway is negatively regulated by CSK-mediated phosphorylation of their C-terminal tyrosines. Phosphorylation of conserved ITAM motif tyrosines leads to recruitment of SH2 domain–containing effectors, including Syk, Lyn, and Fyn, and further activation of these effectors, initiating downstream pathways leading to cell activating (green arrows) and opposing regulatory signaling (red arrows). Among these proximally acting kinases, Lyn uniquely initiates both activating and regulatory circuitry by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) embedded in cytoplasmic tails of membrane proteins, including FCRLs, CD72, CD22, FcγRIIB, and other molecules. These phosphorylated motifs propagate inhibitory signals via activation of SHP and SHIP phosphatases. Lyn may also act through other intermediaries, e.g., monophosphorylated antigen receptor ITAMs, casein kinase 2, and components of the BLK/BANK1/InsP3 receptor complex on ER membranes, to trigger regulatory circuitry. Shown in red lettering are molecules in which certain allelic forms have been shown to increase risk of development of SLE.