Soluble HLA in the aqueous humour of uveal melanoma is associated with unfavourable tumour characteristics

A high HLA expression in uveal melanoma (UM) is part of the prognostically unfavorable inflammatory phenotype. We wondered whether the presence of soluble HLA (sHLA) in the aqueous humour is associated with clinical, histopathological or genetic tumour characteristics, and represents tumour HLA expression and intratumoural inflammation. Aqueous humour from 108 UM patients was analysed for the presence of sHLA, using a Luminex assay specific for HLA Class I. Clinical and genetic parameters were compared between sHLA-positive and negative eyes. A qPCR analysis was performed on tumour tissue using a Fluidigm assay. In 19/108 UM-containing eyes, the sHLA level in the aqueous was above the detection limit. Tumours in sHLA-positive eyes were significantly larger, more frequently involved the ciliary body, and more often showed monosomy 3, gain of chromosome 8q and loss of BAP1 staining. Melanoma-related survival was worse in patients with sHLA-positive aqueous humour. sHLA in the aqueous did not represent the tumour's HLA expression and did not relate to immune cell infiltration in the tumour. We conclude that UM-containing eyes may contain sHLA in the aqueous humour, where it is a prognostically-unfavourable sign and may influence local immune responses

A Uniform Genomic Minor Histocompatibility Antigen Typing Methodology and Database Designed to Facilitate Clinical Applications

BACKGROUND: Minor Histocompatibility (H) antigen mismatches significantly influence the outcome of HLA-matched allogeneic stem cell transplantation. The molecular identification of human H antigens is increasing rapidly. In parallel, clinical application of minor H antigen typing has gained interest. So far, relevant and simple tools to analyze the minor H antigens in a quick and reliable way are lacking. METHODOLOGY AND FINDINGS: We developed a uniform PCR with sequence-specific primers (PCR-SSP) for 10 different autosomal minor H antigens and H-Y. This genomic minor H antigen typing methodology allows easy incorporation in the routine HLA typing procedures. DNA from previously typed EBV-LCL was used to validate the methodology. To facilitate easy interpretation for clinical purposes, a minor H database named dbMinor (http://www.lumc.nl/dbminor) was developed. Input of the minor H antigen typing results subsequently provides all relevant information for a given patient/donor pair and additional information on the putative graft-versus-host, graft-versus-tumor and host-versus-graft reactivities. SIGNIFICANCE: A simple, uniform and rapid methodology was developed enabling determination of minor H antigen genotypes of all currently identified minor H antigens. A dbMinor database was developed to interpret the genomic typing for its potential clinical relevance. The combination of the minor H antigen genomic typing methodology with the online dbMinor database and applications facilitates the clinical application of minor H antigens anti-tumor targets after stem cell transplantation

The combination of maternal KIR-B and fetal HLA-C2 is associated with decidua basalis acute atherosis in pregnancies with preeclampsia

Acute atherosis is an arterial lesion most often occurring in pregnancies complicated by preeclampsia, a hypertensive pregnancy disorder. Acute atherosis predominates in the maternal spiral arteries in the decidua basalis layer of the pregnant uterus. This layer forms the fetal-maternal immunological interface, where fetal extravillous trophoblasts interact with maternal immune cells to promote decidual spiral artery remodeling and maternal immune tolerance towards the fetus. Of the classical polymorphic class I HLAs, extravillous trophoblasts express only HLA-C. HLA-C is a ligand for killer immunoglobulin-like receptors (KIR) on NK- and T-cells. Genetic combinations of fetal HLA-C and maternal KIRs affect pregnancy outcome. However, the role of HLA and KIR genes in acute atherosis is unknown. We hypothesized that specific genetic combinations of fetal HLA and maternal KIR are associated with the presence of acute atherosis lesions in the decidua basalis. We genotyped HLA class-I and II loci in paired fetal and maternal DNA samples from 166 pregnancies (83 preeclamptics, 83 controls). Acute atherosis was identified in 38 of these. Maternal KIR-loci were also genotyped. We found that the combination of maternal KIR-B haplotype and fetal HLA-C2 was significantly associated with acute atherosis in preeclampsia. In preeclamptic pregnancies with acute atherosis, 60% had this combination, compared to 24.5% in those without acute atherosis (p = 0.001). We suggest that interactions between fetal HLA-C2 and activating KIRs on maternal decidual NK-cells or T-cells may contribute to the formation of acute atherosis by promoting local decidual vascular inflammation

Increased HLA-G Expression in Term Placenta of Women with a History of Recurrent Miscarriage Despite Their Genetic Predisposition to Decreased HLA-G Levels

Human leukocyte antigen (HLA)-G is an immune modulating molecule that is present on fetal extravillous trophoblasts at the fetal-maternal interface. Single nucleotide polymorphisms (SNPs) in the 3 prime untranslated region (3′UTR) of the HLA-G gene can affect the level of HLA-G expression, which may be altered in women with recurrent miscarriages (RM). This case-control study included 23 women with a medical history of three or more consecutive miscarriages who delivered a child after uncomplicated pregnancy, and 46 controls with uncomplicated pregnancy. Genomic DNA was isolated to sequence the 3′UTR of HLA-G. Tissue from term placentas was processed to quantify the HLA-G protein and mRNA levels. The women with a history of RM had a lower frequency of the HLA-G 3′UTR 14-bp del/del genotype as compared to controls (Odds ratio (OR) 0.28; p = 0.039), which has previously been related to higher soluble HLA-G levels. Yet, HLA-G protein (OR 6.67; p = 0.006) and mRNA (OR 6.33; p = 0.010) expression was increased in term placentas of women with a history of RM as compared to controls. In conclusion, during a successful pregnancy, HLA-G expression is elevated in term placentas from women with a history of RM as compared to controls, despite a genetic predisposition that is associated with decreased HLA-G levels. These findings suggest that HLA-G upregulation could be a compensatory mechanism in the occurrence of RM to achieve an ongoing pregnancy