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.

Mitochondrial microsatellite instability (mtMSI), a change in length in mtDNA microsatellite sequences between normal and tumor tissue, has been described as a frequent occurrence in colorectal cancer (CRC). We evaluated the prevalence and prognostic value of mtMSI and its relation to nuclear microsatellite instability (MSI) in patients with metastatic CRC (mCRC). At six loci (D310, D514, D16184, ND1, ND5, and COX1), the mitochondrial DNA sequence was analyzed in normal and tumor tissue, and the mtMSI status was determined. We evaluated the prevalence and outcome in terms of overall survival (OS) in 83 CRC patients with a MSI tumor (including 39 patients with Lynch syndrome) and in 99 mCRC patients with a microsatellite stable (MSS) tumor. A meta-analysis was performed to compare our findings with existing data. mtMSI at the D-loop region was found in 54.4 % (99 out of 182) of all patients. Prevalence of mtMSI was most pronounced at the D310 locus (50.5 %). Prevalence of mtMSI at the D-loop region was not different among patients with MSI compared to MSS tumors. There was no effect of mtMSI on prognosis in patients with MSI or MSS tumors. Prevalence of mtMSI was high in mCRC patients with both MSI and MSS tumors, but there was no correlation with prognosis. mtMSI was particularly present at the D310 locus.Electronic supplementary materialThe online version of this article (doi:10.1007/s00428-015-1733-8) contains supplementary material, which is available to authorized users.

Soluble HLA‐G (sHLA‐G) levels in human seminal plasma (SP) can be diverse and may affect the establishment of maternal‐fetal tolerance and thereby the outcome of pregnancy. We investigated whether sHLA‐G levels in SP are associated with polymorphisms in the 3′‐untranslated region (UTR) and UTR haplotypes of the HLA‐G gene. Furthermore, we compared the HLA‐G genotype distribution and sHLA‐G levels between men, whose partner experienced unexplained recurrent miscarriage (RM), and controls. Soluble HLA‐G levels (n = 156) and HLA‐G genotyping (n = 176) were determined in SP samples. The concentration of sHLA‐G was significantly associated with several single‐nucleotide polymorphisms (SNPs): the 14 base pair (bp) insertion/deletion (indel), +3010, +3142, +3187, +3196, and + 3509. High levels of sHLA‐G were associated with UTR‐1 and low levels with UTR‐2, UTR‐4, and UTR‐7 (P < .0001). HLA‐G genotype distribution and sHLA‐G levels in SP were not significantly different between the RM group (n = 44) and controls (n = 31). In conclusion, seminal sHLA‐G levels are associated with both singular SNPs and 3UTR haplotypes. HLA‐G genotype and sHLA‐G levels in SP are not different between men whose partner experienced RM and controls, indicating that miscarriages are not solely the result of low sHLA‐G levels in SP. Instead, it is more likely that these miscarriages are the result of a multifactorial immunologic mechanism, whereby the HLA‐G 3′UTR 14 bp ins/ins genotype plays a role in a proportion of the cases. Future studies should look into the functions of sHLA‐G in SP and the consequences of low or high levels on the chance to conceive.

Couples of whom the woman has had a miscarriage have two major concerns: the cause and possible risk of recurrence. Unfortunately, a significant proportion of cases of recurrent miscarriage (RM) remain unexplained despite detailed investigation. Because data suggest that regulatory T cells (Treg) are involved in the maternal acceptance of the allogeneic foetus, RM could possibly be explained by a disturbance of the Treg network. The possible role of Tregs in RM is described in this review, as well as their potential application in diagnostics and therapeutic intervention trials.

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