AUTHOR=Peris Sempere Vicente , Luo Guo , Muñiz-Castrillo Sergio , Pinto Anne-Laurie , Picard Géraldine , Rogemond Véronique , Titulaer Maarten J. , Finke Carsten , Leypoldt Frank , Kuhlenbäumer Gregor ,  GENERATE study group , Jones Hannah F. , Dale Russell C. , Binks Sophie , Irani Sarosh R. , Bastiaansen Anna E. , de Vries Juna M. , de Bruijn Marienke A. A. M. , Roelen Dave L. , Kim Tae-Joon , Chu Kon , Lee Soon-Tae , Kanbayashi Takamichi , Pollock Nicholas R. , Kichula Katherine M. , Mumme-Monheit Abigail , Honnorat Jérôme , Norman Paul J. , Mignot Emmanuel 

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

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1423149

DOI=10.3389/fimmu.2024.1423149

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p>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 (<italic>HLA</italic>) and killer-cell immunoglobulin-like receptors (<italic>KIR</italic>), 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.</p></sec><sec><title>Methods</title><p>We conducted a Genome Wide Association Study (GWAS) with subsequent control-matching using Principal Component Analysis (PCA) and <italic>HLA</italic> imputation, in a multi-ethnic cohort of anti-NMDAR encephalitis (n=479); <italic>KIR</italic> and <italic>HLA</italic> were further sequenced in a large subsample (n=323). PCA-controlled logistic regression was then conducted for carrier frequencies (<italic>HLA</italic> and <italic>KIR</italic>) and copy number variation (<italic>KIR</italic>). 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.</p></sec><sec><title>Results</title><p>Anti-NMDAR encephalitis showed a weak <italic>HLA</italic> association with <italic>DRB1*01:01~DQA1*01:01~DQB1*05:01</italic> (OR=1.57, 1.51, 1.45; respectively), and <italic>DRB1*11:01</italic> (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 <italic>KIR2DL5B</italic> (OR=1.72), principally due to an overrepresentation of <italic>KIR2DL5B*00201</italic>. Further, we identified two allele associations in framework genes, <italic>KIR2DL4*00103</italic> (25.4% vs. 12.5% in controls, OR=1.98) and <italic>KIR3DL3*00302</italic> (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<sup>dim</sup> or CD56<sup>bright</sup> NK cells did not differ between cases and controls.</p></sec><sec><title>Discussion</title><p>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.</p></sec>