Regulatory Cell Populations in Relapsing-Remitting Multiple Sclerosis (RRMS) Patients: Effect of Disease Activity and Treatment Regimens

Abstract

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) of autoimmune etiology that results from an imbalance between CNS-specific T effector cells and peripheral suppressive mechanisms mediated by regulatory cells (RC). In this research, we collected blood samples from 83 relapsing remitting MS (RRMS) patients and 45 healthy persons (HC), to assess the sizes of their RC populations, including CD4+CD25highFoxp3+ (nTregs), CD3+CD4+HLA−G+, CD3+CD8+CD28−, CD3+CD56+, and CD56bright cells, and how RC are affected by disease activity (acute phase or remission) and types of treatment (methylprednisolone, interferon, or natalizumab). In addition, we isolated peripheral blood mononuclear cells (PBMC) and cultured them with peptides mapping to myelin antigens, to determine RC responsiveness to autoantigens. The results showed decreased levels of nTregs in patients in the acute phase ± methylprednisolone and in remission + natalizumab, but HC levels in patients in remission or receiving interferon. Patients + interferon had the highest levels of CD3+CD4+HLA−G+ and CD3+CD8+CD28− RC, and patients in the acute phase + methylprednisolone the lowest. Patients in remission had the highest levels of CD3+CD56+, and patients in remission + natalizumab the highest levels of CD56bright cells. Only nTregs responded to autoantigens in culture, regardless of disease activity or treatment. The highest suppressive activity was exhibited by nTregs from patients in remission. In conclusion, in RRMS disease activity and type of treatment affect different RC populations. nTregs respond to myelin antigens, indicating that it is possible to restore immunological tolerance through nTreg induction.

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

“…NZ is a humanized monoclonal IgG4 antibody against the alpha-4 subunit of very late antigen-4 (VLA4) of α4β1 and α4β7 integrins [280] that are located on the plasma membrane of lymphocytes and monocytes. NZ is effective in RRMS patients and mainly prevents the infiltration of leukocytes into the MS brain [281], but also more specific effects on immune cells and hematopoietic populations in the CNS have been described [282]. Furthermore, NZ has important additional effects on the MS-affected CNS, including a reduction of oxidative stress and LPS-binding protein (LBP) levels [283], as wells as CSF levels of markers for intrathecal inflammation, axonal damage and demyelination [29].…”

HLA-G Expressing Immune Cells in Immune Mediated Diseases

“…Multiple sclerosis (MS) is an immune-mediated disorder of the central nervous system (CNS) leading to demyelination as well as axonal and neuronal damage, with progressive neurological impairment ( 79 ). The course of MS can follow four clinical patterns that include relapsing remitting MS (RRMS, which accounts for 80–90% of MS cases at onset), secondary progressive MS (SPMS), primary progressive MS (PPMS), and progressive relapsing MS (PRMS) ( 80 ). Although the pathogenesis of MS is still not completely understood, it is known that central tolerance may be defective leading to the development of self-reactive T cells that transmigrate into the CNS where they can be activated by APCs and determine brain damage ( 79 ).…”

“…The main aspect favoring the autoimmune etiology of MS consists of the presence of activated IFN-producing T helper 1 (Th1) cells, that recognize peptides of the myelin sheath, including myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG) ( 80 ). HLA-G immunoreactivity was detected in the transition zone between the plaque center and the perilesional areas as well as in both acute and chronic active plaques.…”

“…The frequency of CSF-derived HLA-G+CD4+ Tregs correlates positively with the disease status in MS patients with active disease ( 22 ). Increased levels of HLA-G+CD4+ Tregs have been detected in MS patients responses to IFN or natalizumab treatment ( 80 ).…”

Fibroblasts as an Alternative to Mesenchymal Stem Cells with Successful Treatment and Immune Modulation in EAE Model of Multiple Sclerosis

“…The condition presents either as relapse remitting, which as the name suggests, undergoes periods of spontaneous remission, or primary progressive disease, in which the disease advances without remission. It is known that remission is associated with reduction of pathogenic T cells and upregulation of number and activity of T regulatory (Treg) cells (1), while progression is associate with augmentation of myelin-reactive T cells and suppression of Treg activity and number (2). Current treatments for MS include non-specific immune modulators such as Avonex, Capaxone, Rebif, Tysabri and Campath (3).…”