Impaired inhibitory Fcγ receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy

The inhibitory Fc-gamma receptor Fc gamma RIIB, expressed on myeloid and B cells, has a critical role in the balance of tolerance and autoimmunity, and is required for the antiinflammatory activity of intravenous Ig (IVIG) in various murine disease models. However, the function of Fc gamma RIIB and its regulation by IVIG in human autoimmune diseases are less well understood. Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common treatable acquired chronic polyneuropathy, and IVIG is widely used as a first-line initial and maintenance treatment. We found that untreated patients with CIDP, compared with demographically matched healthy controls, showed consistently lower Fc gamma RIIB expression levels on naive B cells, and failed to up-regulate or to maintain up-regulation of Fc gamma RIIB as B cells progressed from the naive to the memory compartment. Concomitantly, the rare -386C/-120A Fc gamma RIIB promoter polymorphism resulting in reduced promoter activity previously associated with autoimmune phenotypes was overrepresented in CIDP. Also, Fc gamma RIIB protein expression was up-regulated on monocytes and B cells after clinically effective IVIG therapy. Thus, our results suggest that the inhibitory Fc gamma RIIB is impaired at a critical B cell differentiation checkpoint in CIDP, and that modulating Fc gamma RIIB expression might be a promising approach to efficiently limit antibody-mediated immunopathology in CIDP.