Current multiple sclerosis treatments have improved our understanding of MS autoimmune pathogenesis

Abstract

Multiple sclerosis (MS) is the most common inflammatory disorder of the central nervous system (CNS) in young adults. When MS is not treated, it leads to irreversible and severe disability. The etiology of MS and its pathogenesis are not fully understood. The recent discovery that MS-associated genetic variants code for molecules related to the function of specific immune cell subsets is consistent with the concept of MS as a prototypic, Tcell-mediated autoimmune disease targeting the CNS. While the therapeutic efficacy of the currently available immunomodulatory therapies further strengthen this concept, differences observed in responses to MS treatment as well as additional clinical and imagingobservations have also shown that the autoimmune pathogenesis underlying MS is much more complex than previously thought. There is therefore an unmet need for continued detailed phenotypic and functional analysis of disease-relevant adaptive immune cells and tissues directly derived from MS patients to unravel the immune etiology of MS in its entire complexity. In this review, we will discuss the currently available MS treatment options and approved drugs, including how they have contributed to the understanding of the immune pathology of this autoimmune disease.Keywords: Autoantibodies r Autoimmune pathogenesis r Autoimmunity r Autoreactive B cells r Autoreactive T cells r Experimental autoimmune encephalomyelitis r Multiple sclerosis r Treatment Introduction-MS as an autoimmune diseaseMS is considered a prototypic organ-specific autoimmune disease targeting the CNS with inflammatory lesions, demyelination, axonal/neuronal damage, and metabolic changes [1,2]. Relapsing-remitting and secondary progressive MS (RRMS, SPMS) are the two most frequent forms of MS, which often affect young adults between 20 and 40 years of age, and women three times more often than men [3]. Typical clinical signs include temporary loss of vision, sensory and motor problems, but also fatigue, neurocognitive changes, and impairment of bladder, bowel, and Correspondence: Britta Engelhardt ; Roland Martin e-mail: bengel@tki.unibe.ch; roland.martin@usz.ch sexual functions. During the relapsing-remitting phase neurological deficits, which occur in bouts and may last from days to a few weeks, usually disappear again, but after several years, disability gradually builds up. Depending on the individual course this secondary progressive disease with continuously increasing disability may never set in, but often starts after 15-20 years of RRMS. In a small percentage of patients such a progressive course is seen from the beginning, which is referred to as primary progressive MS (PPMS) and seen in females and males with equal frequency [3].Evidence for an autoimmune pathogenesis of MS was shown in its animal model, experimental autoimmune encephalomyelitis (EAE) (summarized in [4,5] Treatments of MSAs already noted above, the various treatments of MS deserve particular mentioning not only because they have changed clinical practice and can be considered ...

No Evidence of Disease Activity after Five Years of Autologous Hematopoietic Stem Cell Therapy for Multiple Sclerosis: Detailed Report of Five Patients

“…Multiple sclerosis (MS) is the most prevalent chronic inflammatory disease that affects the central nervous system (CNS) and is considered to be the prototype disease immune-mediated by auto-reactive T cell [1]. Inflammatory reaction targeting self CNS myelin and axonal proteins evolves to demyelination and degeneration in multiple areas of white and gray matter, which leads to progressive disability in genetically susceptible young people [2].…”

“…The pathophysiology currently accepted is that myelin-reactive T cells are activated in the peripheral circulation or peripheral lymph nodes by antigens with which susceptible hosts had been in contact, possibly during childhood, constituting a breach of auto-tolerance to CNS antigen [1]. Later, these T cells cross the blood-brain barrier and encounter the myelin antigen in the CNS parenchyma, presented by activated microglia, starting an inflammatory response that causes myelin destruction and axon degeneration [1].…”

“…Later, these T cells cross the blood-brain barrier and encounter the myelin antigen in the CNS parenchyma, presented by activated microglia, starting an inflammatory response that causes myelin destruction and axon degeneration [1]. As other antigens become exposed through cell destruction, epitope spreading or activation of T cells against multiple other antigens occurs, and the inflammation is thus perpetuated in the inflammatory reaction.…”

Metalloproteinases and their inhibitors as therapeutic targets for multiple sclerosis: current evidence and future perspectives

“…2 Therefore, many attempts have been made to downregulate MMP activity and expression in order to limit tissue damage occurring in MS ( Table 1). The current management of MS patients is challenging and includes pharmacotherapy with corticosteroids, antibodies (Abs) and immunomodulant and immunosuppressive drugs 3 (Box 1). All the therapies currently used can only slow disease progression Note: *The list of MMP inhibitors is not exhaustive; it refers to drugs and compounds used for the treatment of MS in clinical trials and in human and animal studies and to those cited in the paper.…”

RANKL/RANK/OPG Axis Is Deregulated in the Cerebrospinal Fluid of Multiple Sclerosis Patients at Clinical Onset

“…In MS, cytokines and chemokines produced by activated myelin-reactive CD4+ helper T (Th) lymphocytes play a crucial role in triggering the disease onset, as well as in further development of the disease. Disturbed cytokine network is marked by upregulated proinflammatory cytokines such as interleukin (IL)-6, IL-17, IL-1, IL-22 and tumor necrosis factor (TNF)-α, and downregulated immunosuppressive cytokines including IL-3 and IL-10 [3][4][5]. In addition, immunomodulatory and chemotactic effects of chemokine signals have a role in MS pathogenesis and the migration of inflammatory cells to the site of demyelinating lesions [6].…”