Núñez Concepción, Cénit M Carmen, Alvarez-Lafuente Roberto, Río Jordi, Fernández-Arquero Miguel, Arroyo Rafael, Montalbán Xavier, Fernández Oscar, Oliver-Martos Begoña, Leyva Laura, Comabella Manuel, Urcelay Elena
Immunology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
Multiple Sclerosis Unit, Neurology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
J Med Genet. 2014 Jun;51(6):395-400. doi: 10.1136/jmedgenet-2014-102348. Epub 2014 Apr 19.
Recombinant interferon β (IFNβ) is a first-line therapy for relapsing-remitting multiple sclerosis (MS), with a proven effect on the inflammatory activity. Neutralising antibodies against IFNβ (NAbs) promote a loss of IFNβ bioactivity in a titre-dependent way and their development was associated with certain human leucocyte antigen (HLA) alleles. We investigated the contribution conferred by HLA alleles on the development of NAbs in independent cohorts of Southern Europe.
Serum NAbs from 610 MS patients with HLA-genotype data were evaluated by cytopathic effect assay: negative tests included at least one negative result (NAb titres<20 NU/mL) after 1 year treatment; NAb-titres ≥20 NU/mL were positive tests and NAb titres ≥150 NU/mL in any test were classified as high-titre positives.
The combined presence of DRB107/DQA102 with A26 or B14 was found in 20% of patients with NAbs at high titres, but only in 5.4% of NAb-negative patients (p=0.00052, OR (95% CI) 4.34 (1.85 to 10.13)). The DRB104:01 allele was also more frequently carried by patients with high titres of NAbs (10% vs 4.5%; p=0.046, OR (95% CI) 2.38 (0.93 to 5.92)). The alleles carried at a significantly lower frequency in patients with high persistent NAbs corresponded to the A11 allele (3.3% vs 13.8%; p=0.023, OR (95% CI) 0.22 (0.02 to 0.87)), as well as the DRB103/DQA105/DQB102 haplotype (16.3% vs 26.8%; p=0.02, OR (95% CI) 0.53 (0.27 to 1.03)) and the DRB113/DQA101:03/DQB106:03 haplotype (2.5% vs 9.1%; p=0.045, OR (95% CI) 0.25 (0.03 to 1.02)).
50% of the studied MS patients carried some of the five independently associated HLA allele/allele combinations described in this work. This relevant percentage of patients could benefit a therapeutic decision.
重组干扰素β（IFNβ）是复发缓解型多发性硬化症（MS）的一线治疗药物，对炎症活动有确切疗效。抗IFNβ中和抗体（NAbs）以滴度依赖的方式导致IFNβ生物活性丧失，其产生与某些人类白细胞抗原（HLA）等位基因有关。我们在南欧的独立队列中研究了HLA等位基因对NAbs产生的影响。
采用细胞病变效应试验评估610例有HLA基因型数据的MS患者血清中的NAbs：阴性检测定义为治疗1年后至少有一次阴性结果（NAb滴度<20 NU/mL）；NAb滴度≥20 NU/mL为阳性检测，任何一次检测中NAb滴度≥150 NU/mL则分类为高滴度阳性。
在20%的高滴度NAbs患者中发现DRB107/DQA102与A26或B14同时存在，但在NAb阴性患者中仅为5.4%（p = 0.00052，比值比（95%可信区间）4.34（1.85至10.13））。DRB104:01等位基因在高滴度NAbs患者中携带频率也更高（10%对4.5%；p = 0.046，比值比（95%可信区间））。在持续高NAbs患者中携带频率显著较低的等位基因对应于A11等位基因（3.3%对13.8%；p = 0.023，比值比（95%可信区间）0.22（0.02至0.87）），以及DRB103/DQA105/DQB102单倍型（16.3%对26.8%；p = 0.02，比值比（95%可信区间）0.53（0.27至1.03））和DRB113/DQA101:03/DQB106:03单倍型（2.5%对9.1%；p = 0.045，比值比（95%可信区间）0.25（0.03至1.02））。
50%的研究MS患者携带了本研究中描述的五个独立相关的HLA等位基因/等位基因组合中的一些。这一相当比例的患者可能从治疗决策中获益。
