IgG4-related disease -Mechanistic insights from both clinical and immunologic understanding of this condition.

IgG4-related disease (IgG4-RD) is a chronic inflammatory disease characterized by tumescent lesions with characteristic storiform fibrosis, obliterative phlebitis and a marked lymphoplasmacytic infiltrate that includes a large number of IgG4 positive plasma cells. It's widely accepted that rituximab-mediated B cell depletion therapy is effective for this disease. Important mechanistic insights correlated with the pathogenesis of IgG4-RD have been gradually disclosed from studies of patients treated by B cell depletion. 1) IgG4-RD patients have the large clonal expansion of activated plasmablasts and CD4(+)CTLs, so this disease might be antigen-driven. 2) CD4(+)CTLs are the dominant population in affected tissues, on the other hands direct examination of TH1 and TH2 cells in tissues reveal that these subsets are sparse. 3) CD4(+)CTLs into affected lesions secret cytotoxic, inflammatory, and pro-fibrotic cytokines, indicating reactivation by antigen in tissue sites. 4) The decline in CD4(+)CTLs number by B cell depletion is associated with clinical remission of IgG4-RD patients. 5) CD4(+)CXCR5(+)TFH cells that express IL-4 are located outside germinal centers and specialized TFH cells that expanded dramatically in conditions with polarized class switching to IgG4. These results suggested that the disease pathogenesis might be based on orchestrating of activated plasmablasts, CD4(+)CTLs, and TFH cells.