Fingolimod has recently been approved for the therapy of relapsing multiple sclerosis. This drug binds to different sphingosine-1-phosphate receptors.
To analyze basic mechanisms of action that can account for the efficacy of this drug in multiple sclerosis.
Fingolimod acts as an inverse agonist on sphingosine-1-phosphate receptors, inducing degradation of receptors. On lymphoid circulation, this effect causes retention in lymph nodes of naive and central memory T cells, including Th17 T lymphocytes, bearing CCR7 and CD62L receptors. As a result, the level of circulating T cells is markedly decreased. B ell circulation is impaired and complex effects on other immune cells are also induced. Fingolimod enters the central nervous system and binds to receptors on glial cells and neurons. In experimental autoimmune encephalomyelitis, the therapeutic efficacy of fingolimod is not only associated with a reduced entry of inflammatory cells into the nervous system, but also with a direct effect mostly on astroglial cells.
In multiple sclerosis patients, the available evidence indicates that fingolimod efficacy is directly associated with impairment of circulation of several T cell subsets and possibly B cells. Animal studies raise the possibility that an additional effect on glial cells might also contribute to the clinical efficacy.
[Show abstract][Hide abstract] ABSTRACT: The scientific advances regarding the ethiopathogenesis and physiopathology of multiple sclerosis are so fast that periodic update of concepts is awaited. Moreover, new epidemiological data and criteria improving differential diagnosis have been described. The objective of this review is to update concepts about epidemiology, ethiopathogenesis, physiopathology and differential diagnosis of multiple sclerosis. Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system more frequent in young ages and in the female sex, the incidence of which increases with latitude. Recent studies indicate an increase in the incidence and earlier onset in women. Although the cause of the disease is unknown, genetic and environmental risk factors have been identified. The HLA allele HLA-DRB1*15 is the genetic factor more strongly associated with the risk of developing multiple sclerosis; the better established environmental factors are the exposition to the Epstein-Barr virus, smoking and vitamin D levels. The combination of environmental factors with a certain individual genetic predisposition, discloses an immunological dysregulation. Multiple sclerosis is considered to be mediated by T cells and its physiopathology is complex, intervening various immunological factors. From adaptive immunity, it must be emphasized the role of Th17 populations, with secretion of proinflammatory cytokines, cytotoxic T CD8+ and B lymphocytes. The innate immunity also participates in multiple sclerosis immunopathogenesis, mainly through microglia activation. The action of humoral and cellular changes induces focal inflammation with demyelination and axonal damage pointing to a dual face - inflammatory and degenerative - of the disease. Despite the natural repair mechanisms leading to remyelination and axonal recovery, in later stages this ability becomes exhausted and disease progresses. The absence of specific diagnostic biomarkers for multiple sclerosis imposes the exclusion of other inflammatory diseases with neurological involvement, especially when a first demyelinating event occurs - clinically isolated syndrome. The main neurological manifestations appearing in that condition that allow to support or reject the diagnosis of multiple sclerosis are described. The characteristic clinical and paraclinical data of other idiopathic demyelinating (neuromyelitis optica, acute disseminated encephalomyelitis, acute transverse myelitis, optic neuritis) and systemic inflammatory disorders with neurological involvement (systemic erythematous lupus, Behçet's disease, Sjögren'disease) are presented. In conclusion, the knowledge of the factors that contribute to the development of multiple sclerosis and the pathological processes taking place in the nervous system favours a better understanding of the disease and the discovery of new immunotherapeutic targets. The precise diagnosis of multiple sclerosis requires a rigorous systematization of differential diagnoses.
Sinapse 01/2012; 12(2):5-14.
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