T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by the progressive loss of axonal myelin in several areas of the central nervous system (CNS) that is responsible for clinical symptoms such as muscle spasms, optic neuritis, and paralysis. The progress made in more than one decade of research in animal models of MS for clarifying the pathophysiology of MS disease validated the concept that MS is an autoimmune inflammatory disorder caused by the recruitment in the CNS of self-reactive lymphocytes, mainly CD4+ T cells. Indeed, high levels of T helper (Th) cells and related cytokines and chemokines have been found in CNS lesions and in cerebrospinal fluid (CSF) of MS patients, thus contributing to the breakdown of the blood–brain barrier (BBB), the activation of resident astrocytes and microglia, and finally the outcome of neuroinflammation. To date, several types of Th cells have been discovered and designated according to the secreted lineage-defining cytokines. Interestingly, Th1, Th17, Th1-like Th17, Th9, and Th22 have been associated with MS. In this review, we discuss the role and interplay of different Th cell subpopulations and their lineage-defining cytokines in modulating the inflammatory responses in MS and the approved as well as the novel therapeutic approaches targeting T lymphocytes in the treatment of the disease.

A validated generally applicable approach using the systematic assessment of disease modules by GWAS reveals a multi-omic module strongly associated with risk factors in multiple sclerosis

“…As we used GWAS enrichment as a selection criterion, the high GWAS enrichment of the final module was partly expected, which led us to analyze its biological functions and their potential epigenetic associations to MS. First, pathway enrichment analysis showed that the multi-omics module genes are significantly involved in several inter-linked immune-related pathways, most of which have been previously associated to MS, including the T cell receptor(Carbone et al 2014) (adjusted P = 3.6 x 10 -47 ), PI3K/Akt (Mammana et al 2018) (P = 4.6 x 10 -35 ), ErbB (Holley et al 2003) (P = 7.7 x 10 -32 ), Fc epsilon RI (Pedotti et al 2003) (P = 8.3 x 10 -30 ), chemokine (Cui et al 2020;Krumbholz et al 2006) (P = 2.6 x 10 -28 ), MAPK (Krementsov et al 2013;Kotelnikova et al 2019) (P = 2.0 x 10 -25 ), and B cell receptor (Kotelnikova et al 2019) (P = 3.9 x 10 -19 ) signaling pathways; Th17 (P = 9.6 x 10 -29 ), and Th1 and Th2 (P = 6.9 x 10 -19 ) cell differentiation (Kunkl et al 2020); natural killer cell mediated cytotoxicity (P = 1.6 x 10 -27 ); and leukocyte transendothelial migration (P = 3.9 x 10 -20 ), which indeed supports their relevance in MS. Interestingly, the module was also highly preprint (which was not certified by peer review) is the author/funder. All rights reserved.…”

CD28 Autonomous Signaling Orchestrates IL-22 Expression and IL-22-Regulated Epithelial Barrier Functions in Human T Lymphocytes

“…IL-22 is an important cytokine that strengthen epithelial barrier functions against extracellular pathogen and regulates tissue homeostasis and repair. However, excessive production of IL-22 has been also associated with severe complications in several pathogen infections ( 12 ), including the recently identified Sars-Cov2 ( 18 ) as well as with inflammatory bowel diseases such as Crohn’s disease ( 23 ), neurological disorders such as MS and Guillain-Barrè syndrome ( 25 , 26 ), and rheumatoid arthritis ( 53 , 54 ). Therefore, the identification of receptors and associated signaling mediators regulating IL-22 expression could represent an important goal of the ongoing research in inflammation and autoimmunity.…”

“…More recently, a novel severe acute respiratory syndrome-related coronavirus 2 (SARS-Cov2) has been identified as the etiological agent of COVID-19 (16), a respiratory pandemic disease that, in several patients, causes ARDS associated with high levels of pro-inflammatory cytokines (17) including Th17 cytokines such as IL-22, IL-17, and IL-6 (18,19). Moreover, an excessive production of IL-22 together with other cytokines of the Th17 signature has also been involved in maintaining and amplifying the chronic state of several inflammatory and autoimmune diseases (20)(21)(22)(23)(24)(25)(26). Therefore, the identification of stimulatory molecules and associated signaling pathways regulating and/or amplifying IL-22 production may provide new insight into immune defense against pathogens and novel therapeutic targets for inflammatory and autoimmune diseases.…”

COVID-19: dealing with a potential risk factor for chronic neurological disorders

“…Nevertheless, unbalance of peripheral lymphocyte subsets induced by COVID-19, and in particular B cell overshooting, may hypothetically represent an additional risk for MS relapses in patients with pre-existing diagnosis, as observed in similar immunological framework [55]. The "cytokine storm" in response to the SARS-CoV2 infection may promote a switch toward a pro-inflammatory status of T cell subsets, such as Th17, which are implicated in MS pathogenesis [56] COVID-19 may indeed trigger MS or its clinical manifestation also through other mechanisms. In MS, intestinal dysbiosis and changes in intestinal permeability are increasingly recognized as modulators of neuroinflammatory mechanisms through the so-called gut-brain axis [57].…”