Quantitative genetic variation in CD19 expression correlates with autoimmunity

Signaling thresholds influence the balance between humoral immunity and aut oimmunity. Cell surface CD19 regulates intrinsic and Ag receptor-induced B lymphocyte signaling thresholds, and transgenic mice that overexpress CD19 by 3-fold generate spontaneous autoantibodies in a genetic background not a ssociated with autoimmunity. To quantify the extent that genetically determ ined differences in expression of a single cell surface molecule can influe nce autoantibody production, we have assessed autoimmunity in a C57BL/6-tra nsgenic mouse line with subtle 15-29% increases in CD19 cell surface expres sion (CD19 transgenic). Antinuclear Abs, especially anti-spindle pole Abs, rheumatoid factor, and autoantibodies for ssDNA, dsDNA, and histone were pr oduced in these transgenic mice, but not littermate controls. This demonstr ates that small changes in CD19 expression can induce autoantibody producti on. Remarkably, similar changes in CD19 expression were found on B cells fr om patients,vith systemic sclerosis, a multisystem disorder of connective t issue with autoantibody production. CD19 density on blood B cells from syst emic sclerosis patients was significantly (similar to 20%) higher compared with normal individuals, whereas CD20, CD22, and CD40 expression were norma l, These results suggest that modest changes in the expression or function of regulatory molecules such as CD19 may shift the balance between toleranc e and immunity to autoimmunity. Thereby autoimmune disease may result from a collection of subtle multigenic alterations that could include incrementa l density changes in cell surface signaling molecules.