Immunogenetic contributions to recurrent pregnancy loss

Abstract

While sporadic pregnancy loss is common, occurring in 15 % of pregnancies, recurrent pregnancy loss (RPL) impacts approximately 5 % of couples. Though multiple causes are known (including structural, hormonal, infectious, autoimmune, and thrombophilic causes), after evaluation, roughly half of all cases remain unexplained. The idiopathic RPL cases pose a challenging therapeutic dilemma in addition to incurring much physical and emotional morbidity. Immunogenetic causes have been postulated to contribute to these cases of RPL. Natural Killer cell, T cell expression pattern changes in the endometrium have both been shown in patients with RPL. Human leukocyte antigen (HLA) and cytokine allelic variations have also been studied as etiologies for RPL. Some of the results have been promising, however the studies are small and have not yet put forth outcomes that would change our current diagnosis and management of RPL. Larger database studies are needed with stricter control criteria before reasonable conclusions can be drawn.

Keywords: HY-Antibodies; Human leukocyte antigens; Immunogenetics; Recurrent pregnancy loss; T regulatory cell.

Fig. 1

Natural killer cells. NK cells migrate from the bone marrow to the uterus in response to progesterone and estrogen [17]. NK cells detect altered MHC class 1 proteins and use perforin and granzymes to destroy extravillous trophoblastic cells [42]

Fig. 2

T cells. T cell expression and regulation is an important process in the establishment and maintenance of early pregnancy. There are still many unknowns regarding their mechanisms of action. This diagram gives a general overview. Estrogen, βHCG, and G-CSF are all known to induce expression of Treg cells and migration to the endometrium [–71]. There they express IL-10, TGFβ, and TNFα [10]. TNF-α is produced by all CD4+ T cells [, –75]. IL-10 inhibits macrophages and Th1 cell proliferation [76, 77]. Th1 cells both produce and are promoted by IFN-γ [11, 72, 73, 78, 79]. They secrete IL-12 as well [41]. They can induce Th17 and NK cells. Th2 cells produce IL-4, -5, -13 [41]. IL-4 is known to inhibit Th1 [76]. IL-6 is known to promote Th2 cells [80]. Th17 are derived in response to TGFβ and IL-6 as well as inflammation [41]. They secrete IL-17, -21, -22 [, –86]