Dandekar Sugandha, Wijesuriya Hemani, Geiger Tim, Hamm David, Mathern Gary W, Owens Geoffrey C
Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles , Los Angeles, CA , USA.
Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California Los Angeles , Los Angeles, CA , USA.
Front Immunol. 2016 Dec 19;7:608. doi: 10.3389/fimmu.2016.00608. eCollection 2016.
Rasmussen encephalitis (RE) is a rare pediatric neuroinflammatory disease characterized by intractable seizures and unilateral brain atrophy. T cell infiltrates in affected brain tissue and the presence of circulating autoantibodies in some RE patients have indicated that RE may be an autoimmune disease. The strongest genetic links to autoimmunity reside in the MHC locus, therefore, we determined the human leukocyte antigen (HLA) class I and class II alleles carried by a cohort of 24 RE surgery cases by targeted in-depth genomic sequencing. Compared with a reference population the allelic frequency of three alleles, DQA104:01:01, DQB104:02:01, and HLA-C07:02:01:01 indicated that they might confer susceptibility to the disease. It has been reported that HLA-C07:02 is a risk factor for Graves disease. Further, eight patients in the study cohort carried HLA-A03:01:01:01, which has been linked to susceptibility to multiple sclerosis. Four patients carried a combination of three HLA class II alleles that has been linked to type 1 diabetes (DQA105:01:01:01DQB1*02:01:01DRB103:01:01:01), and five patients carried a combination of HLA class II alleles that has been linked to the risk of contracting multiple sclerosis (DQA101:02:01:01, DQB106:02:01, DRB115:01:01:01). We also analyzed the diversity of αβ T cells in brain and blood specimens from 14 of these RE surgery cases by sequencing the third complementarity regions (CDR3s) of rearranged T cell receptor β genes. A total of 31 unique CDR3 sequences accounted for the top 5% of all CDR3 sequences in the 14 brain specimens. Thirteen of these sequences were found in sequencing data from healthy blood donors; the remaining 18 sequences were patient specific. These observations provide evidence for the clonal expansion of public and private T cells in the brain, which might be influenced by the RE patient's HLA haplotype.
拉斯穆森脑炎（RE）是一种罕见的小儿神经炎性疾病，其特征为顽固性癫痫发作和单侧脑萎缩。在受影响的脑组织中存在T细胞浸润，并且一些RE患者体内存在循环自身抗体，这表明RE可能是一种自身免疫性疾病。与自身免疫最强的基因联系存在于MHC基因座中，因此，我们通过靶向深度基因组测序确定了24例RE手术病例群体所携带的人类白细胞抗原（HLA）I类和II类等位基因。与参考人群相比，三个等位基因DQA104:01:01、DQB104:02:01和HLA-C07:02:01:01的等位基因频率表明它们可能使个体易患该疾病。据报道，HLA-C07:02是格雷夫斯病的一个危险因素。此外，研究队列中的8名患者携带HLA-A03:01:01:01，该等位基因与多发性硬化症的易感性有关。4名患者携带与1型糖尿病相关的三个HLA II类等位基因组合（DQA105:01:01:01DQB1*02:01:01DRB103:01:01:01），5名患者携带与患多发性硬化症风险相关的HLA II类等位基因组合（DQA101:02:01:01、DQB106:02:01、DRB115:01:01:01）。我们还通过对重排的T细胞受体β基因的第三个互补决定区（CDR3）进行测序，分析了其中14例RE手术病例的脑和血标本中αβ T细胞的多样性。在14个脑标本中，共有31个独特的CDR3序列占所有CDR3序列的前5%。这些序列中有13个出现在健康献血者的测序数据中；其余18个序列是患者特有的。这些观察结果为脑中公共和私有T细胞的克隆性扩增提供了证据，这可能受RE患者的HLA单倍型影响。
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