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

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 () and killer-cell immunoglobulin-like receptors (), 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 imputation, in a multi-ethnic cohort of anti-NMDAR encephalitis (n=479); and were further sequenced in a large subsample (n=323). PCA-controlled logistic regression was then conducted for carrier frequencies ( and ) and copy number variation (). 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 association with (OR=1.57, 1.51, 1.45; respectively), and (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 (OR=1.72), principally due to an overrepresentation of . Further, we identified two allele associations in framework genes, (25.4% vs. 12.5% in controls, OR=1.98) and (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 or CD56 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.