Premium
Endoplasmic reticulum aminopeptidase 1 polymorphism Ile276Met is associated with atopic dermatitis and affects the generation of an HLA ‐C associated antigenic epitope in vitro
Author(s) -
NiepiekłoMiniewska W.,
Mpakali A.,
Stratikos E.,
Matusiak Ł.,
Narbutt J.,
Lesiak A.,
Kuna P.,
Wilczyńska K.,
Nowak I.,
Wiśniewski A.,
Zwolińska K.,
Ponińska J.,
Płoski R.,
Szepietowski J.C.,
Kuśnierczyk P.
Publication year - 2019
Publication title -
journal of the european academy of dermatology and venereology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.655
H-Index - 107
eISSN - 1468-3083
pISSN - 0926-9959
DOI - 10.1111/jdv.15449
Subject(s) - single nucleotide polymorphism , epitope , human leukocyte antigen , biology , aminopeptidase , gene , atopic dermatitis , antigen , immunology , genetics , genotype , amino acid , leucine
Background Atopic dermatitis ( AD ) is a common inflammatory skin disease of complex aetiology, with interactions between susceptibility genes and environmental factors. We have previously described a protective effect of the KIR 2 DS 1 gene encoding the natural killer cell receptor, whose ligands are HLA ‐C molecules. Here, we found an association of HLA ‐C*05:01 allele with AD . KIR ‐ HLA ‐C interactions are affected by peptides presented by HLA ‐C. The generation of these peptides is strongly influenced by endoplasmic reticulum aminopeptidases 1 and 2 ( ERAP 1 and ERAP 2). Expression and activity of ERAP molecules depend on the polymorphisms of their genes. Objective Possible associations of several single nucleotide polymorphisms ( SNP s) in the ERAP 1 and ERAP 2 genes with susceptibility to AD . Methods Peripheral blood DNA isolation from 318 patients and 549 controls. PCR ‐ SSO or PCR ‐ SSP for HLA ‐C typing; TaqMan Genotyping Assay for ERAP typing. Results Only one SNP in the ERAP 1 gene, rs26618T>C, causing the amino acid change Ile276Met, had an association with AD . To gain insight on the functional role of this SNP , we produced recombinant variants differing only at position 276 (Ile or Met) and tested their aminopeptidase activity against a N‐terminally extended precursor LIVDRPVTLV of the HLA ‐C*05:01 epitope IVDRPVTLV . Both ERAP 1 variants were able to efficiently generate the epitope, although the 276Ile allotype was able to do this about 50% faster. Furthermore, both variants were quite inefficient in further degradation of the mature epitope. Finally, we found that the effect of 276Met on susceptibility to AD was seen only in KIR 2 DS 1‐negative individuals, not protected by this KIR . Conclusion Associations of HLA ‐C*05:01 allele and rs26618T>C (Ile276Met) ERAP 1 polymorphism with AD , and a significant difference between these two ERAP 1 variants in their ability to generate an epitope for the HLA ‐C*05:01 molecule was found.