Endoplasmic reticulum aminopeptidase 1 polymorphism Ile276Met is associated with atopic dermatitis and affects the generation of an HLA-C associated antigenic epitope in vitro.

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 KIR2DS1 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 (ERAP1 and ERAP2). Expression and activity of ERAP molecules depend on the polymorphisms of their genes. OBJECTIVE: Possible associations of several single nucleotide polymorphisms (SNPs) in the ERAP1 and ERAP2 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 ERAP1 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 ERAP1 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 KIR2DS1-negative individuals, not protected by this KIR. CONCLUSION: Associations of HLA-C*05:01 allele and rs26618T>C (Ile276Met) ERAP1 polymorphism with AD, and a significant difference between these two ERAP1 variants in their ability to generate an epitope for the HLA-C*05:01 molecule was found.

Lack of detectable fetal microchimerism in psoriasis vulgaris lesions and in non-affected skin in spite of its presence in peripheral blood CD34-positive and CD34-negative cells.

BACKGROUND: Microchimerism is defined as a stable presence of low numbers of cells derived from a different individual due to cell transfer between twins or between mother and fetus during pregnancy. OBJECTIVE: Fetal cells in the organism of the mother (FMc) are postulated to play a role in autoimmune diseases. Psoriasis is a disease which has an autoimmune component, but no study on microchimerism in this disease has been reported. METHODS: The easiest way to detect microchimerism is to look for male cells in blood or other tissues of a woman who previously delivered a son. Here, we looked for the presence of male cells in mononuclear cell subpopulations from peripheral blood and in skin samples of women with psoriasis and of healthy women. RESULTS: We detected FMc in similar proportions of patients and controls in CD4+, CD8+ and CD34+ cells, whereas in CD34- cells they were present in higher fraction of controls, and similar but non-significant difference was observed in CD19+ cells. No microchimeric cells were detected in patients' skin samples, both from affected and non-affected skin, or in skin tissue from healthy control individuals. CONCLUSION: Our result does not prove the involvement of microchimerism in the aetiology of psoriasis.