De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease

Background: IgG(4)-related disease (IgG(4)-RD) is a poorly understood, multiorgan, chronic inflammatory disease characterized by tumefactive lesions, storiform fibrosis, obliterative phlebitis, and accumulation of IgG(4)-expressing plasma cells at disease sites. Objective: The role of B cells and IgG(4) antibodies in IgG(4)-RD pathogenesis is not well defined. We evaluated patients with IgG(4)-RD for activated B cells in both disease lesions and peripheral blood and investigated their role in disease pathogenesis. Methods: B-cell populations from the peripheral blood of 84 patients with active IgG(4)-RD were analyzed by using flow cytometry. The repertoire of B-cell populations was analyzed in a subset of patients by using next-generation sequencing. Fourteen of these patients were longitudinally followed for 9 to 15 months after rituximab therapy. Results: Numbers of CD19(+)CD27(+)CD20(-)CD38(hi) plasmablasts, which are largely IgG(4)(+), are increased in patients with active IgG(4)-RD. These expanded plasmablasts are oligoclonal and exhibit extensive somatic hypermutation, and their numbers decrease after rituximab-mediated B-cell depletion therapy; this loss correlates with disease remission. A subset of patients relapse after rituximab therapy, and circulating plasmablasts that re-emerge in these subjects are clonally distinct and exhibit enhanced somatic hypermutation. Cloning and expression of immunoglobulin heavy and light chain genes from expanded plasmablasts at the peak of disease reveals that disease-associated IgG(4) antibodies are self-reactive. Conclusions: Clonally expanded CD19(+)CD27(+)CD20(-)CD38(hi) plasmablasts are a hallmark of active IgG(4)-RD. Enhanced somatic mutation in activated B cells and plasmablasts and emergence of distinct plasmablast clones on relapse indicate that the disease pathogenesis is linked to de novo recruitment of naive B cells into T cell-dependent responses by CD4(+) T cells, likely driving a self-reactive disease process.