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

Abstract

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 T_H1 and T_H2 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⁺T_FH cells that express IL-4 are located outside germinal centers and specialized T_FH 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 T_FH cells.