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

Abstract

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.

Evaluation of IL-35, as a Possible Biomarker for Follow-Up after Therapy, in Chronic Human Schistosoma Infection

“…No significant differences in IL-35 were found between single and co-infected S. mansoni patients, thereby discounting any confounding factor of co-infection for this cytokine. This general scenario aligns with the balance of the pro-and anti-inflammatory cytokines already reported in other helminth human infections [48].…”

IL-17 and IL-17-producing cells in protection versus pathology

“…Infection of mice with the helminth Fasciola hepatica suppresses T H 17 cells and γδT17 cells that mediate EAE through helminth induction of TGFβ 187 , type 2 cytokines and eosinophils 188 . In humans, helminth infections can reduce disease severity in patients with MS and this has been linked with IL-35 production by regulatory B cells 189 .…”

Characterization of Definitive Regulatory B Cell Subsets by Cell Surface Phenotype, Function and Context

“…A third study reported that IL-35 was higher in MS patients as compared to healthy controls (79). In a fourth study, MS patients infected with helminths had higher levels of IL-35-producing B cells in the CSF, which correlated with reduced MRI lesions, as compared to uninfected patients (80). In vitro studies, showed that IL-35 could drive IL-35 and IL-10 production by CD19 + B cells and induce a Treg-like phenotype (80).…”

“…In a fourth study, MS patients infected with helminths had higher levels of IL-35-producing B cells in the CSF, which correlated with reduced MRI lesions, as compared to uninfected patients (80). In vitro studies, showed that IL-35 could drive IL-35 and IL-10 production by CD19 + B cells and induce a Treg-like phenotype (80). While these studies are interesting, the lack of definitive B cell phenotyping limits impact.…”