Multiple Sclerosis and T Lymphocytes: An Entangled Story

Abstract

Multiple sclerosis (MS) is the prototypic inflammatory disease of the central nervous system (CNS) characterized by multifocal areas of demyelination, axonal damage, activation of glial cells, and immune cell infiltration. Despite intensive years of research, the etiology of this neurological disorder remains elusive. Nevertheless, the abundance of immune cells such as T lymphocytes and their products in CNS lesions of MS patients supports the notion that MS is an immune-mediated disorder. An important body of evidence gathered from MS animal models such as experimental autoimmune encephalomyelitis (EAE), points to the central contribution of CD4 T lymphocytes in disease pathogenesis. Both Th1 (producing interferon-γ) and Th17 (producing interleukin 17) CD4 T lymphocytes targeting CNS self-antigens have been implicated in MS and EAE pathobiology. Moreover, several publications suggest that CD8 T lymphocytes also participate in the development of MS lesions. The migration of activated T lymphocytes from the periphery into the CNS has been identified as a crucial step in the formation of MS lesions. Several factors promote such T cell extravasation including: molecules (e.g., cell adhesion molecules) implicated in the T cell-blood brain barrier interaction, and chemokines produced by neural cells. Finally, once in the CNS, T lymphocytes need to be reactivated by local antigen presenting cells prior to enter the parenchyma where they can initiate damage. Further investigations will be necessary to elucidate the impact of environmental factors (e.g., gut microbiota) and CNS intrinsic properties (e.g., microglial activation) on this inflammatory neurological disease.

Intracranial delivery of interleukin-17A via adeno-associated virus fails to induce physical and learning disabilities and neuroinflammation in mice but improves glucose metabolism through AKT signaling pathway

“…As seen in humans, certain behavioral changes can be observed in EAE mice (Acharjee et al, 2013; Franco-Pons et al, 2007; Jones et al, 2008; Legroux and Arbour, 2015; Moore et al, 2014; Serra-de-Oliveira et al, 2015; Ulrich et al, 2010; Wang et al, 2013). Clinical signs and paralysis in EAE mice are scored on a scale from 0 (clinically normal) to 5 (moribund) (Miller et al, 2010).…”

“…The mounting evidence suggests that T helper 1 (Th1) and T helper 17 (Th17) cells are the main immunological players, resulting in experimental autoimmune encephalomyelitis (EAE) and MS (Babaloo et al, 2015; Hofstetter et al, 2009; Legroux and Arbour, 2015; Liu et al, 2014; Platten et al, 2009; Tzartos et al, 2008; Wang et al, 2009). Th1 cells, however, migrate across the blood-brain barrier into the CNS less efficiently than Th17 cells (Kebir et al, 2007; Marwaha et al, 2012).…”

Co-delivery of autoantigen and dexamethasone in incomplete Freund's adjuvant ameliorates experimental autoimmune encephalomyelitis

“…Both MS and the murine model of the disease, experimental autoimmune encephalomyelitis (EAE), are believed to be primarily Th1 and T-helper type-17 (Th17)-mediated [17, 18]. Utilizing an adjuvant initially developed for protective vaccination against foreign pathogens, incomplete Freund’s adjuvant (IFA), studies have shown a shift from an autoantigen-specific Th1/Th17 towards a Th2/humoral response resulting in the suppression of autoimmune disease in animals [19, 20].…”

Characterization of variations in IL23A and IL23R genes: possible roles in multiple sclerosis and other neuroinflammatory demyelinating diseases

“…MS is considered the prototype [2] of IDD and affects over 2 million people worldwide [3]. The main manifestations of MS are transient and recurrent bouts of handicap[2], affecting mostly young adults with a strong sex bias of female to male about 4:1 [4], but the molecular mechanisms of IDD are essentially unclear.…”

“…Complex interactions between genetic and environmental factors play key roles in the inflammatory process of the diseases [2] or influence the susceptibility to these diseases [5]. Many lines of clinical and experimental evidence have shown the involvement of the immune system in IDD, especially MS [6].…”