KIR2DL4 genetic diversity in a Brazilian population sample: implications for transcription regulation and protein diversity in samples with different ancestry backgrounds

Weiss, Emiliana; Andrade, Heloisa S.; Lara, Juliana R.; Souza, Andréia S.; Paz, Michelle A.; Porto, Iane O. P.; Silva, Nayane S. B.; Castro, Camila Ferreira Bannwart; Grotto, Rejane Maria Tommasini; Donadi, Eduardo Antônio; Mendes-Junior, Celso Teixeira; Castelli, Erick C.

doi:10.1007/s00251-021-01206-9

Cited by 2 publications

(1 citation statement)

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“…KIR2DL4 is likely an activating receptor that recognizes HLA-G as its ligand ( 58 ). HLA-G is highly expressed in trophoblast, although expression is also present in thymus, cornea, and pancreas islet ( 65 , 66 ). HLA-G is also present as a secreted protein.…”

Section: Discussionmentioning

confidence: 99%

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

Peris Sempere,

Luo,

Muñiz-Castrillo

et al. 2024

Front. Immunol.

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IntroductionGenetic 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.MethodsWe 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.ResultsAnti-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.DiscussionOur 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.

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Section: Discussionmentioning

confidence: 99%

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

Peris Sempere,

Luo,

Muñiz-Castrillo

et al. 2024

Front. Immunol.

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Advances in the study of HLA class Ib in maternal-fetal immune tolerance

et al. 2022

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The HLA class Ib molecule is an alloantigen that causes transplant rejection on behalf of individual human and plays an important role in maternal-fetal immune tolerance. Early studies on HLA class Ib focused on the mechanism of HLA-G-induced immune escape, but in recent years, studies on the mechanism of HLA-G have deepened and gradually explored the mechanism of HLA-E and HLA-F, which are also HLA class Ib molecules. In the maternal-fetal interface, trophoblast cells express HLA class Ib molecules to protect the fetus from maternal immune cells by binding to inhibitory receptors of decidual immune cells (DICs) and shifting Th1/Th2 balance toward Th2 bias. Further studies on the molecular mechanism of HLA class Ib molecules provide a reference for its application in the field of clinical assisted reproduction.

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KIR2DL4 genetic diversity in a Brazilian population sample: implications for transcription regulation and protein diversity in samples with different ancestry backgrounds

Cited by 2 publications

References 85 publications

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

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

Advances in the study of HLA class Ib in maternal-fetal immune tolerance

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