Lung transplantation (LTx) is a valid therapeutic option for selected patients with end‐stage lung disease. Soluble HLA‐G (sHLA‐G) has been associated with increased graft survival and decreased rejection episodes in solid organ transplantation. HLA‐G haplotypes named UTRs, defined by SNPs from both the 5′URR and 3′UTR, have been reported to reliably predict sHLA‐G level. The aim of this retrospective study was to determine the impact of HLA‐G alleles and UTR polymorphism from LTx recipients on anti‐HLA allo‐immunization risk, overall survival and chronic rejection (CLAD). HLA‐G SNPs were genotyped in 124 recipients who underwent LTx from 1996 to 2010 in Marseille, 123 healthy individuals and 26 cystic fibrosis patients not requiring LTx. sHLA‐G levels were measured for 38 LTx patients at D0, M3 and M12 and for 123 healthy donors. HLA‐G*01:06∼UTR2 was associated with a worse evolution of cystic fibrosis (p = 0.005) but not of long‐term survival post‐LTx. HLA‐G*01:04∼UTR3 haplotype was associated with lower levels of sHLA‐G at D0 and M3 (p = 0.03), impaired long‐term survival (p = 0.001), increased CLAD occurrence (p = 0.03) and the production of de novo donor‐specific antibodies (DSA) at M3 (p = 0.01). This study is the first to show the deleterious association of different HLA‐G alleles and UTRs in LTx.

Hypoxia-inducible factor 1 (HIF-1) is a master transcriptional regulator of genes regulating oxygen homeostasis. The HIF-1 protein is composed of two HIF-1α and HIF-1β/aryl hydrocarbon receptor nuclear translocator (ARNT) subunits. The prognostic relevance of HIF-1α protein overexpression has been shown in breast cancer. The impact of HIF-1α alternative splice variant expression on breast cancer prognosis in terms of metastasis risk is not well known.

Polymorphisms have been identified in the Xq28 locus as risk loci for rheumatoid arthritis (RA). Here, we investigated the association between three polymorphisms in the Xq28 region containingTMEM187andIRAK1(rs13397, rs1059703, and rs1059702) in two unstudied populations: Tunisian and French. The rs13397 G and rs1059703 T major alleles were significantly increased in RA patients (n=408) compared with age-matched controls (n=471) in both Tunisian and French women. These results were confirmed by a meta-analysis replication study including two independent Greek and Korean cohorts. The rs1059702 C major allele was significantly associated with RA, only with French women. In the French population, the GTC haplotype displayed a protective effect against RA, while the ATC, GCC, and GTT haplotypes conferred significant risk for RA. No association for these haplotypes was found in the Tunisian population. Our results replicated for the first time the association of the three Xq28 polymorphisms with RA risk in Tunisian and French populations and suggested that RA susceptibility is associated withTMEM187-IRAK1polymorphisms in women. Our data further support the involvement of X chromosome in RA susceptibility and evidence ethnicities differences that might be explained by differences in the frequencies of SE HLA-DRB1 alleles between both populations.

The biological relevance of genes initially categorized as “pseudogenes” is slowly emerging, notably in innate immunity. In the HLA region on chromosome 6, HLA-H is one such pseudogene; yet, it is transcribed, and its variation is associated with immune properties. Furthermore, two HLA-H alleles, H*02:07 and H*02:14, putatively encode a complete, membrane-bound HLA protein. Here we thus hypothesized that HLA-H contributes to immune homeostasis similarly to tolerogenic molecules HLA-G, -E, and -F. We tested if HLA-H*02:07 encodes a membrane-bound protein that can inhibit the cytotoxicity of effector cells. We used an HLA-null human erythroblast cell line transduced with HLA-H*02:07 cDNA to demonstrate that HLA-H*02:07 encodes a membrane-bound protein. Additionally, using a cytotoxicity assay, our results support that K562 HLA-H*02:07 inhibits human effector IL-2–activated PBMCs and human IL-2–independent NK92-MI cell line activity. Finally, through in silico genotyping of the Denisovan genome and haplotypic association with Denisovan-derived HLA-A*11, we also show that H*02:07 is of archaic origin. Hence, admixture with archaic humans brought a functional HLA-H allele into modern European and Asian populations. Key Points HLA-H*02:07 encodes a membrane-bound protein. HLA-H*02:07 inhibits human effector cell activity. HLA-H*02:07 is of archaic origin.