Figure 1. Patients with IgG4-RD possess genetic variants responsible for Th2 polarization and T cell activation.

(A) Three members of a family were affected by IgG4-RD: the father (teal square) and two daughters (teal circles). The mother was unaffected (white circle). (B) Rare variants were detected in the genome sequence of the affected individuals. The GOF IKAROS-R183H variant increases FYN expression, and the LOF UBR4-C4179Ter variant inhibits clearance of the tyrosine phosphatase CD45, which removes inhibitory phosphate, sparing phosphorylation at the activating tyrosine residue and leading to activation of FYN. The consequence of these variants for FYN stabilizes JunB to drive Th2 response genes and T cell activation.