HLA and KIR genetic association and NK cells in anti-NMDAR encephalitis

作者：Vicente Peris Sempere, Guo Luo, Sergio Muñiz‐Castrillo, Anne‐Laurie Pinto, Géraldine Picard, Véronique Rogemond, Maarten J. Titulaer, Carsten Finke, Frank Leypoldt, Gregor Kuhlenbäumer, GENERATE study group, Hannah F Jones, Russell Clive Dale, Sophie N. M. Binks, Sarosh R. Irani, Anna E.M. Bastiaansen, Juna M. de Vries, Marienke A.A.M. de Bruijn, Dave L. Roelen, Tae‐Joon Kim, Kon Chu, Soon‐Tae Lee, Takamichi Kanbayashi, Nicholas R. Pollock, Katherine M. Kichula, Abigail Mumme‐Monheit, Jérôme Honnorat, Paul J. Norman, Emmanuel Mignot · 发表于：Frontiers in Immunology · 年份：2024 · DOI：10.3389/fimmu.2024.1423149 · 被引用次数：17 · 研究领域：Autoimmune Neurological Disorders and Treatments、Immune Cell Function and Interaction、Artificial Immune Systems Applications

Introduction 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. Methods 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. Results 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 wi...