Mechanism of Human Chorionic Gonadotrophinmediated Immunomodulation in Pregnancy

Amolak S Bansal; Shabana A Bora; Srdjan Saso; J Richard Smith; Mark R Johnson; Meen-Yau Thum


Expert Rev Clin Immunol. 2012;8(8):747-753. 

In This Article

Abstract and Introduction


Human chorionic gonadotrophin (hCG) is released within hours of fertilization and has a profound ability to downregulate maternal cellular immunity against trophoblastic paternal antigens. It also promotes angiogenic activity of the extravillous trophoblast, and impairment of this function may lead to inadequate placentation and an increased risk of preeclampsia. There is increasing evidence that hCG alters the activity of dendritic cells via an upregulation of indoleamine 2,3-dioxygenase activity. This reduces T-cell activation and cytokine production, as well as encouraging Treg cell recruitment to the fetal–maternal interface. These changes are critical in promoting maternal tolerance. hCG is also able to increase the proliferation of uterine natural killer cells, while reducing the activity of cytotoxic peripheral blood natural killer cells. There are rare reports of autoantibodies directed against hCG or the luteinizing hormone/hCG receptor in women with recurrent miscarriage. These autoantibodies are more frequent in women with thyroid autoimmunity. This may explain the association between thyroid autoimmunity and impaired fertility. Downregulating these anti-hCG and anti-luteinizing hormone/hCG receptor autoantibodies may be helpful in some women with early miscarriage or recurrent failed in vitro fertilization.


Human chorionic gonadotrophin (hCG) is a glycoprotein hormone with a 92 amino acid α and a 145 amino acid β subunit. The β subunit confers specificity to the hormone and has an interesting set of conserved sequences that are similar to TGF-β. This similarity to TGF-β may link hCG to the development of certain cancers and to trophoblastic invasion of the maternal endometrium.[1] However, it is unclear whether the TGF-β-related sequence in hCG plays a role in the alteration of T and natural killer (NK) cell function.

hCG has several distinct molecular forms, which while sharing a common amino acid sequence, differ in their meric structure and in the details of their carbohydrate side chains.[1] The molecular weight of the sugars attached to hCG may account for 30% or more of its total molecular weight. Each type of hCG is produced by a different type of cell and each has a different profile of biological function. hCG and sulfated hCG are hormones produced by placental syncytiotrophoblasts and pituitary gonadotrophs, respectively. Hyperglycosylated hCG is produced by placental cytotrophoblasts and has autocrine effects with a significant role in reducing myometrial contractility[2] and promoting placental angiogenesis.[3]

Normal human pregnancy is a complex process requiring controlled trophoblastic invasion and angiogenesis in the decidual endometrium[3] and downregulation of the maternal immune response to 'non-self' tissue proteins.[4] This is associated with an increase in tolerance-promoting Treg activity[5,6] and a commensurate decrease in the proinflammatory Th17-cell activity.[7] hCG is critical in all these functions and is secreted by the growing embryo as early as the eight-cell stage. It is vitally important to maintain the corpus luteum and its secretion of progesterone. This review focuses on the ability of hCG to reduce maternal immune activity against the paternal HLA-disparate molecules expressed by the trophoblast. The authors also explore the possibility that defective hCG activity resulting from insufficient hCG production or the presence of anti-hCG and/or anti-hCG receptor (hCGR) autoantibodies may explain some early and recurrent miscarriages (RMs).