1. GAS6 signaling tempers Th17 development in patients with multiple sclerosis and helminth infection.
- Author
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Ortiz Wilczyñski, Juan M., Olexen, Cinthia M., Errasti, Andrea E., Schattner, Mirta, Rothlin, Carla V., Correale, Jorge, and Carrera Silva, Eugenio A.
- Subjects
HELMINTHIASIS ,T helper cells ,MULTIPLE sclerosis ,INFLAMMATION ,GENETIC regulation ,PROTEIN-tyrosine kinases - Abstract
Multiple sclerosis (MS) is a highly disabling neurodegenerative autoimmune condition in which an unbalanced immune response plays a critical role. Although the mechanisms remain poorly defined, helminth infections are known to modulate the severity and progression of chronic inflammatory diseases. The tyrosine kinase receptors TYRO3, AXL, and MERTK (TAM) have been described as inhibitors of the immune response in various inflammatory settings. We show here that patients with concurrent natural helminth infections and MS condition (HIMS) had an increased expression of the negative regulatory TAM receptors in antigen-presenting cells and their agonist GAS6 in circulating CD11b
high and CD4+ T cells compared to patients with only MS. The Th17 subset was reduced in patients with HIMS with a subsequent downregulation of its pathogenic genetic program. Moreover, these CD4+ T cells promoted lower levels of the co-stimulatory molecules CD80, CD86, and CD40 on dendritic cells compared with CD4+ T cells from patients with MS, an effect that was GAS6-dependent. IL-10+ cells from patients with HIMS showed higher GAS6 expression levels than Th17 cells, and inhibition of phosphatidylserine/GAS6 binding led to an expansion of Th17 effector genes. The addition of GAS6 on activated CD4+ T cells from patients with MS restrains the Th17 gene expression signature. This cohort of patients with HIMS unravels a promising regulatory mechanism to dampen the Th17 inflammatory response in autoimmunity. Author summary: Helminths have co-evolved with human civilization, and the rapid exclusion from their environment, in the last few decades, has tremendously affected the immune development and regulation. Moreover, several epidemiological studies have shown an inverse correlation between the exposure of these organisms and the development of autoimmunity in industrialized countries. In this sense, helminth therapy appears to be a promising concept to oppose chronic inflammatory and autoimmune diseases because they are master manipulators of host immunity, albeit the mechanisms remain poorly defined. For this reason, it is essential to decipher the main regulatory pathways to hijack the immune response in the absence of parasite infection. Our research described how helminth infection promotes regulatory mechanisms based on the tyrosine kinase TYRO3, AXL, MERTK (TAM) receptors, and their ligand GAS6 to dampen Th17 development and the inflammatory response in patients with multiple sclerosis (MS), a neurodegenerative autoimmune disorder. We show here that GAS6 plays a critical role in the regulation of pro-inflammatory cytokines, transcriptional programs, and plasticity of IL-17 subset. Our work substantiates the hypothesis that enhancing the TAM axis in a manner similar to helminth infection could be a promising alternative for autoimmune diseases. [ABSTRACT FROM AUTHOR]- Published
- 2020
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