Anti‐HY Responses in Pregnancy Disorders

Abstract

Problem Cellular and humoral immune responses against male-specific minor histocompatibility (HY) antigens are important in the pathogenesis of graft-versus-host reactions and can be detected in women who have previously given birth to a boy. However, the importance of these responses for pregnancy outcome is unclear. Method of study Review of the current knowledge about the impact of anti-HY immunity on pregnancy outcome in terms of risk of miscarriage, placental abrup-tion and low birth weight. Results Women with secondary recurrent miscarriage (RM) more often have given birth to a boy compared with a girl prior to a series of miscarriages (P < 0.0001) and a firstborn boy seems significantly to reduce the chance of a subsequent live in these patients (P = 0.0003). Human leu-kocyte antigen (HLA) class II alleles known to restrict CD4 T-cell-mediated anti-HY responses were investigated among 358 patients with secondary RM and 203 of their children born prior to the miscarriages. The chance of a subsequent live birth in secondary RM patients with firstborn boys compared with firstborn girls was significantly lower in women with HY-restricting HLA class II alleles [OR: 0.17 (0.1-0.4), P = 0.0001]. In patients without these alleles, the chance of live birth was similar in those with firstborn boys and girls, respectively. In early pregnancy, both antibodies against HLA and HY antigens were found with increased prevalence in secondary patients with RM and in particular in those with a firstborn boy compared with controls (P = 0.005). The presence of these antibodies was associated with a low subsequent live birth rate, and the presence of HY antibodies was associated with a low male ⁄ female ratio (12% boys versus 88% girls) in subsequent live births (P = 0.03). Register-based population studies suggested that births of boys also are associated with subsequent adverse obstetric outcomes also in the background population. Conclusion Findings strongly indicate that aberrant maternal immune reactions against fetal HY antigens playing a role in secondary RM and other pregnancy complications. We propose pathogenetic pathways for these conditions that in our view best explain the findings.

Minor Histocompatibility Antigens and the Maternal Immune Response to the Fetus During Pregnancy

“…Specifically, Christiansen et al have found that women who experience secondary recurrent miscarriage are more likely than the general population to possess the appropriate Class II MHC to present Y‐chromosome‐encoded mHAgs and that secondary recurrent miscarriage is more likely to occur in women who have previously given birth to a male baby, thus presenting the possibility that the development of secondary recurrent miscarriage is related to the generation of a maternal immune response specific for Y‐chromosome‐encoded antigens during the preceding, successful pregnancy. One theory regarding this phenomenon is that pregnancy complications late in the first pregnancy may disrupt the tolerogenic environment required for maintaining maternal immune tolerance toward the fetus and that this disruption contributes to the failure of subsequent pregnancies, especially those with a male fetus . It is important to note that disruption of the tolerogenic environment and maternal T‐cell recognition of both autosomal and Y‐chromosome encoded fetal mHAgs may contribute to many cases of idiopathic infertility as well as numerous pregnancy complications.…”

An altered endometrial CD8 tissue resident memory T cell population in recurrent miscarriage

“…The trophoblast cells that invade the endometrium, specifically extravillous cytotrophoblast, come into direct contact with T cells, but they are inhibited by factors secreted from both the trophoblast and decidualised endometrium, such as indoleamine 2,3-dioxygenase and soluble HLA-G, implying their functions can be dangerous to the developing conceptus19. Despite the release of these factors, inhibition is not complete and T cell responses directed towards the conceptus are formed; peripheral and decidual T cells restricted by male-specific minor histocompatibility (HY) antigens can be detected throughout pregnancy and postpartum202122 and T cells may be activated by other factors such as NK cell receptor ligands23. There is evidence that an immunological memory response to pregnancy can be generated as secondary RM is more frequent after a first successful male, rather than female pregnancy24; and pregnancies ending in miscarriage rather than live birth are associated with an increased risk of further miscarriage25.…”

Genetics of Transfusion Recipient Alloimmunization: Can Clues from Susceptibility to Autoimmunity Pave the Way?

“…The neonatal conditions linked to alloimmunization include fetal and neonatal alloimmune thrombocytopenia [126,127], fetal and neonatal hemolytic anemia [128], alloimmune neonatal neutropenia [129], hydrops fetalis [130], neonatal hemochromatosis [131], biliary atresia [132], and neonatal glomerulopathy [133]. Alloimmunization was also proposed to at least partially explain implantation failure, recurrent pregnancy loss and pre-eclampsia/eclampsia [134,135] as well as inflammatory lesions of the placental villi during pregnancy [136]. It is therefore clear that the lessons learned from genetics of lupus and autoimmunity in general may have a broader impact than initially thought.…”