Immune deficiencies, infection, and systemic immune disorders
IL-10 mediates plasmacytosis-associated immunodeficiency by inhibiting complement-mediated neutrophil migration

https://doi.org/10.1016/j.jaci.2015.10.018Get rights and content

Background

Plasmacytosis (ie, an expansion of plasma cell populations to much greater than the homeostatic level) occurs in the context of various immune disorders and plasma cell neoplasia. This condition is often associated with immunodeficiency that causes increased susceptibility to severe infections. Yet a causative link between plasmacytosis and immunodeficiency has not been established.

Objective

Because recent studies have identified plasma cells as a relevant source of the immunosuppressive cytokine IL-10, we sought to investigate the role of IL-10 during conditions of polyclonal and neoplastic plasmacytosis for the regulation of immunity and its effect on inflammation and immunodeficiency.

Methods

We used flow cytometry, IL-10 reporter (Vert-X) and B cell–specific IL-10 knockout mice, migration assays, and antibody-mediated IL-10 receptor blockade to study plasmacytosis-associated IL-10 expression and its effect on inflammation and Streptococcus pneumoniae infection in mice. ELISA was used to quantify IL-10 levels in patients with myeloma.

Results

IL-10 production was a common feature of normal and neoplastic plasma cells in mice, and IL-10 levels increased with myeloma progression in patients. IL-10 directly inhibited neutrophil migration toward the anaphylatoxin C5a and suppressed neutrophil-dependent inflammation in a murine model of autoimmune disease. MOPC.315.BM murine myeloma leads to an increased incidence of bacterial infection in the airways, which was reversed after IL-10 receptor blockade.

Conclusion

We provide evidence that plasmacytosis-associated overexpression of IL-10 inhibits neutrophil migration and neutrophil-mediated inflammation but also promotes immunodeficiency.

Section snippets

Mice

C57BL/6 and BALB/c mice were purchased from Charles River (Bar Harbor, Me). IL-10 reporter (Vert-X), BALB/c forkhead box protein 3 (Foxp3) reporter (Foxp3eGFP), and CD19 Cre/IL-10 flox/flox mice and their littermate controls were bred at the animal facility of the University of Lübeck. Experiments were performed at the animal facilities of the Universities of Lübeck and Greifswald.

Experimental epidermolysis bullosa acquisita and polyclonal plasmacytosis

Epidermolysis bullosa acquisita was induced by means of subcutaneous immunization and scored, as previously

Polyclonal and neoplastic plasmacytosis is associated with increased IL-10 production

B lineage cells with a CD138hi plasma cell/plasmablast phenotype can significantly contribute to IL-10 production and thereby control T cell–mediated autoimmune inflammation.28 Here, we first tested the possibility that plasmacytosis increases production of immunosuppressive IL-10. This cytokine was detectable in sera from 6 of 8 patients with advanced myeloma. In contrast, it was present only at a relatively low level in 1 of 7 healthy control subjects and undetectable in patients exhibiting

Discussion

Recent studies identified plasma cells as a relevant source of IL-10 that can control T cell–mediated inflammation.27, 28 The present study extends these findings and demonstrates that polyclonal and neoplastic plasmacytosis-associated IL-10 mediates suppression of effective neutrophil function. Even moderate GMD-induced polyclonal plasmacytosis was sufficient to block neutrophil-mediated inflammation and pathophysiology in an autoimmune setting, whereas neutrophil migration was completely

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    Supported by the Excellence Cluster “Inflammation at Interfaces,” the IRTG 1911, and the GRK1727. D.M.W. was supported by an internal program grant of the University of Lübeck. U.K. was supported by the priority program of the University of Lübeck “SPP-MIA.” F.D.F. is supported by the US Department of Veterans Affairs. K.B. received support from DFG-KFO 21.

    Disclosure of potential conflict of interest: U. Kulkarni receives travel support from The German Research Foundation. B. Tiburzy, L. Meng, R. J. Ludwig, K. Pollok, F. D. Finkelman, J. Köhl, and R. A. Manz receive research support from the German Research Foundation. T. Kamradt receives research support from Novartis Germany. C. Langer serves on the Advisory Board for Celegene, Janssen and Bristol-Myers Squibb. F. D. Finkelman is an Associate Editor of the Journal of Allergy and Clinical Immunology. The rest of the authors declare that they have no relevant conflicts of interest.

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