Buckner, Jane H.

IgG4-related disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory disease whose pathomechanisms remain poorly understood. Here, we identified gene variants in familial IgG4-RD and determined their functional consequences. All 3 affected members of the family shared variants of the transcription factor IKAROS, encoded by IKZF1 , and the E3 ubiquitin ligase UBR4. The IKAROS variant increased binding to the FYN promoter, resulting in higher transcription of FYN in T cells. The UBR4 variant prevented the lysosomal degradation of the phosphatase CD45. In the presence of elevated FYN, CD45 functioned as a positive regulatory loop, lowering the threshold for T cell activation. Consequently, T cells from the affected family members were hyperresponsive to stimulation. When transduced with a low-avidity, autoreactive T cell receptor, their T cells responded to the autoantigenic peptide. In parallel, high expression of FYN in T cells biased their differentiation toward Th2 polarization by stabilizing the transcription factor JunB. This bias was consistent with the frequent atopic manifestations in patients with IgG4-RD, including the affected family members in the present study. Building on the functional consequences of these 2 variants, we propose a disease model that is not only instructive for IgG4-RD but also for atopic diseases and autoimmune diseases associated with an IKZF1 risk haplotype.