IgG4-related disease: why is it so important?

IgG4-related disease (IgG4-RD) is a recently defined systemic inflammatory and fibrous condition of unknown etiology and multiple clinical presentations. Characteristic features include elevated serum IgG4 levels in approximately 70% of patients; diffuse lymphoplasmocytic infiltrates rich in IgG4(+) cells; a "storiform" fibrosis pattern; and obliterative phlebitis affecting various organs. The disease responds well to corticosteroid treatment, with a second-line therapy involving B-cell-directed immunosuppressive biologic agents. Despite intense studies, the pathogenesis of IgG4-RD remains unclear. The inflammatory infiltrates present in affected tissues contain also multiple polyclonal T and B cells, plasma cells, and - often - eosinophils. Cytokines secreted by type 2 helper T-cells and regulatory T-cells are known to cause B-cell differentiation into IgG4-producing plasma cells. On the other hand, large numbers of IgG4(+) plasma cells can be observed in nonspecific chronic inflammatory conditions, areas adjacent to neoplastic lesions with an inflammatory response, and in autoimmune inflammatory infiltrates. Thus, the fundamental question about the role of IgG4(+) cells in the pathogenesis of inflammation, tissue damage, and fibrosis in IgG4-RD still remains unanswered: does IgG4 stimulate or rather - which is more consistent with its natural properties - play a regulatory function in the inflammatory process?