Downregulation of Mgat1 by IL7RA*C and IL2RA*T is opposed by MGAT1 (IV(A)V(T-T)) and vitamin D(3), optimizing branching and mitigating MS risk when combined with enhanced CTLA-4 N-glycosylation by CTLA-4 Thr17.
Multiple sclerosis (MS) is a complex trait in which alleles at or near the class II loci HLA-DRB1 and HLA-DQB1 contribute significantly to genetic risk.
While in these 397 families, 8 markers showed significant association with MS, through conditional tests we determined that these MOG variants were not associated with MS independently of the main DRB1-DQB1 disease associations.
CNS-specific ANA were more frequent in MS than in NMOSD patients or HCs (13.5% vs 0% for both comparisons, both p < .05) and were associated with HLA-DRB1*15:01 (p = .0174).
A central role for T cells in MS is supported by mouse models, association of the major histocompatibility complex region, and association of critical T cell growth regulator genes such as interleukin-2 receptor (IL-2RA) and interleukin-7 receptor (IL-7RA).
Although the possibility that IL2RA is a risk factor for MS development was not confirmed in this Japanese population, IL2RA gene polymorphisms were able to modify the disease activity in female MS patients, but had no influence on either susceptibility or disease phenotype in NMO/NMOSD patients.
The expected MS associated HLA-pattern of Caucasoid patients, however, was found in the MS-only patients (42% carried DRB1*1501-DQB1*0602, 58% carried DQA1*0102), while the prevalence of T1DM susceptibility and 'resistance' alleles was not different from the general population.
Although the interaction was not statistically significant, there appeared to be a trend of increasing risk of MS in participants who were homozygous for the HLA-DRB1*1501 allele in association with the more active form of the VDR (Fok1).
The C allele of a single nucleotide polymorphism (SNP), rs6897932, located in the interleukin-7 receptor alpha chain (IL7RA) was recently found to be associated with multiple sclerosis and Type I diabetes.
We confirmed the association of DRB1*1501-DQB1*0602 haplotype carriage with MS in both Wexford [odds ratio (OR) = 2.95, P= 0.0020, P(cor)= 0.0220] and Donegal (OR = 2.29, P= 0.0030, P(cor)= 0.0420).
Moreover, IL-7Rα membrane expression was significantly increased in MS in naive and memory CD8 (all p < 0.05) with a similar trend in CD8EM (p = 0.055).
TLR4 and CD40 co-stimulation synergistically increased the frequency of IL-10-producing but not pro-inflammatory cytokine-producing B cells at MS relapse.
Furthermore, the DR2-associated DRB1*1501 allele and DRB5*0101 allele were associated with Western-type MS (41.2%), but not with either Asian-type MS (0%) or healthy control subjects (14.2%).
To closer model presentation of human MOG by astrocytes in MS patients, we generated astrocytes from transgenic mice expressing the MS-associated MHC class II alleles HLA-DR2 (DRB1*1501) and HLA-DR4 (DRB1*0401).
Variants in TNFRSF1A and in the vicinity of IRF8 were confirmed to be associated in these independent cohorts, which supports the role of these loci in etiology of multiple sclerosis.
Association between IL2RA and MS is clearly established, although the functional variation is still unknown: the effect of IL2RA might be better described by several SNPs than by a single one.