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

• Published in: Journal of allergy and clinical immunology Vol. 134; no. 3; pp. 679 - 687
• Main Authors: Mattoo, Hamid, Mahajan, Vinay S., Della-Torre, Emanuel, Sekigami, Yurie, Carruthers, Mollie, Wallace, Zachary S., Deshpande, Vikram, Stone, John H., Pillai, Shiv
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.09.2014; Elsevier
• Subjects: Adult; Aged; Aged, 80 and over; Allergy and Immunology; Antibodies, Monoclonal, Murine-Derived - administration & dosage; Antibodies, Monoclonal, Murine-Derived - adverse effects; Antibody Diversity - genetics; Antibody-Producing Cells - drug effects; Antibody-Producing Cells - physiology; Antigens, CD - metabolism; Autoantigens - immunology; autoreactivity; B-Lymphocytes - drug effects; B-Lymphocytes - physiology; Biological and medical sciences; CDR3; Cell Proliferation; Clone Cells; Disease Progression; Female; Follow-Up Studies; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; IgG4-related disease; Immune System Diseases - immunology; Immune System Diseases - therapy; Immunoglobulin G - metabolism; immunoglobulin heavy chain variable region repertoire; Immunopathology; Lymphocyte Activation; Lymphocytosis - immunology; Lymphocytosis - therapy; Male; Medical sciences; Middle Aged; next-generation sequencing; plasmablasts; Recurrence; Rituximab; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; somatic hypermutation; Somatic Hypermutation, Immunoglobulin - genetics; Young Adult; plasmablasts; autoreactivity; IgG4-related disease; somatic hypermutation; next-generation sequencing; immunoglobulin heavy chain variable region repertoire; CDR3; rituximab; IgG4-RD; IGHV; IgG 4-related disease; Immunoglobulin heavy chain variable region; IgG 4-RD; Relapse; Variable region; IgG; Monoclonal antibody; Somatic mutation; Immunology; Immunotherapy; Immunologic repertoire; Expansion; Sequencing; related disease; Immunopathology; Heavy peptide chain; Immunoglobulins; Nucleotide sequence; Rituximab; De novo; Complementary determining region 3; Treatment; Plasmablast; IgG4 related disease; IgG-related disease
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2014.03.034

IgG4-related disease (IgG4-RD) is a poorly understood, multiorgan, chronic inflammatory disease characterized by tumefactive lesions, storiform fibrosis, obliterative phlebitis, and accumulation of IgG4-expressing plasma cells at disease sites. The role of B cells and IgG4 antibodies in IgG4-RD pathogenesis is not well defined. We evaluated patients with IgG4-RD for activated B cells in both disease lesions and peripheral blood and investigated their role in disease pathogenesis. B-cell populations from the peripheral blood of 84 patients with active IgG4-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. Numbers of CD19+CD27+CD20−CD38hi plasmablasts, which are largely IgG4+, are increased in patients with active IgG4-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 IgG4 antibodies are self-reactive. Clonally expanded CD19+CD27+CD20−CD38hi plasmablasts are a hallmark of active IgG4-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.