Mechanisms of allergy and clinical immunology
De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease

https://doi.org/10.1016/j.jaci.2014.03.034Get rights and content

Background

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.

Objective

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.

Methods

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.

Results

Numbers of CD19+CD27+CD20CD38hi 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.

Conclusions

Clonally expanded CD19+CD27+CD20CD38hi 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.

Section snippets

Patients

This study was approved by the institutional review board, and informed written consent was obtained from all patients with IgG4-RD referred to or presenting at the rheumatology clinic of the Massachusetts General Hospital. Samples from 84 patients with IgG4-RD were chosen for this study (organ involvement and patients' demographics are listed in Table E1 in this article’s Online Repository at www.jacionline.org). Patients with IgG4-RD were compared with 16 healthy control subjects (age, 32-70

Expansion of plasmablasts in patients with IgG4-RD

Immunohistochemical analysis of IgG4-RD lesions frequently reveals the presence of CD20+ B-cell follicles surrounded by CD19+CD20 cells with variable expression of IgG4. These latter cells could be either tissue plasmablasts or plasma cells (Fig 1, A). Flow cytometric analysis of the peripheral blood revealed large expansions of CD19+CD27+CD38hi plasmablasts in multiple patients with IgG4-RD (Fig 1, B). The plasmablasts are negative for CD20 and largely surface IgG4+ and express high levels of

Discussion

Expanded populations of oligoclonal CD19+CD20CD27+CD38+ plasmablasts represent perhaps the best available indication of IgG4-RD disease activity, especially because serum IgG4 levels are not always increased in patients with this disease. The fact that IgG4 antibodies are generally considered to be noninflammatory has made it difficult to cogently postulate a role for these antibodies in the disease process. The tight correlation between the loss of circulating IgG4+ plasmablasts and clinical

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    Supported by grants AI 064930 and AI 076505 from the National Institutes of Health and a pilot grant from the Harvard Institute of Translational Immunology supported by the Helmsley Charitable Trust (to S.P.).

    Disclosure of potential conflict of interest: H. Mattoo and V. S. Mahajan have received research support from the National Institutes of Health. J. H. Stone has received research support and consultancy fees from Genentech and Roche. S. Pillai has received research support from the National Institutes of Health and Pfizer, has received consulting fees from Genentech, and has received consultancy fees from Abide Pharmaceuticals. The rest of the authors declare that they have no relevant conflicts of interest.

    These authors contributed equally to this work.

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