From the Laboratory of Neurological Complex Disorders (M.S., S.S., L.F., E.M., F.C., A.G., M.C., F.E.), Division of Neuroscience, Institute of Experimental Neurology (INSPE), IRCCS San Raffaele Scientific Institute; Neurology and Neurorehabilitation Unit (L.F., A.G., M.C., M.L., V.M., M.F., F.E.), IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University (M.F.); Neurophysiology Unit (M.F.), IRCCS San Raffaele Scientific Institute; and Neuroimaging Research Unit, Division of Neuroscience, Institute of Experimental Neurology (INSPE) (P.F.), IRCCS San Raffaele Scientific Institute, Milan, Italy.
Neurol Neuroimmunol Neuroinflamm. 2023 Feb 15;10(3). doi: 10.1212/NXI.0000000000200093. Print 2023 May.
The major histocompatibility complex (MHC) locus has a predominant role in the genetic predisposition to multiple sclerosis (MS), with 32 associations found to be involved. We aimed to investigate the impact of MHC MS-risk alleles on T-cell repertoire in patients with MS.
We studied 161 untreated patients with relapsing-remitting MS for whom Class I and II human leukocyte antigen (HLA) alleles were inferred from whole-genome genotyping data, and T-cell receptor (TCR) CDR3 sequences were obtained through next-generation sequencing. T-cell repertoire features including diversity, public clones, and architecture were evaluated.
We identified 5 MS-risk loci associated with TCR diversity: HLA-DRB115:01 (7.65 × 10), rs9271366 (1.96 × 10), rs766848979 A (1.89 × 10), rs9277626 (2.95 × 10), and rs11751659 (1.92 × 10), with evidence of expanded clonotypes in carriers of risk alleles. Moreover, HLA-DRB115:01 (4.99 × 10), rs9271366 (6.54 × 10), rs1049079 C (4.37 × 10), AA DQΒ1 position -5 L (1.05 × 10), and AA DQΒ1 position 221 Q (9.39 × 10) showed an association with the CDR3 aminoacidic sequence architecture, suggesting an impact on the antigen recognition breadth as well. Evaluating the sharing of clones across MS-risk allele carrier individuals revealed the presence of highly shared clonotypes predicted to target viral antigens, including Epstein-Barr virus.
Our study supports the association between MHC-risk alleles and macrofeatures of the T-cell repertoire in the context of MS. Further studies are needed to understand the underlying molecular mechanisms.
主要组织相容性复合体（MHC）基因座在多发性硬化症（MS）的遗传易感性中起着主要作用，已发现 32 个相关联。我们旨在研究 MHC MS 风险等位基因对 MS 患者 T 细胞库的影响。
我们研究了 161 名未经治疗的复发缓解型 MS 患者，他们的 I 类和 II 类人类白细胞抗原（HLA）等位基因是从全基因组基因分型数据推断出来的，通过下一代测序获得了 T 细胞受体（TCR）CDR3 序列。评估了 T 细胞库特征，包括多样性、公共克隆和结构。
我们确定了与 TCR 多样性相关的 5 个 MS 风险基因座：HLA-DRB115:01（7.65×10）、rs9271366（1.96×10）、rs766848979 A（1.89×10）、rs9277626（2.95×10）和 rs11751659（1.92×10），风险等位基因携带者中存在扩展的克隆型。此外，HLA-DRB115:01（4.99×10）、rs9271366（6.54×10）、rs1049079 C（4.37×10）、AA DQΒ1 位置 -5 L（1.05×10）和 AA DQΒ1 位置 221 Q（9.39×10）与 CDR3 氨基酸序列结构相关联，表明它们也对抗原识别广度有影响。评估 MS 风险等位基因携带者个体之间克隆的共享情况表明，存在高度共享的预测针对病毒抗原的克隆型，包括 EBV。
我们的研究支持 MHC 风险等位基因与 MS 背景下 T 细胞库的宏观特征之间的关联。需要进一步的研究来了解潜在的分子机制。
