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 CD11bhigh 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.
Highlights
Multiple sclerosis (MS) is a chronic demyelinating and neurodegenerative autoimmune disease of the central nervous system (CNS) that frequently begins between 20 and 40 years of age
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 have found a significantly lower percentage (%) of monocytes (CD11bhighCD4mid) and dendritic cells (DCs) (CD1chighCD11blow) expressing TYRO3 in patients with MS compared to helminth infections and MS condition (HIMS) or healthy control (HC) groups (Fig 1B, 1C, 1E and 1F, respectively)
Summary
Multiple sclerosis (MS) is a chronic demyelinating and neurodegenerative autoimmune disease of the central nervous system (CNS) that frequently begins between 20 and 40 years of age. A strong correlation exists with certain HLA II alleles (mainly HLA-DRB1 15:01 and DRB5 01:01), pointing directly to CD4+ T cells as key players in MS [1,2,3]. Evidence shows that both Th1 and Th17 subsets are necessary for both the onset and progression of the disease. During the last century in developed countries, a significant increase in autoimmune and allergic diseases has been observed [9] that cannot be attributed to significant genetic alterations, implying a critical environment change occurred in this period. Factors may influence disease onset at any time in the life of an individual and affect relapse rates in patients presenting relapsing-remitting forms of MS [10]
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