IL-35 is a critical regulator of immunity during helminth infections associated with multiple sclerosis
Author(s): ,
J. Correale
Neurology, Institute for Neurological Research Dr Raul Carrea, Buenos Aires, Argentina
M.F. Farez
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
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.


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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