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

Autor:	Peris Sempere V; Stanford Center for Sleep Science and Medicine, Stanford University, Palo Alto, CA, United States., Luo G; Stanford Center for Sleep Science and Medicine, Stanford University, Palo Alto, CA, United States., Muñiz-Castrillo S; Stanford Center for Sleep Science and Medicine, Stanford University, Palo Alto, CA, United States., Pinto AL; French Reference Center on Paraneoplastic Neurological Syndrome and Autoimmune Encephalitis, Hospices Civils de Lyon, Lyon, France.; Institut MeLiS INSERM U1314/CNRS UMR 5284, Université Claude Bernard Lyon 1, Lyon, France., Picard G; French Reference Center on Paraneoplastic Neurological Syndrome and Autoimmune Encephalitis, Hospices Civils de Lyon, Lyon, France.; Institut MeLiS INSERM U1314/CNRS UMR 5284, Université Claude Bernard Lyon 1, Lyon, France., Rogemond V; French Reference Center on Paraneoplastic Neurological Syndrome and Autoimmune Encephalitis, Hospices Civils de Lyon, Lyon, France.; Institut MeLiS INSERM U1314/CNRS UMR 5284, Université Claude Bernard Lyon 1, Lyon, France., Titulaer MJ; Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands., Finke C; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.; Berlin School of Mind and Brain, Humboldt-Universität zu Berlin, Berlin, Germany., Leypoldt F; Department of Neurology, Christian-Albrechts-University/University Hospital Schleswig-Holstein, Kiel, Germany.; Neuroimmunology, Institute of Clinical Chemistry, University Hospital Schleswig-Holstein Kiel/Lübeck, Kiel, Germany., Kuhlenbäumer G; Department of Neurology, Christian-Albrechts-University/University Hospital Schleswig-Holstein, Kiel, Germany., Jones HF; Starship Hospital, Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand., Dale RC; Kids Neuroscience Centre, Children's Hospital at Westmead clinical school, University of Sydney, Sydney, NSW, Australia., Binks S; Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.; Department of Neurology, John Radcliffe Hospital, Oxford, United Kingdom., Irani SR; Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.; Departments of Neurology and Neurosciences, Mayo Clinic, Jacksonville, FL, United States., Bastiaansen AE; Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands., de Vries JM; Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands., de Bruijn MAAM; Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands., Roelen DL; Department of Immunogenetics and Transplantation Immunology, Leiden University Medical Center, Leiden, Netherlands., Kim TJ; Department of Neurology, Ajou University School of Medicine, Suwon, Republic of Korea., Chu K; Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea., Lee ST; Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea., Kanbayashi T; Department of Neurology, Teikyo University School of Medicine, Tokyo, Japan., Pollock NR; Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO, United States.; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States., Kichula KM; Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO, United States.; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States., Mumme-Monheit A; Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO, United States.; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States., Honnorat J; French Reference Center on Paraneoplastic Neurological Syndrome and Autoimmune Encephalitis, Hospices Civils de Lyon, Lyon, France.; Institut MeLiS INSERM U1314/CNRS UMR 5284, Université Claude Bernard Lyon 1, Lyon, France., Norman PJ; Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO, United States.; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States., Mignot E; Stanford Center for Sleep Science and Medicine, Stanford University, Palo Alto, CA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Jul 10; Vol. 15, pp. 1423149. Date of Electronic Publication: 2024 Jul 10 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1423149
Abstrakt:	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 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 CD56 dim or CD56 bright NK cells did not differ between cases and controls. Discussion: 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. Competing Interests: MT has filed a patent, on behalf of the Erasmus MC, for methods for typing neurologic disorders and cancer, and devices for use therein; has received research funds for serving on a scientific advisory board of AmGen, for consultation at Guidepoint Global LLC, for consultation at UCB; and has received an unrestricted research grant from Euroimmun AG and from CSL Behring. FL discloses speaker honoraria from Grifols, Teva, Biogen, Bayer, Roche, Novartis, Fresenius, travel funding from Merck, Grifols and Bayer and serving on advisory boards for Roche, Biogen and Alexion. SI is a co-applicant and receives royalties on patent application WO/210/046716 U.K. patent no., PCT/GB2009/051441 entitled “Neurological Autoimmune Disorders”; the patent has been licensed for the development of assays for LGI1 and other VGKC-complex antibodies; has filed a patent Diagnostic Strategy to improve specificity of CASPR2 antibody detection; Ref. JA94536P.GBA; has received research support from and/or consultancy with UCB, RocheADC therapeutics, CSL Behring and ONO Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Peris Sempere, Luo, Muñiz-Castrillo, Pinto, Picard, Rogemond, Titulaer, Finke, Leypoldt, Kuhlenbäumer, GENERATE study group, Jones, Dale, Binks, Irani, Bastiaansen, de Vries, de Bruijn, Roelen, Kim, Chu, Lee, Kanbayashi, Pollock, Kichula, Mumme-Monheit, Honnorat, Norman and Mignot.)
Databáze:	MEDLINE
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