We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
HLA and KIR genetic association and NK cells in anti-NMDAR encephalitis.
- Authors
Peris Sempere, Vicente; Guo Luo; Muñiz-Castrillo, Sergio; Pinto, Anne-Laurie; Picard, Géraldine; Rogemond, Véronique; Titulaer, Maarten J.; Finke, Carsten; Leypoldt, Frank; Kuhlenbäumer, Gregor; 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.; Tae-Joon Kim; Kon Chu
- Abstract
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). PCAcontrolled 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 CD56dim or CD56bright 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.
- Subjects
ANTI-NMDA receptor encephalitis; KILLER cells; MONONUCLEAR leukocytes; GENOME-wide association studies; HLA histocompatibility antigens; METHYL aspartate receptors
- Publication
Frontiers in Immunology, 2024, p1
- ISSN
1664-3224
- Publication type
Academic Journal
- DOI
10.3389/fimmu.2024.1423149