A Novel Immunoglobulin-Immunoglobulin Interaction in Autoimmunity

Well over six decades since its first description, the Rheumatoid Factor (RF)—autoantibodies recognizing Fc (constant) portion of IgG through their own Fab (antigen binding variable segments)—is believed to have come of age. Autoimmune pancreatitis is a unique form of pancreatitis, biologically characterized by an elevated serum IgG4 concentration. Given the fact that IgG4 myeloma proteins can act as RF, we initially hypothesized that IgG4 in autoimmune pancreatitis might do likewise, hence potentially contributing to disease pathogenesis. Indeed Western blotting clearly showed that IgG4 binds to IgG1 κ, IgG2 κ, IgG3 κ myeloma proteins, as well as to IgG Fc, in line with a typical RF activity. Further experiments however unraveled the unexpected fact that unlike hitherto known RF, IgG4 does not engage IgG Fc through its Fab, but its very own Fc. These data therefore collectively describe a Novel RF (NRF) in autoimmune pancreatitis. In the future, the relevance of NRF, beyond autoimmune pancreatitis, in both diagnosis/prognosis as well as pathophysiology of autoimmune and other systemic diseases where IgG4's role seems paramount, needs to be systematically assessed