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- Epidemiologic Studies
- HLA Studies
- HLA Antibodies
- HY Antibodies
HY antigens are encoded by genes on the Y-chromosome and are ubiquitously expressed in male cells including fetal and trophoblast cells.1 Studies using human leukocyte antigen (HLA)-class-I- and HLA-class-II-restricted CD8+ and CD4+ T-cell clones have identified a series of peptides derived from HY proteins that are recognized by these clones.2 In the non-physiologic situation of stem cell transplantation (SCT), male recipients of parous female HLA-matched SC grafts are more prone to develop graft-versus-host disease (GvHD) than recipients of either nulliparous female grafts or male grafts suggesting that previous pregnancy of the female SC donor can enhance GvHD after SCT.3,4 In SCT, anti-HY antibodies develop significantly more often in male recipients with female SC donors than in those with male donors, and the presence of the antibodies correlates with chronic GvHD.5
In the physiologic situation of pregnancy, maternal cellular immune recognition of the HY antigens is described in women following pregnancies with boys.6,7 Furthermore, anti-HY antibodies are detected in approximately 30% of women, but are rare in healthy men.8 These immune responses were presumably caused by exposure to male cells through pregnancy.
In general, cellular and humoral anti-HY immunity in pregnancy must be considered well tolerated by the fetus because half of all newborns are healthy boys. However, a series of studies primarily from our group have provided evidence that in a minority of women, anti-HY immunity may cause complications in early and late pregnancy.
We here provide a review of the current knowledge of the impact of anti-HY immunity on pregnancy complications with special focus on recurrent miscarriage (RM), severe placental abruptions and low birth weight. This knowledge is based on epidemiologic studies, HLA investigations and measurements of anti-HY and anti-HLA antibodies.
- Top of page
- Epidemiologic Studies
- HLA Studies
- HLA Antibodies
- HY Antibodies
Maternal acceptance of the fetal semi-allograft is an immunologic paradox. We here report the current evidence for the impact of anti-HY immunity on adverse pregnancy outcome with a special focus on patients with secondary RM.
Epidemiologic studies from two centers showed that firstborn boys predispose to secondary RM and affect the prognosis of subsequent pregnancies negatively with regard to the chance of live birth and perinatal complications. Whereas the male/female sex ratio is elevated before secondary RM, it is significantly decreased after secondary RM suggesting that male embryos are preferentially miscarried.
The influence of the presence of the known HY-presenting HLA class I and class II alleles in both the mother and the child born prior to the miscarriages was investigated. The maternal carriage of HY-restricting HLA class II alleles significantly decreased the chance of live birth in patients with secondary RM and firstborn boys compared with those with firstborn girls. The chance of a live birth decreased in a dose–response manner with increasing number of maternal HY-restricting HLA class II alleles in patients with firstborn boys. No impact of maternal HY-restricting HLA class II alleles on the chance of live birth was observed in secondary RM patients with firstborn girls.
The observation that HLA class II but not class I HY-restricting alleles are associated with adverse pregnancy outcomes might reflect the participation of CD4+ T cells providing help for the CD8+ cytotoxic T cells in their response against minor histocompatibility (HY) antigens. Indeed, presence of CD4+ T cells with anti-recipient activity rather than CD8+ T cells was earlier reported in association with GvHD.30–32
The association of pregnancy outcome in secondary RM and maternal (but not fetal) carriage of HY-restricting HLA class II alleles implies that the HY antigens are presented to the immune system via the indirect pathway (maternal HLA alleles present fetal HY antigens). Accepting the hypothesis that there is an association between HLA class II alleles and pregnancy complications relating to male fetuses, it is relevant to look at the presence of specific antibodies in patients with secondary RM because CD4+ Th cell recognition of HY epitopes is HLA class II restricted and Th cells activate B cells to secrete antibodies.
We found, as expected, that the frequency of anti-HLA antibodies was increased in women with secondary RM compared with primary RM, but surprisingly the frequency in secondary RM was significantly higher than in controls who had given birth at least twice and it was also significantly higher in secondary RM patients with a firstborn boy relative to a firstborn girl. Finally, the presence of HLA antibodies decreased the chance of live birth with 35% in the next pregnancy in all patients with RM (P = 0.006) (Table III).
The frequency of HY-specific IgG antibodies was also significantly increased in patients with secondary RM compared with control females who previously had given birth to boys and compared with patients with primary RM. Furthermore, the presence of these antibodies in early pregnancy seemed to be correlated with low male/female sex ratio at birth but no significantly increased clinical miscarriage rate in patients with RM (Table III). This provides support for a direct, early (preclinical) and male-specific embryotoxic response. Such impact of HY antisera has been shown in studies aiming at non-invasive techniques for sex selection of pre-implantation cattle embryos to increase profitability of dairy and beef cattle production.33 Between 80 and 87% of murine and bovine male embryos that are cultured in high-titer rat HY antisera, at the morula stage, stop their development in contrast to female embryos.33,34
In general, alloantibodies (e.g. against paternal HLA) have never convincingly been found to play any pathologic role for outcome in early pregnancy and are so far thought to be a result of previous ongoing pregnancies.35,36 The mechanisms behind the association between future miscarriage rate and the presence of HLA antibodies in the Danish study are unknown. Presence of HLA antibodies may be the direct cause of the increased miscarriage frequency or it may an epiphenomenon that reflects that immunologic recognition has taken place because of prior transfers of fetal cells to the maternal immune circulation. Microchimerism associated with previous obstetric complications may play an important role in the pathogenesis of the miscarriages in patients with secondary RM, and this microchimerism may secondary be associated with an increased prevalence of HLA and HY antibodies.
We can only speculate about the underlying afferent immunologic mechanisms of our epidemiologic finding that maternal carriage of HY-restricting HLA class II alleles significantly reduces the chance of a live birth in secondary RM patients with a firstborn boy. Anti-HY immunization may have taken place during the first ongoing pregnancy with a boy. Maternal immune recognition of HY antigens can be demonstrated in women following pregnancies with boys.6,7 These responses must in general be well tolerated but HY immunization may also have harmful effects as indicated in SCT.37–40 In late pregnancy, apoptotic syncytiotrophoblast debris is normally shed in large quantities (several grams per day) from the placenta,41 and after being processed, peptides derived from HLA, HY and other minor HY antigens are presented to CD4+ and CD8+ T lymphocytes42 in local lymph nodes. This presentation usually takes place under non-inflammatory conditions; resulting in T lymphocytes being tolerized against fetally derived peptides.43 In a significant proportion of ongoing pregnancies with boys prior to secondary RM, complications such as stillbirth, placental abruption or fetal growth retardation occur, which are associated with increased production of inflammatory cytokines systemically or locally in uterus.44–46 Accordingly, the circumstances for sensitization of the adaptive immune system against fetal or trophoblast antigens are present in patients with secondary RM; this risk may be further increased in those patients carrying the HY-restricting HLA class II alleles.
The anti-HY-related efferent pathophysiologic mechanisms for the maternal non-acceptance of the fetus in the patients with secondary RM need to be further elucidated. Anti-HY and anti-HLA antibodies may play a direct role or may only be epiphenomenons. Subnormal levels of and functionally deficient T regulatory (Treg) cells may play a role in RM.47 It is in theory possible that cellular anti-HY responses through production of Th1 cytokines such as TNF-α could be one of the mechanisms reducing Tregs with specificity for non-sex-specific trophoblast antigens thereby increasing the risk of miscarriage of both male and female fetuses.