Association of HY-restricting HLA class II alleles with pregnancy outcome in patients with recurrent miscarriage subsequent to a firstborn boy

Abstract

Healthy females, pregnant with a boy, generate immune responses against male-specific minor histocompatibility (HY) antigens. The clinical importance of these responses is evident in stem cell transplantation. Birth of a boy prior to a series of miscarriages reduces the chance of a subsequent live birth. This study explores the putative impact of known HY-presenting HLA alleles on future pregnancy outcome in women with at least three consecutive miscarriages following a birth [secondary recurrent miscarriage (SRM)]. HLA-A, -B, -DRB1, DRB3-5 and DQB1 genotyping was performed in 358 SRM patients and in 203 of their children born prior to the miscarriages. The subsequent live birth in women with boys prior to the miscarriages compared with girls is lower in women with HY-restricting HLA class II alleles [odds ratio (OR): 0.17 (0.1-0.4), P = 0.0001]. One HY-restricting HLA class II allele in women with firstborn boys significantly reduces the chances of a live birth [OR: 0.46 (0.2-0.9), P = 0.02]. Two HY-restricting HLA class II alleles further reduced this chance [OR: 0.21 (0.1-0.7), P = 0.02]. HY-restricting HLA class II did not reduce the chances of a live birth in SRM women with firstborn girls. HY-restricting HLA class II alleles are associated with a decreased chance of a live birth in SRM women with firstborn boys. These findings strongly indicate an aberrant maternal immune reaction against fetal HY-antigens in SRM. The results may shed light on the as-yet unknown immunological causes of SRM and may help understand the successful maternal acceptance of the fetal semi-allograft.

Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics

“…In another study, the prevalence of a 14 base pair insertion in exon 8 of the HLA-G gene was found to be increased significantly in secondary RM patients, compared with controls. These studies provide evidence that particular HLA polymorphisms characterize secondary RM [5][6][7].…”

“…However, pregnancy with a boy may prime the mother's HY immunity. Nielsen et al found that maternal carriage of HLA class II alleles that restrict anti-HY antigen responses reduces the chances of a live birth in secondary RM patients with a firstborn boy compared with a firstborn girl (OR = 0·17; 95% CI = 0·1-0·4; P = 0·0001) [6]. In another study, the prevalence of a 14 base pair insertion in exon 8 of the HLA-G gene was found to be increased significantly in secondary RM patients, compared with controls.…”

“…In another study, the prevalence of a 14 base pair insertion in exon 8 of the HLA-G gene was found to be increased significantly in secondary RM patients, compared with controls. These studies provide evidence that particular HLA polymorphisms characterize secondary RM [5][6][7].Huge heterogeneity between eight randomized placebocontrolled trials of IVIg to patients with RM has been observed, with live birth rates in placebo groups ranging from 29 to 79% [8][9][10][11][12][13][14][15]. The differences in live birth rates observed between these studies raises questions as to whether the patient categories are the same.…”

Fetal-Specific CD8+ Cytotoxic T Cell Responses Develop during Normal Human Pregnancy and Exhibit Broad Functional Capacity

“…It may also be potentially important in the pathogenesis of fetal loss with epidemiological evidence that women with recurrent miscarriage and a male first child may, due to priming against HY Ags, have a reduced chance of future successful pregnancy (35,36). Additionally, when women with recurrent miscarriage have an HLA class II type known to be able to present immunodominant HY epitopes, this is associated with a reduction in subsequent live births (37).…”

The Role of Glucocorticoids in Pregnancy: Four Decades Experience with Use of Betamethasone in the Prevention of Pregnancy Loss

“…Activation along the Th-1 pathway, instead, results in the production of abortive cytokines (Raghupathy et al, 2000). Maternal HY-restricting HLA class II alleles are associated with a decreased chance of a live birth in women with secondary recurrent miscarriage with a firstborn boy (Nielsen et al, 2009). Although such mechanisms are intriguing, there is a paucity of validated tests to assess the maternal immune response in pregnancy.…”