IL-10 mediates plasmacytosis-associated immunodeficiency by inhibiting complement-mediated neutrophil migration

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• 作者：Upasana Kulkarni ; PhD^a ; ^b ; Christian M. Karsten ; PhD^a ; Thomas Kohler ; PhD^c ; Sven Hammerschmidt ; PhD^c ; Kurt Bommert ; PhD^d ; Benjamin Tiburzy ; MS^a ; Lingzhang Meng ; MS^a ; Lara Thieme ; MS^a ; Andreas Recke ; MD^e ; Ralf J. Ludwig ; MD^e ; Karolin Pollok ; MS^f ; Kathrin Kalies ; PhD^g ; Bjarne Bogen ; MD ; PhD^h ; Martin Boettcher ; PhD^b ; Thomas Kamradt ; MD^b ; Anja E. Hauser ; PhD^f ; Christian Langer ; MDⁱ ; Markus Huber-Lang ; MD^j ; Fred D. Finkelman ; MD^k ; ^l ; J&ouml ; rg K&ouml ; hl ; MD^a ; ^l ; David M. Wong ; PhD^a ; Rudolf Armin Manz ; PhD^a ; ^{Rudolf.Manz@uksh.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Plasmacytosis ; IL-10 ; immunodeficiency ; neutrophil ; inflammation
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：137
• 期：5
• 页码：1487-1497.e6
• 全文大小：3213 K

文摘

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 m>Streptococcus pneumoniaem> 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.