Interleukin‐35 is a critical regulator of immunity during helminth infections associated with multiple sclerosis

• Published in: Immunology Vol. 164; no. 3; pp. 569 - 586
• Main Authors: Correale, Jorge, Marrodan, Mariano, Carnero Contentti, Edgar
• Format: Journal Article
• Language: English
• Published: Oxford Wiley Subscription Services, Inc 01.11.2021; John Wiley and Sons Inc
• Subjects: Antigens; Autoimmune diseases; CD19 antigen; CD25 antigen; CD4 antigen; Cell activation; Cell proliferation; Cerebrospinal fluid; Cytokines; EAE; Environmental factors; Gene expression; helminths; Helper cells; IL‐10; IL‐35; Immunity; Immunoregulation; Infections; Interferon; Interferon regulatory factor 4; Interleukins; Lymphocytes; Lymphocytes B; Lymphocytes T; Magnetic resonance imaging; Multiple sclerosis; Myelin; Original; Parasites; regulatory B cells; regulatory T cells; Transcription
• ISSN: 0019-2805; 1365-2567; 1365-2567
• DOI: 10.1111/imm.13389

Multiple sclerosis (MS) is currently thought to arise by interactions between genetic susceptibility and environmental factors. Infections in general trigger autoimmune responses causing clinical manifestations of disease. However, as a result of regulatory T (Treg)‐ and regulatory B (Breg)‐cell induction, helminth infections tend to dampen disease activity. IL‐35, the newest member of the IL‐12 family, is an inhibitory cytokine composed of an EBI3β chain subunit, and an IL‐12p35 subunit. The aim of this study was to investigate the role of IL‐35 during parasite infections occurring in individuals with MS. Numbers of IL‐35‐producing Breg cells are higher in CSF from helminth‐infected than from uninfected MS subjects, a finding associated with decreased MRI disease activity. Interestingly, stimulation of CD19+ B cells with IL‐35 promotes conversion of these cells to Breg cells producing both IL‐35 and IL‐10. Coculture of B cells from helminth‐infected MS patients inhibits proliferation of Th1 and Th17 myelin peptide‐specific T cells, as well as production of IFN‐γ and IL‐17. Following activation, CD4+CD25+ Treg cells significantly upregulate expression of EBI3 and IL‐12p35 mRNA. Furthermore, CD4+CD25− T cells activated in the presence of IL‐35 induce a population of cells with regulatory function, known as iTR35. Finally, B cells from normal individuals cultured in vitro in the presence of the helminth antigen SEA increase expression of the transcription BATF, IRF4 and IRF8, acquiring a pattern similar to that of IL‐35 Breg cells. These data highlight the important immunoregulatory effects of IL‐35 on both Breg and Treg cells, observed in helminth‐infected MS subjects. Helminth infections dampen MS disease activity as a result of regulatory B (Breg) and regulatory T (Treg) cells. Helminth antigens induce IL‐35‐ and IL‐10‐producing Breg cells, either directly through TLR ligands or through BCR cross‐linking and CD40 ligation. IL‐35 exerts autocrine and paracrine effects, triggering IL‐10 production and inhibiting Th1 and Th17 effector T‐cell response.