Histocompatibility Gene Products and Their Role in Pregnancy Loss
Histocompatibility gene products, specifically HLA antigens, in the context of pregnancy loss
- Semi-Allograft Nature: Pregnancy involves the development of a fetal placental unit, which can be considered a semi-allograft due to the presentation of allogenic paternal HLA antigens to the mother.
- Protective Role of HLA-G and -E: Extravillous cytotrophoblasts express nonclassical class I HLA-G and -E molecules, potentially serving to protect trophoblasts from cytotoxicity. Experimental evidence in mice supports the idea that blastocyst MHC (similar to HLA-G1 and HLA-G2 in humans) can protect trophoblasts from NK cell-mediated rejection.
- HLA-G Inhibition of NK Cells: In humans, HLA-G inhibits natural killer (NK) cells through NKAT3, contributing to the survival of the fetal semi-allograft during pregnancy. However, clinical correlation between HLA-G expression and recurrent pregnancy losses remains unestablished.
- Regulation of T Cells: HLA-G is not limited to NK cell modulation; it also regulates T cells. The soluble HLA-G1 isoform downregulates both CD8+ and CD4+ T cell reactivity.
- Immune Modulation: HLA-G has an impact on innate immunity by binding to NK and/or decidual receptors, leading to the secretion of certain cytokines. Variability in the 5'-upstream regulatory region of HLA-G may be associated with fetal loss rates, with specific polymorphisms linked to increased risk.
- HLA Antigen Sharing: Excess human leukocyte antigen (HLA) sharing is reported in both primary and secondary recurrent aborters, particularly sharing of HLA-A and DQ antigens. Maternal-fetal histocompatibility for HLA-Class II loci, such as HLA DQA1 alleles, may influence fetal outcomes, with evidence suggesting that HLA-DQA1 compatible fetuses may be aborted early in pregnancy.
- Immune Response and Pregnancy Outcome: Couples with increased HLA sharing and recurrent pregnancy losses often exhibit a lack of anti-paternal cytotoxic antibodies (APCA), anti-idiotypic antibodies (Ab2), and mixed lymphocyte reaction blocking antibodies (MLR-Bf). Overactivity of T helper-1 (Th-1) cytokines and natural killer (NK) cells is associated with recurrent spontaneous abortion (RSA), potentially linked to specific HLA antigens or closely linked genes. HLA class II histoincompatibility may have implications for autoimmune conditions during pregnancy, warranting further investigation.
Reference:
Kwak-Kim J, Kim JW, Gilman-Sachs A. Immunology and Pregnancy Losses: HLA, Autoantibodies and Cellular Immunity. Landes Bioscience; 2000-2013.