■对具有抗N-甲基-D-天冬氨酸受体(NMDAR)抗体的自身免疫性脑炎的遗传易感性了解甚少。鉴于相关环境因素的多样性(肿瘤,感染),我们假设人类白细胞抗原(HLA)和杀伤细胞免疫球蛋白样受体(KIR),两个极端多态的基因复合物是免疫系统的关键,可能与抗NMDAR脑炎的遗传易感性有关。值得注意的是,KIR主要由自然杀伤(NK)细胞表达,识别不同的HLAI类同种异型,并在抗肿瘤和抗感染反应中起主要作用。
■我们进行了全基因组关联研究(GWAS),随后使用主成分分析(PCA)和HLA插补进行对照匹配,在抗NMDAR脑炎的多种族队列中(n=479);在一个大的子样本中(n=323)对KIR和HLA进行了进一步测序.然后对载波频率(HLA和KIR)和拷贝数变异(KIR)进行PCA控制的逻辑回归。还对HLA-KIR相互作用关联进行建模。此外,对16例和16例对照的外周血单个核细胞进行单细胞测序,对NK细胞进行分选和表型分析。
■抗NMDAR脑炎显示与DRB1*01:01〜DQA1*01:01〜DQB1*05:01的弱HLA关联(OR=1.57,1.51,1.45;分别),和DRB1*11:01(OR=1.60);这些作用在欧洲后代和没有潜在卵巢畸胎瘤的患者中更强。更有趣的是,我们发现KIR2DL5B的拷贝数变异增加(OR=1.72),主要是由于KIR2DL5B*00201的代表过多。Further,我们确定了框架基因中的两个等位基因关联,KIR2DL4*00103(25.4%与在对照组中为12.5%,OR=1.98)和KIR3DL3*00302(5.3%与1.3%,OR=4.44)。值得注意的是,这些KIR2DL4和KIR3DL3的配体,已知HLA-G和HHLA2充当具有免疫抑制功能的免疫检查点。然而,我们没有发现病例和对照组之间特异性KIR-HLA配体相互作用或HLA-G多态性的差异.同样,CD56dim或CD56brightNK细胞的基因表达在病例和对照组之间没有差异。
■我们的观察首次表明HLA-KIR轴可能与抗NMDAR脑炎有关。虽然已确定的多态性赋予的遗传风险似乎很小,该轴在该疾病的病理生理学中的作用似乎很合理,应在未来的研究中进行分析。
UNASSIGNED: Genetic predisposition to autoimmune encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDAR) is poorly understood. Given the diversity of associated environmental factors (tumors, infections), we hypothesized that human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptors (KIR), two extremely polymorphic gene complexes key to the immune system, might be relevant for the genetic predisposition to anti-NMDAR encephalitis. Notably, KIR are chiefly expressed by Natural Killer (NK) cells, recognize distinct HLA class I allotypes and play a major role in anti-tumor and anti-infection responses.
UNASSIGNED: We conducted a Genome Wide Association Study (GWAS) with subsequent control-matching using Principal Component Analysis (PCA) and HLA imputation, in a multi-ethnic cohort of anti-NMDAR encephalitis (n=479); KIR and HLA were further sequenced in a large subsample (n=323). PCA-controlled logistic regression was then conducted for carrier frequencies (HLA and KIR) and copy number variation (KIR). HLA-KIR interaction associations were also modeled. Additionally, single cell sequencing was conducted in peripheral blood mononuclear cells from 16 cases and 16 controls, NK cells were sorted and phenotyped.
UNASSIGNED: Anti-NMDAR encephalitis showed a weak HLA association with DRB1*01:01~DQA1*01:01~DQB1*05:01 (OR=1.57, 1.51, 1.45; respectively), and DRB1*11:01 (OR=1.60); these effects were stronger in European descendants and in patients without an underlying ovarian teratoma. More interestingly, we found increased copy number variation of KIR2DL5B (OR=1.72), principally due to an overrepresentation of KIR2DL5B*00201. Further, we identified two allele associations in framework genes, KIR2DL4*00103 (25.4% vs. 12.5% in controls, OR=1.98) and
KIR3DL3*00302 (5.3% vs. 1.3%, OR=4.44). Notably, the ligands of these KIR2DL4 and
KIR3DL3, respectively, HLA-G and HHLA2, are known to act as immune checkpoint with immunosuppressive functions. However, we did not find differences in specific KIR-HLA ligand interactions or HLA-G polymorphisms between cases and controls. Similarly, gene expression of CD56dim or CD56bright NK cells did not differ between cases and controls.
UNASSIGNED: Our observations for the first time suggest that the HLA-KIR axis might be involved in anti-NMDAR encephalitis. While the genetic risk conferred by the identified polymorphisms appears small, a role of this axis in the pathophysiology of this disease appears highly plausible and should be analyzed in future studies.