多发性硬化症体液免疫反应的遗传决定因素。
Genetic determinants of the humoral immune response in MS.
机构信息
From the Department of Neurology (C.G., T.F.M.A., A. Keating, B.K., A. Klein, V.P., A. Berthele, B.H.), Klinikum rechts der Isar, School of Medicine, Technical University of Munich; Institute of Human Genetics (P.L.), Helmholtz Zentrum München, Neuherberg; Department of Neurology (R.G.), St. Josef Hospital, Ruhr-University Bochum; Department of Neurology, Focus Program Translational Neurosciences (FTN) and Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn2) (F.Z.), University Medical Center of the Johannes Gutenberg University Mainz; Department of Neurology and Translational Center for Regenerative Medicine (F.T.B.), University of Leipzig; Clinical Neuroimmunology and Neurochemistry (M.S.), Department of Neurology, Hannover Medical School, Hannover; Department of Neurology (H.T.), University of Ulm; Clinic of Neurology Dietenbronn (H.T.), Schwendi; Department of Neurology (B.W.), University Hospital Heidelberg; Department of Neurology (H.W.), University of Münster; Department of Neurology (A. Bayas), University Hospital Augsburg; Institute of Clinical Neuroimmunology (T.K.), University Hospital and Biomedical Center, Ludwig-Maximilians University Munich; Department of Neurology (U.K.Z.), Neuroimmunological Section, University of Rostock; Department of Neurology (R.A.L.), University Hospital Erlangen; Department of Neurology (R.A.L.), University of Regensburg; Department of Neurology & Stroke and Hertie-Institute for Clinical Brain Research (U.Z.), Eberhard-Karls-Universität Tübingen; Max Planck Institute of Psychiatry (M.K.), Munich; Department of Neurology (C.W.), Medical Faculty, Heinrich Heine University, Düsseldorf; Department of Neurology (C.W.), University Hospital Cologne; Institute of Neuroimmunology and Multiple Sclerosis (M.A.F), University Medical Centre Hamburg-Eppendorf, Hamburg; NeuroCure Clinical Research Center (F.P.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin; Berlin Institute of Health and Experimental and Clinical Research Center (F.P.), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin; and Center of Neuroimmunology (B.T.), Philipps-University Marburg; and Munich Cluster for Systems Neurology (SyNergy) (B.H.), Germany.
出版信息
Neurol Neuroimmunol Neuroinflamm. 2020 Jul 16;7(5). doi: 10.1212/NXI.0000000000000827. Print 2020 Sep.
OBJECTIVE
In this observational study, we investigated the impact of genetic factors at the immunoglobulin heavy chain constant locus on chromosome 14 and the major histocompatibility complex region on intrathecal immunoglobulin G, A, and M levels as well as on B cells and plasmablasts in the CSF and blood of patients with multiple sclerosis (MS).
METHODS
Using regression analyses, we tested genetic variants on chromosome 14 and imputed human leukocyte antigen (HLA) alleles for associations with intrathecal immunoglobulins in 1,279 patients with MS or clinically isolated syndrome and with blood and CSF B cells and plasmablasts in 301 and 348 patients, respectively.
RESULTS
The minor alleles of variants on chromosome 14 were associated with higher intrathecal immunoglobulin G levels (β = 0.58 [0.47 to 0.68], lowest adjusted = 2.32 × 10), and lower intrathecal immunoglobulin M (β = -0.56 [-0.67 to -0.46], = 2.06 × 10) and A (β = -0.42 [-0.54 to -0.31], = 7.48 × 10) levels. Alleles from the HLA-B07:02-DRB115:01-DQA101:02-DQB106:02 haplotype were associated with higher (lowest = 2.14 × 10) and HLA-B44:02 with lower (β = -0.35 [-0.54 to -0.17], = 1.38 × 10) immunoglobulin G levels. Of interest, different HLA alleles were associated with lower intrathecal immunoglobulin M (HLA-C02:02, β = -0.45 [-0.61 to -0.28], = 1.01 × 10) and higher immunoglobulin A levels (HLA-DQA101:03-DQB106:03-DRB1*13:01 haplotype, β = 0.40 [0.21 to 0.60], = 4.46 × 10). The impact of HLA alleles on intrathecal immunoglobulin G and M levels could mostly be explained by associations with CSF B cells and plasmablasts.
CONCLUSION
Although some HLA alleles seem to primarily drive the extent of humoral immune responses in the CNS by increasing CSF B cells and plasmablasts, genetic variants at the immunoglobulin heavy chain constant locus might regulate intrathecal immunoglobulins levels via different mechanisms.
目的
在这项观察性研究中，我们研究了 14 号染色体上免疫球蛋白重链恒定区的遗传因素和主要组织相容性复合物区域对多发性硬化症（MS）患者脑脊液中免疫球蛋白 G、A 和 M 水平以及脑脊液和血液中的 B 细胞和浆母细胞的影响。
方法
使用回归分析，我们检测了 14 号染色体上的遗传变异，并对 1279 名 MS 或临床孤立综合征患者的脑脊液中免疫球蛋白、301 名患者的血液和 348 名患者的脑脊液中的 B 细胞和浆母细胞进行了人类白细胞抗原（HLA）等位基因的推断，以检测与这些变量的关联。
结果
14 号染色体上变异的次要等位基因与较高的鞘内免疫球蛋白 G 水平相关（β=0.58 [0.47 至 0.68]，调整后最低 = 2.32×10），而较低的鞘内免疫球蛋白 M（β=-0.56 [-0.67 至 -0.46]， = 2.06×10）和 A（β=-0.42 [-0.54 至 -0.31]， = 7.48×10）水平。HLA-B07:02-DRB115:01-DQA101:02-DQB106:02 单倍型的等位基因与较高的免疫球蛋白 G 水平相关（最低 = 2.14×10），而 HLA-B44:02 与较低的免疫球蛋白 G 水平相关（β=-0.35 [-0.54 至 -0.17]， = 1.38×10）。有趣的是，不同的 HLA 等位基因与较低的鞘内免疫球蛋白 M（HLA-C02:02，β=-0.45 [-0.61 至 -0.28]， = 1.01×10）和较高的免疫球蛋白 A 水平（HLA-DQA101:03-DQB106:03-DRB1*13:01 单倍型，β=0.40 [0.21 至 0.60]， = 4.46×10）相关。HLA 等位基因对鞘内免疫球蛋白 G 和 M 水平的影响可主要通过与脑脊液 B 细胞和浆母细胞的关联来解释。
结论
尽管一些 HLA 等位基因似乎通过增加脑脊液 B 细胞和浆母细胞来主要驱动中枢神经系统体液免疫反应的程度，但免疫球蛋白重链恒定区的遗传变异可能通过不同的机制调节鞘内免疫球蛋白水平。
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