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New treatments for multiple sclerosis (MS) focused on B cells have created an atmosphere of excitement in the MS community. B cells are now known to play a major role in disease, demonstrated by the highly impactful effect of a B cell-depleting antibody on controlling MS. The idea that a virus may play a role in the development of MS has a long history and is supported mostly by studies demonstrating a link between B cell-tropic Epstein–Barr virus (EBV) and disease onset. Efforts to develop antiviral strategies for treating MS are underway. Although gaps remain in our understanding of the etiology of MS, the role, if any, of viruses in propagating pathogenic immune responses deserves attention. Clinical studies show that depletion of B cells reduces disease burden in both relapsing-remitting and progressive multiple sclerosis (MS) patients. B cell-tropic viruses may trigger aberrant immune responses in MS in genetically susceptible individuals owing, in part, to a failure in viral surveillance and clearance. The most compelling data supporting an etiologic role for viral involvement in MS have emerged for Epstein–Barr virus (EBV). Targeting mechanisms by which EBV is thought to participate in MS pathogenesis provides an opportunity for new drug development in MS. [ABSTRACT FROM AUTHOR]

Epstein-Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies: (Trends in Molecular Medicine, 26:3 p:296-310, 2020). [Extracted from the article]

Abstract: It has been noted since 1981 that late primary infection with the Epstein–Barr virus (EBV) in adolescence or young adulthood can account for the epidemiology of multiple sclerosis (MS), including the association with higher socio-economic status, the latitudinal variation in prevalence, the effects of migration on the risk of acquiring MS, and the occurrence of clusters and epidemics. Virtually all (>99%) people with MS are EBV seropositive, suggesting that EBV infection is essential for the development of MS. The EBV-infected autoreactive B-cell hypothesis of autoimmunity published in 2003 proposes that, in genetically susceptible individuals, EBV-infected autoreactive B cells seed the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells. This hypothesis makes several predictions, some of which have been verified in the case of MS, namely: the presence of EBV-infected B cells in the central nervous system; a beneficial response to B-cell depletion with rituximab; and decreased CD8+ T-cell immunity to EBV-infected B cells. The hypothesis also predicts that chronic autoimmune diseases will respond to treatment which controls EBV infection. Thus it is proposed that vaccination against EBV will prevent MS, and that effective antiviral drugs will inhibit disease progression in people with MS and potentially be curative. [Copyright &y& Elsevier]

Summary: This study was performed to determine whether increased ganglioside-specific T cell reactivity can be detected in the peripheral blood of patients with Guillain–Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). T cell responsiveness to the gangliosides GM1, GM3, GD1a, GD1b, GD3, GT1b, GQ1b and sulphatide was assessed in peripheral blood mononuclear cells from untreated GBS patients (57), CIDP patients (43), patients with other peripheral neuropathies (55) and healthy control subjects (74) in a standard 6-day proliferation assay. Increased T cell reactivity to GM1 occurred in GBS patients compared to healthy controls and patients with other neuropathies. There was increased reactivity to GM3 in GBS patients compared to patients with other neuropathies but not compared to healthy controls. The frequencies of increased T cell reactivity to GM1 and GM3 in CIDP patients were intermediate between those of GBS patients and controls. We suggest that T cell reactivity to gangliosides might play a contributory role in the pathogenesis of GBS and perhaps CIDP. [Copyright &y& Elsevier]

I hypothesize that human chronic autoimmune diseases are based on infection of autoreactive B lymphocytes by Epstein–Barr virus (EBV), in the following proposed scenario. During primary infection, autoreactive B cells are infected by EBV, proliferate and become latently infected memory B cells, which are resistant to the apoptosis that occurs during normal B-cell homeostasis because they express virus-encoded anti-apoptotic molecules. Genetic susceptibility to the effects of B-cell infection by EBV leads to an increased number of latently infected autoreactive memory B cells, which lodge in organs where their target antigen is expressed, and act there as antigen-presenting cells. When CD4+ T cells that recognize antigens within the target organ are activated in lymphoid organs by cross-reactivity with infectious agents, they migrate to the target organ but fail to undergo activation-induced apoptosis because they receive a co-stimulatory survival signal from the infected B cells. The autoreactive T cells proliferate and produce cytokines, which recruit other inflammatory cells, with resultant target organ damage and chronic autoimmune disease. [Copyright &y& Elsevier]

The NF-κB signalling pathway plays an important role in controlling cellular immune responses, inflammation and apoptosis. In multiple sclerosis (MS), there is evidence of dysregulation of NF-κB signalling in patients with a relapsing-remitting disease course, but thus far there is little information on whether it is also dysregulated in patients with progressive disease. We hypothesised that patients with progressive MS would have more activation of NF-κB than relapsing-remitting MS patients. Using several different methods, we showed that there was more nuclear translocation of p65 in cells from progressive MS patients, particularly in T cells and monocytes. In addition, the amount of p65 translocated to the nucleus in cells of patients with progressive MS was not increased upon non-specific activation of the cells with the mitogen Con A. These results suggest that NF-κB dysregulation occurs in patients with progressive MS patients, as well as those with relapsing-remitting MS. [ABSTRACT FROM AUTHOR]

Vitamin D deficiency is common and implicated in risk of several human diseases. Evidence on the relative quantitative contribution of environmental, genetic and phenotypic factors to vitamin D status (assessed by the serum concentration of 25-hydroxyvitamin D, 25(OH)D) in free-living populations is sparse. We conducted a cross-sectional study of 494 Caucasian adults aged 18–61years, randomly selected from the Australian Electoral Roll according to groups defined by age, sex and region (spanning 27°–43°South). Data collected included personal characteristics, sun exposure behaviour, biomarkers of skin type and past sun exposure, serum 25(OH)D concentration and candidate single nucleotide polymorphisms. Ambient ultraviolet radiation (UVR) levels in the month six weeks before blood sampling best predicted vitamin D status. Serum 25(OH)D concentration increased by 10nmol/L as reported time in the sun doubled. Overall, 54% of the variation in serum 25(OH)D concentration could be accounted for: 36% of the variation was explained by sun exposure-related factors; 14% by genetic factors (including epistasis) and 3.5% by direct measures of skin phenotype. Novel findings from this study are demonstration of gene epistasis, and quantification of the relative contribution of a wide range of environmental, constitutional and genetic factors to vitamin D status. Ambient UVR levels and time in the sun were of prime importance but it is nonetheless important to include the contribution of genetic factors when considering sun exposure effects. This article is part of a Special Issue entitled ‘Vitamin D Workshop’. [ABSTRACT FROM AUTHOR]

Abstract: Multiple sclerosis (MS) is a common cause of neurological disability in young adults. The disease generally manifests in early to middle adulthood and causes various neurological deficits. Autoreactive T lymphocytes and their associated antigens have long been presumed important features of MS pathogenesis. The Protein tyrosine phosphatase receptor type C gene (PTPRC) encodes the T-cell receptor CD45. Variations within PTPRC have been previously associated with diseases of autoimmune origin such as type 1 diabetes mellitus and Graves'' disease. We set out to investigate two variants within the PTPRC gene, C77G and C772T in subjects with MS and matched healthy controls to determine whether significant differences exist in these markers in an Australian population. We employed high resolution melt analysis (HRM) and restriction length polymorphism (RFLP) techniques to determine genotypic and allelic frequencies. Our study found no significant difference between frequencies for PTPRC C77G by either genotype (Χ 2 =0.65, P =0.72) or allele (Χ 2 =0.48, P =0.49). Similarly, we did not find evidence to suggest an association between PTPRC C772T by genotype (Χ 2 =1.06, P =0.59) or allele (Χ 2 =0.20, P =0.66). Linkage disequilibrium (LD) analysis showed strong linkage disequilibrium between the two tested markers (D''=0.9970, SD=0.0385). This study reveals no evidence to suggest that these markers are associated with MS in the tested Australian Caucasian population. Although the PTPRC gene has a significant role in regulating CD4+ and CD8+ autoreactive T-cells, interferon-beta responsiveness, and potentially other important processes, our study does not support a role for the two tested variants of this gene in MS susceptibility in the Australian population. [Copyright &y& Elsevier]

Abstract: Multiple sclerosis (MS) is a chronic neurological disease characterized by central nervous system (CNS) inflammation and demyelination. The C677T substitution variant in the methylenetetrahydrofolate reductase (MTHFR) gene has been associated with increased levels of circulating homocysteine and is a mild risk factor for vascular disease. Higher blood levels of homocysteine have also been reported in MS. Thus, the C677T mutation of the MTHFR gene may influence MS susceptibility. Noradrenaline, a neurotransmitter believed to play an immunosupressive role in neuroinflammatory disorders, is catabolized by catechol-O-methyl transferase (COMT). The COMT G158A substitution results in a three- to four-fold decreased activity of the COMT enzyme, which may influence CNS synaptic catecholamine breakdown and could also play a role in MS inflammation. We tested DNA from Australian MS patients and unaffected control subjects, matched for gender, age and ethnicity. Specifically, we genotyped the MTHFR C677T and the COMT G158A mutations. Genotype distributions showed that the homozygous mutant MTHFR genotype (T/T) and the COMT (H/H) genotype were slightly over-represented in the MS group (16% versus 11% and 24% versus 19%, respectively), but both variations failed to reach statistical significance (P =0.15 and P =0.32, respectively). Hence, results from the present study do not support a major role for either functional gene mutation in MS susceptibility. [Copyright &y& Elsevier]

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) affecting most commonly the Caucasian population. Nitric oxide (NO) is a biological signaling and effector molecule and is especially important during inflammation. Inducible nitric oxide synthase (iNOS) is one of the three enzymes responsible for generating NO. It has been reported that there is an excessive production of NO in MS concordant with an increased expression of iNOS in MS lesions. This study investigated the role of a bi-allelic tetranucleotide polymorphism located in the promoter region of the human iNOS (NOS2A) gene in MS susceptibility. A group of MS patients (n = 101) were genotyped and compared to an age- and sex-matched group of healthy controls (n = 101). The MS group was subdivided into three subtypes, namely relapsing-remitting MS (RR-MS), secondary-progressive MS (SP-MS) and primary-progressive MS (PP-MS). Results of a chi-squared analysis and a Fisher’s exact test revealed that allele and genotype distributions between cases and controls were not significantly different for the total population (χ2 = 3.4, Pgenotype = 0.15; χ2 = 3.4, Pallele = 0.082) and for each subtype of MS (P > 0.05). This suggests that there is no direct association of this iNOS gene variant with MS susceptibility. [Copyright &y& Elsevier]