IL-35 is a critical regulator of immunity during helminth infections associated with multiple sclerosis
Author(s): ,
J. Correale
Affiliations:
Neurology, Institute for Neurological Research Dr Raul Carrea, Buenos Aires, Argentina
M.F. Farez
Affiliations:
Neurology, Institute for Neurological Research Dr Raul Carrea, Buenos Aires, Argentina
ECTRIMS Online Library. Correale J. Oct 8, 2015; 115556; 612
Jorge Correale
Jorge Correale
Contributions
Abstract
Abstract: P377

Type: Poster

Abstract Category: Immunology

Background and goals: Helminth-infected MS patients have shown lower disease activity compared with uninfected ones. Parasite regulation of host immunity is mediated, at least in part by the induction of T (Treg) and B regulatory (Breg) cells producing high levels of IL-10. IL-35 is the newest member of the IL-12 family of heterodimeric cytokines, and is composed of an EBI3 b chain subunit, and the IL12 p35 α subunit. Our aim was to investigate the role of IL-35 on Breg and Treg cell induction during parasite infections in MS patients.

Methods: Peripheral blood CD19+ B cells, CD4+CD25- and CD4+CD25high T cells from 16 helminth-infected MS patients, 16 patients without infection, and 16 healthy controls were purified by cell sorting. Production of IL-10, IL-17, IL-35, IFN-g, and TGF-b, as well as activation of STAT1, STAT3, and STAT4 was assessed by ELISA. Proliferation assays were assessed using 3H-thymidine incorporation.

Results: Both IL-10 and IL-35 production by B cells were significantly higher in helminth-infected MS patients than in uninfected MS subjects and healthy controls. Stimulation of B cells with IL-35 promoted conversion to Breg cells producing both IL-35, and IL-10. IL-35 production blockade significantly decreased IL-10 production by Breg cells. Furthermore, co-culture of B cells from helminth-infected MS patients inhibited proliferation of polarized Th1 and Th17 MBP-specific T cell lines, as well as production of IFN-g, and IL-17. Inhibitory effects were significantly decreased by silencing IL-35, and completely abrogated when IL-10 was silenced. Moreover, IL-35 activated STAT1 and STAT3 in Breg cells.

CD4-CD25- T cells activated with anti-αCD3/CD28 in the presence of IL-35 dramatically upregulated EBI3 and IL12A mRNA, the two constituents of IL-35, but not IL-10 or TGFβ, inducing a regulatory population, termed iTR35. Foxp3 was neither induced nor required for iTR35 generation. As occurred with Breg cells, co-culture of polarized Th1 and Th17 MBP- T cell lines together with IL-35-iTR cells, significantly suppressed T cell proliferation, as well as IFN-g and IL-17 production. Neutralizing mAbs to IL-35, but not to IL-10 or TGFβ, blocked suppression capacity. Interestingly, IL-35 activated STAT1, STAT3 and STAT4, in T cells.

Conclusions: The data presented highlights the importance of IL-35 for both Breg and Treg cells, in helminth-infected MS patients, conditioning many of the immunoregulatory effects observed in these patients.

Disclosure:

Jorge Correale is a board member of Merck-Serono Argentina, Biogen-IdecLATAM, and Merck-Serono LATAM, and Genzyme global.

Dr. Correale has received reimbursement for developing educational presentations for Merck-Serono Argentina, Merck-Serono LATAM, Biogen-Idec Argentina, Genzyme Argentina, and TEVA-Tuteur Argentina, as well as professional travel/accommodations stipends.

Mauricio F Farez has received professional travel/accommodations stipends from Merck-Serono Argentina and Novartis Argentina.

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