The HLA-DRB1 and HLA-DQB1 alleles are associated with multiple sclerosis disability progression in Slovak population

Objective: The aim of our present study was to analyse the association of HLA-DRB1 and -DQB1 alleles and genotypes with Multiple Sclerosis (MS) disability progression in a cohort of Central European Slovak population.

Methods: The allele and genotype variants were analyzed in 282 non-related MS patients. Rate of disease disability progression was evaluated using EDSS score in the 5^th, 7^th, 10^th, and 15^th year of disease duration, time to reach EDSS score 3 and 5, and MSSS score. Genotyping was performed by polymerase chain reaction with sequence-specific primers.

Results: We found that carriers of homozygous genotype for alleles DRB1*15 and DQB1*03 reached EDSS score 3 significantly earlier than non-carriers of these alleles (p = 0.0172; p = 0.00183, respectively). Genotype DQB1*03/03 carriage was also associated with significantly reduced time to reach EDSS score 5 (p = 0.00316). Lower EDSS score in the 5^th year of disease duration was found in carriers of DRB1*07 allele (p _cor = 0.028). When MSSS score was used, genotype DRB1*15/15 was found to be less frequent in slow progressing MS patients, when compared to MS patients with mid-rate and rapid disease disability progression (p _cor = 0.0305).

Discussion: We showed for the first time that HLA-DRB1 and -DQB1 genotypes are genetic markers associated with disability progression in Slovak MS patients. Genotypes DRB1*15/15 and DQB1*03/*03 were identified as short-term clinical negative prognostic factors, while allele DRB1*07 carriage appeared to be a positive prognostic marker of better MS outcome.     

HLA-DRB1基因型与多发性硬化易患性的关系

目的：探讨HLA基因型与多发性硬化（MS）易患者的关系。以及临床表现与基因型的关系。方法：30例MS患者（包括2对双生子患者）、40名健康对照组，应用序列特异性引物聚合酶链反应（PCR－SSP）方法进行HLA－DRB1基因分型，对2个双生子家系进行家系分析。结果：单卵双生子？（经遗传标记确定）同患MS，病变均累及大脑，脑干和脊髓，基因型为HLA－DRB1＊09＊14．1。异卵双生子之一为复发缓解型视神经脊髓炎，基因型为DRB1＊01＊12，其未患病双生子妹妹为DRB1＊17＊12。根据病变部位。30例MS中视神经脊髓炎型和西方型各15个。脊髓（70．0％），和视神经（56．7％）是最常见病变累及部位。DR15的等位基因频率在MS组无显著增高，但DR12等位基因频率在MS中显著升高（10／30vs 4/40,P=0.0157)，分层分析显示视神经脊髓炎患者中DR12等位基因频率升高，差异有极显著意义（8／15vs 4/40,P=0.0019,RR=5.33)。结论：单卵双生子与异卵双生子的患病一致性差异表明，遗传因素在MS发病中起一定作用。DR12可能是部分视神经脊髓炎型MS的易患基因，关联基因的差异可能是东西方MS临床表现和病变部位不同的原因之一。     

HLA-DRB1 and disease outcome in multiple sclerosis

The association between susceptibility to multiple sclerosis (MS) and the class II MHC allele HLA-DRB1*15 is well established although a possible relationship between this allele and outcome in MS is less clear. HLA-DRB1 typing was performed on 375 unrelated white patients with clinically definite MS and on 367 healthy controls. Putative associations of the gene with outcome were examined by dividing patients into two groups: those with an EDSS of 0-5.5 (mild/moderate disease) and those with an EDSS of 6-10 (severe disease). In order to minimise the effects of disease variability patients with a disease duration of at least 10 years or 15 years were examined. As subsidiary HLA-DRB1*03 and HLA-DRB1*04 associations have been previously reported, the effect of these alleles was also examined. As expected, HLA-DRB1*15 was found more frequently in patients than in controls (P < 0.000001). HLA-DRB1*15 positive patients had a significantly earlier age at onset than HLA-DRB1*15 negative patients. No significant associations were noted between HLA-DRB1*15 and outcome in the total patient group or in patients with a disease duration of 10 years or longer. In patients with a disease duration of at least 15 years HLA-DRB1*15 negative status was associated with a worse prognosis, although this did not remain significant after correction for multiple testing. It is thus likely that the contribution of HLA in MS is primarily towards onset and initial triggering mechanisms rather than influencing disease progression, chronicity and severity.     

Combined effect of HLA-DRB11501 and interleukin-1 receptor antagonist gene allele 2 in susceptibility to relapsing/remitting multiple sclerosis

Susceptibility to multiple sclerosis (MS) is associated with HLA-DRB1^*1501. Many reports have suggested associations with other loci but these results remain unconfirmed. We studied the IL-1 receptor antagonist (IL-1ra) gene polymorphism and the HLA-DR and DQ allele frequencies by DNA-based methods in both the primary chronic progressive form (PP MS) and the relapsing/remitting form (R/R MS). The frequency of DRB1^*1501 and IL-1ra allele 2 were significantly higher in R/R MS. Association was more marked in the female sex and in patients with benign forms of R/R MS. On the other hand DR4 subtypes carrying a Val at position 86 in the DRβ chain were increased in PP MS. The present study indicates that MS is genetically heterogeneous and shows a combined effect of HLA-DR and IL-1ra genes in susceptibility to the R/R form of the disease.     

人类白细胞抗原DRB1基因与多发性硬化遗传易患性研究

目的　分析多发性硬化遗传易患的分子免疫遗传背景。方法　采用聚合酶链反应序列特异性引物（ＰＣＲＳＳＰ） 联合技术对４５ 例病例组和１０５ 例正常对照组人类白细胞抗原ＤＲＢ１ 基因（ＨＬＡＤＲＢ１） 进行基因分型。结果　病例组ＨＬＡＤＲ２ 基因频率高于正常对照组,优势比为３．３２１ ,有统计学意义（ Ｐ＜ ０．０１）。结论　ＨＬＡＤＲ２ 基因与多发性硬化遗传易患相关联,提示可能还存在保护性基因。     

HLA-DRB1*1501 risk association in multiple sclerosis may not be related to presentation of myelin epitopes

Susceptibility to multiple sclerosis (MS) is associated genetically with human leucocyte antigen (HLA) class II alleles, including DRB1*1501, DRB5*0101, and DQB1*0602, and it is possible that these alleles contribute to MS through an enhanced ability to present encephalitogenic myelin peptides to pathogenic T cells. HLA-DRB1*1502, which contains glycine instead of valine at position 86 of the P1 peptide-binding pocket, is apparently not genetically associated with MS. To identify possible differences between these alleles in their antigen-presenting function, we determined if T-cell responses to known DRB1*1501-restricted myelin peptides might be diminished or absent in transgenic (Tg) DRB1*1502-expressing mice. We found that Tg DRB1*1502 mice had moderate to strong T-cell responses to several myelin peptides with favorable DRB1*1501 binding motifs, notably myelin oligodendrocyte glycoprotein (MOG)-35-55 (which was also encephalitogenic), proteolipid protein (PLP)-95-116, and MOG-194-208, as well as other PLP and MOG peptides. These peptides, with the exception of MOG-194-208, were also immunogenic in healthy human donors expressing either DRB1*1502 or DRB1*1501. In contrast, the DRB1*1502 mice had weak or absent responses to peptides with unfavorable DRB1*1501 binding motifs. Overall, none of the DRB1*1501-restricted myelin peptides tested selectively lacked immunogenicity in association with DRB1*1502. These results indicate that the difference in risk association with MS of DRB1*1501 versus DRB1*1502 is not due to a lack of antigen presentation by DRB1*1502, at least for this set of myelin peptides, and suggest that other mechanisms involving DRB1*1501 may account for increased susceptibility to MS.     

Understanding the genetic contribution of the human leukocyte antigen system to common major psychiatric disorders in a world pandemic context

The human leukocyte antigen (HLA) is a complex genetic system that encodes proteins which predominantly regulate immune/inflammatory processes. It can be involved in a variety of immuno-inflammatory disorders ranging from infections to autoimmunity and cancers. The HLA system is also suggested to be involved in neurodevelopment and neuroplasticity, especially through microglia regulation and synaptic pruning. Consequently, this highly polymorphic gene region has recently emerged as a major player in the etiology of several major psychiatric disorders, such as schizophrenia, autism spectrum disorder and bipolar disorder and with less evidence for major depressive disorders and attention deficit hyperactivity disorder. We thus review here the role of HLA genes in particular subgroups of psychiatric disorders and foresee their potential implication in future research. In particular, given the prominent role that the HLA system plays in the regulation of viral infection, this review is particularly timely in the context of the Covid-19 pandemic.     

HLA‐DRB1: genetic susceptibility and disability progression in a Spanish multiple sclerosis population

Background and objective: The association of HLA‐DRB1*15 with susceptibility to multiple sclerosis (MS) has been consistently reported although its effect on the clinical phenotype is still controversial. The objectives of this study are to investigate the influence of the HLA‐DRB1 alleles on the genetic susceptibility to MS and to study their impact on disability progression in a Spanish population. Methods: HLA‐DRB1 typing was performed by PCR‐SSP in 380 patients with sporadic MS and 1088 unrelated healthy controls. Allelic frequencies were compared between groups. We studied the correlation between the different alleles and the progression of MS. Results: The HLA‐DRB1*15 allele in patients with MS had a statistically significant higher frequency when compared with controls (18.9% in patients vs. 10.1% in controls, Odds ratio (OR) = 2.07, 95% CI = 1.64–2.60, P < 0.001). In the univariate analysis, the DRB1*01 and DRB1*04 alleles were associated with a worse prognosis when considering the time to reach an EDSS of 6, whereas the DRB1*03 was correlated with a better outcome. In the multivariate analysis, the alleles*01 and *04 were demonstrated to be independent factors to have a worse prognosis. Conclusions: HLA‐DRB1*15 is associated with MS when comparing patients with unrelated healthy controls in a Spanish population. The HLA‐DRB1*01 and HLA‐DRB1*04 alleles are related to a worse prognosis when considering the time taken to reach severe disability.     

A functional basis for the association of HLA class II genes adn susceptibility to multiple sclerosis: cellular immune responses to myelin basic protein in a multiplex family

This study has examined the cellular response to myelin basic protein (MBP) ina multiplex family with multiple sclerosis (MS). A total of 81 MBP-specific T cell liens (TCLs) were derived from three affected siblings and four healthy siblings. No difference was observed in estimated precursor frequenceis of MBP-specific TCLs or peptide specificity of TCLs when comparing affected and unaffected siblings. MPB-specific TCLs from affected siblings, however, were restricted to the DRw15/DQw6 allele more frequently than those from unaffected siblings (P < 0.02). These data suggest that restriction of autoantigen-specific T cells may be the functional basis for disease susceptibility related to HLA class II inheritance.     

HLA class II alleles and multiple sclerosis in Tunisian patients

Objective

The aim of our study was to investigate the association of HLA-DRB1 and -DQB1 alleles with multiple sclerosis (MS) in a Tunisian population and their effect on age at onset and disease severity.

Methods

58 MS patients and 105 healthy controls were genotyped for HLA class II alleles by PCR-SSP technique.

Results

An association of MS with HLA-DRB1*15 was found (14.7% vs 3.8%, OR (95% CI) = 4.34 (1.69–11.39), p_c = 2.5 × 10⁻³) after Bonferroni's correction. Moreover, the DRB1*15–DQB1*06 (13.8% vs 2.8%, OR (95% CI) = 5.44 (1.92–17.41), p_c = 1.1 × 10⁻³) and DRB1*04–DQB1*04 (8.6% vs 1.9%, OR (95% CI) = 4.86 (1.36–21.62), p_c = 0.028) haplotypes were found to confer a susceptibility to multiple sclerosis.

Conclusion

To our knowledge, this is the first study performed to analyze the association of HLA-DRB1/DQB1 alleles on MS susceptibility in Tunisia. The modern Tunisian gene pool shows some degree of heterogeneity and reflects a significant gene flow from Mediterranean regions.     

Cytokines and soluble IL-4 in patients with acute optic neuritis and multiple sclerosis

We measured the cerebrospinal fluid (CSF) and plasma concentrations of interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, TNF-β, interferon (IFN)-γ, the IL-1 receptor antagonist, and soluble IL-4 receptor (sIL-4r) by ELISA in 12 patients each with acute, monosymptomatic, idiopathic optic neuritis (ON), ON as part of MS, other attack forms of MS, and in neurological control subjects. CSF concentrations of IL-1β, IL-2 and IFN-γ differed significantly between the different patient groups and were detected most commonly at the highest concentrations in patients with non-ON attacks of MS. TNF-β was detected exclusively in CSF from neurological control patients. The patients with non-ON attacks of MS also had significantly elevated concentrations of sIL-4r in plasma. Increased CSF concentrations of IL-1β, IL-2 and IFN-γ together with increased plasma concentrations of sIL-4r support the concept of MS as an autoimmune disease with preferential activation of proinflammatory or T-helper type 1-like cells. Patients with idiopathic ON or ON as part of MS may, however, differ immunologically from patients with other attack forms of MS.     

HLA and multiple sclerosis in Italy: a review of the literature

Summary HLA antigens of locus A, C, B, DR and DQ were typed in 104 Italian multiple sclerosis patients and in 905 healthy controls; the results have been compared with those published in the Italian literature. The Italian studies have been reviewed regarding the ethnic origin of the typed population and the corresponding prevalence of the disease. The data suggest a lack of association between A3 and B7 antigens and Italian multiple sclerosis and a relevance of other DR locus antigens (mainly DR4 and DR5), in addition to DR2, in the susceptibility to the disease.     

糖皮质激素不同给药方式治疗急性期多发性硬化的疗效观察

目的探讨糖皮质激素3种不同给药方式治疗急性期多发性硬化(multiple sclerosis，MS)的疗效及安全性。方法将1998～2002年于我科治疗的48例MS患者按主要治疗方法的不同分为鞘内注入地塞米松(DXM)组、甲基强的松龙(MPS)冲击组及常规使用激素组。比较治疗后各组不同时间的Kurtzke扩充致残量表(Kurtzke expanded disability status scale，EDSS)评分减少数及副作用的发生率。结果鞘内注入DXM组治疗早期EDSS评分减少较其它两组显著，尤其对于脊髓受累为主的MSEDSS评分改善更为明显。结论鞘内注入DXM与两种常规方法比较见效快，建议用于脊髓受累为主的急性期MS。     

Polymorphisms of RPS6KB1 and CD86 associates with susceptibility to multiple sclerosis in Iranian population

Objective: Multiple sclerosis (MS) is the most prevalent disorder of nervous system inflammation which involves demyelination of spinal cord; this process depends on both environmental and genetic susceptibility factors. In the present study, we examined the association between two SNPs in RPS6KB1 (rs180515) and CD86 (rs9282641) with MS in Iranian population. RPS6KB1gene encodes p70S6K1 protein which plays a key role in mTOR signaling pathway, while CD86 gene codes a membrane protein type I which belongs to immunoglobulin super family act on co-stimulation signaling pathway. Methods: In this case-control study 130 patients with MS and 128 matched healthy controls were enrolled, genomic DNA was isolated and genotyping was performed using mismatched PCR-RFLP. The results were finally analyzed using SPSS. Results: Our results showed significant difference in allelic frequency of SNP rs180515 among cases and controls (P = 0.004). For this variation, AA genotype was shown to have protective effect (P = 0.016 and OR = 0.6), while GG genotype was a susceptive genotype to MS (P = 0.04 and OR = 2.2). Allelic frequency of SNP rs9282641 also showed significant difference between cases and controls (P = 0.006). For this SNP, AG genotype had predisposing effect (P = 0.04, OR = 2.3), and GG genotype showed protective (P = 0.01, OR = 0.411).

Conclusion: We successfully replicated the association of two novel SNPs introduced by a GWAS study, and MS in the Iranian population. This result can open ways for better understanding the mechanisms involved in MS.     

The multiple sclerosis trait and the development of multiple sclerosis: genetic vulnerability and environmental effect

The remarkably low rate of concordance of multiple sclerosis (MS) in monozygotic twins has never been fully explained but it implies the possibility of a systemic condition called the multiple sclerosis trait (MST), which is quite different from asymptomatic MS. It results from the action of an antigenic challenge on the immune system of a genetically vulnerable person that does not cause damage to the nervous parenchyma; it may never evolve into the disease MS. A subsequent environmental viral-antigenic event in some MST-carriers can change the trait into the disease. This event could be an infection, which need not be symptomatic, or a vaccination. The MS may become symptomatic, remain asymptomatic, or manifested only by lesions visible by MRI. It is likely that the development of the MST, called activation, occurs early in life, while the transition from MST to MS, called acquisition, takes place at puberty in most patients. Differences in prevalence between pre-puberal migrants, and the locally born children of migrants, and their population of origin may also be explained by the MST.     

Tumor necrosis factor polymorphisms in multiple sclerosis: No additional association independent of HLA

In order to investigate whether genes coding for tumor necrosis factors (TNF) contribute to the pathogenesis of multiple sclerosis (MS) and also whether they have a non-random association with the MS associated HLA-DRBI * 1501-DQA1 * 0102-DQB1 * 0602 haplotype, 40 MS patients and their parents were characterized at four polymorphic loci in the region of the TNF genes: a Nco I RFLP and three microsatellites. We were able to determine the parental haplotypes and used those which were not transmitted to the proband as controls. Fifty percent of the HLA-DRB1 * 1501-DQA1 * 0102-DQB1 * 0602 haplotypes carried the TNFc1-n2-all-b4 allelic combination in both the patient and the control groups. However, there was no association of any of these TNF polymorphisms with MS, independent of that already described for the class II region. This, with the lack of association of DP alleles with MS, effectively marks the boundaries of the MS associated haplotype.     

T-cell subsets in spinal fluid of multiple sclerosis patients

CSF T-cells and T-cell subsets were characterized by monoclonal antibodies in 15 untreated multiple sclerosis (MS) patients, 17 immunosuppressed chronic progressive MS patients and 9 patients with other neurological diseases. A negative correlation was found between total cell numbers and T suppressor cell percentages in untreated and treated MS patients. A negative correlation (r = -0.71) was found between intrathecal IgG levels and T suppressor cell percentages in untreated MS patients. In peripheral blood, no correlation between T-cells and T-cell subsets with IgG levels was found. It is discussed that T-cell subsets and intrathecal IgG levels may be indicators of the activity of the inflammatory process in the brains of chronic progressive MS patients.     

CTLA-4 and CD28 gene polymorphisms in susceptibility,clinical course and progression of multiple sclerosis

The balance between CD28 and CTLA-4 signalling is important for regulation of the immune response. We were interested whether a genetically mediated disturbance of this balance could be related to susceptibility or severity of multiple sclerosis (MS). We examined three polymorphisms in these genes, CTLA-4-318, CTLA-4+49 and CD28-I3+17, in 514 patients with MS and 181 controls. As the loci cannot be assumed independent of each other, we analysed the effects of each of the three polymorphisms corrected for the presence of the other two. We found no association between carriership of any of the alleles either with susceptibility to MS or with clinical features. For a subgroup of patients, longitudinal magnetic resonance imaging (MRI) data were available. We observed no effects of the polymorphisms on brain and lesion volumes. These data suggest that the polymorphisms under investigation do not affect the risk of developing MS and have no influence on the course of disease.     

Risk factors for increased multiple sclerosis susceptibility in the Iranian population

Multiple sclerosis (MS) is a complex autoimmune disease with increasing prevalence. Many factors have been assessed in relation to its development and its worldwide geographical and racial distribution. Therefore, we decided to conduct a nationwide case-control matched study to estimate the possible influence of putative risk factors on MS status in an Iranian MS population. Between January 2008 and September 2013, 1403 patients diagnosed with MS according to the Poser or McDonald criteria and 883 controls were studied. Of all patients, there were 921 women and 296 men (ratio 3.1:1) with a mean age of 32.6 ± 8.7 years. In the multivariate model adjusted for sex and age (±2 years), we found associated risk factors of MS to be: history of any allergic condition (Odds ratio (OR): 1.92, 95% Confidence interval (CI): 1.55–2.47, p < 0.001), and smoking (OR: 1.93, 95% CI: 1.31–2.73, p < 0.001). Sunlight exposure ⩾3 hours was found to be associated with a reduced risk of MS (OR: 0.23, 95% CI: 0.15–0.31, p < 0.001). As expected, cases were more likely to have a positive family history of MS than controls (OR: 1.91, 95% CI: 1.33–2.75, p < 0.001). A significant association was found between family history of other autoimmune diseases and MS risk (OR: 1.57, 95% CI: 1.18–2.09, p = 0.002). These results support the hypothesis that sun exposure is associated with a decreased risk of MS while smoking, autoimmune family history, MS family history, and personal allergy history are risk factors for MS susceptibility.     

Genetic segregation of multiple sclerosis and histocompatibility (HLA) haplotypes

Summary The possibility that a gene determining susceptibility to multiple sclerosis (MSS) may be closely linked to the major histocompatibility locus (HLA) is suggested by observation of a loose association between multiple sclerosis (MS) and certain HLA determinants. In the present study, the possible association was analyzed by studying the segregation of MS and the HLA haplotypes in families with more than one case of MS. Analysis of 48 published families revealed that the haplotype shared by those with MS within the family was also shared by those without clinical signs of MS at close to the 50% frequency expected by chance. Thus, we were unable to demonstrate that MS is associated with one HLA defined parental haplotype. We discussed reasons for this apparent failure to demonstrate existence of an MSS gene using available multiplex MS families.Supported in part by a grant from the Kroc Foundation