Multiple Sclerosis CD49d+CD154+ As Myelin-Specific Lymphocytes Induced During Remyelination.

Paweł Piatek,Mariola Matysiak,Magdalena Namiecinska,Marek Wieczorek,Przemysław Lewkowicz,Natalia Lewkowicz,Sylwia Michlewska,Maciej Tarkowski,Małgorzata Domowicz

doi:10.3390/cells9010015

Abstract

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS) mediated by autoreactive lymphocytes. The role of autoreactive lymphocytes in the CNS demyelination is well described, whereas very little is known about their role in remyelination during MS remission. In this study, we identified a new subpopulation of myelin-specific CD49d+CD154+ lymphocytes presented in the peripheral blood of MS patients during remission, that proliferated in vitro in response to myelin peptides. These lymphocytes possessed the unique ability to migrate towards maturing oligodendrocyte precursor cells (OPCs) and synthetize proinflammatory chemokines/cytokines. The co-culture of maturing OPCs with myelin-specific CD49d+CD154+ lymphocytes was characterized by the increase in proinflammatory chemokine/cytokine secretion that was not only a result of their cumulative effect of what OPCs and CD49d+CD154+ lymphocytes produced alone. Moreover, maturing OPCs exposed to exogenous myelin peptides managed to induce CD40-CD154-dependent CD49d+CD154+ lymphocyte proliferation. We confirmed, in vivo, the presence of CD49d+CD154+ cells close to maturating OPCs and remyelinating plaque during disease remission in the MS mouse model (C57Bl/6 mice immunized with MOG35-55) by immunohistochemistry. Three weeks after an acute phase of experimental autoimmune encephalomyelitis, CD49d+/CD154+ cells were found to be co-localized with O4+ cells (oligodendrocyte progenitors) in the areas of remyelination identified by myelin basic protein (MBP) labelling. These data suggested that myelin-specific CD49d+CD154+ lymphocytes present in the brain can interfere with remyelination mediated by oligodendrocytes probably as a result of establishing proinflammatory environment.

Highlights

Multiple sclerosis (MS) is an autoimmune lymphocyte-dependent demyelinating disease of the central nervous system (CNS)
Using flow cytometry, we analyzed the rate of CD49d+ CD154+ lymphocytes in Peripheral blood mononuclear cells (PBMCs) isolated from Relapsing-remitting MS (RR-MS) patients during the disease remission or in healthy controls (HCs)
We found that RR-MS PBMCs contained more CD49d+ CD154+ lymphocytes in comparison to HC PBMCs (1.2% vs. 0.4%), and the number of CD49d+ CD154+ lymphocytes was further increased (2.8–3.3%) after the incubations of RR-MS PBMCs with myelin peptides (Figure 1A)

Summary

Introduction

Multiple sclerosis (MS) is an autoimmune lymphocyte-dependent demyelinating disease of the central nervous system (CNS). Relapse mainly involves the brain areas previously affected by the disease where gradual, extensive processes of demyelination and irreversible neuron impairment had already taken place [3]. Slow but constant progression of the disease is caused by inefficient and only partial regeneration of the myelin sheath around the neuronal axons after primary attack or relapse [4]; what still remains is the unsolved aspect of MS pathology. This might be a result of incomplete clearance of inflammatory cells from the brain during disease remission or proliferation of autoreactive cells within remyelinating plaques. Autoreactive myelin-specific lymphocytes might migrate from the periphery to the CNS, preferably to the areas of previous demyelination [5]

Methods

Results

Conclusion