Association of reduced maternal sHLA‐G5 isoform levels and elevated TNF‐α/IL‐4 cytokine ratio with Recurrent Pregnancy Loss: A study on South Indian women

Abstract

Inflammation is of critical importance in successful implantation during pregnancy.However, the establishment of maternal immune tolerance towards semi-allograft foetus is more exigent and is achieved predominantly by human leukocyte antigen-G (HLA-G) isoforms with a special emphasis on soluble HLA-G5 (sHLA-G5).Constant inflammation and lack of resolution by anti-inflammatory milieu, due to aberrant expression of critical immunoregulatory molecules such as sHLA-G5 and dysfunctional T helper cells 1 and 2 (Th1-Th2) cytokine shift, can lead to adverse pregnancy outcomes including recurrent pregnancy loss (RPL). Serum samples of 270 pregnant women (135 healthy parous and 135 with a history of RPL) were evaluated for the concentrations of sHLA-G5, interleukin-4 (IL-4) and tumour necrosis factor-alpha (TNF-α) using sandwich enzyme-linked immunosorbent assay (ELISA) and found elevated levels of sHLA-G5 and IL-4 in controls and higher TNF-α levels and TNF-α:IL-4 ratio in patients (P < .05). Stratified data analysis based on the time of sample collection, that is the first and second trimesters exhibited higher sHLA-G5 and IL-4 in both first and second trimesters in controls than patients, while they displayed lower levels concerning TNF-α and TNF-α:IL-4 ratio (P < .05). However, within patients and controls in the first or second trimesters, there was a significant variation concerning sHLA-G5 alone. Further, the outcome of pregnancies studied in the present investigation revealed a significant elevation in sHLA-G5 levels among women with successful pregnancies compared with women who experienced pregnancy loss, therefore, concluding the potential application of sHLA-G5 isoform as a marker in assisting improved pregnancy outcomes.

Association of human leukocyte antigen‐G and ‐F with recurrent miscarriage and implantation failure: A systematic review and meta‐analysis

“…Five studies reported sHLA‐G levels in women with RM as compared with controls, including three studies that considered the differences during pregnancy, 30–32 and two that focused on non‐pregnant women 12,33 . One targeted only the sHLA‐G5 isoform 31 . The meta‐analysis showed that these five articles had markedly significant heterogeneity ( p = .001, I 2 = 98.0%) and no significant difference were found using the random‐effects model (standardized mean difference [SMD] −1.119, 95% confidence interval [CI] −2.422, 0.815; z = 1.68, p = .093; total 676 women; Figure S1A).…”

“…12,33 One targeted only the sHLA-G5 isoform. 31 The metaanalysis showed that these five articles had markedly significant heterogeneity (p = .001, I 2 = 98.0%) and no significant difference were found using the random-effects model (standardized mean difference…”

“…Five studies reported sHLA-G levels in women with RM as compared with controls, including three studies that considered the differences during pregnancy, [30][31][32] and two that focused on non-pregnant women. 12,33 One targeted only the sHLA-G5 isoform.…”

UP‐regulated levels of sHLA‐G in women with a history of RPL in mid‐gestation presumably to achieve ongoing pregnancy

“…This also includes the production of a glycoprotein molecule HLA‐G, derived from placenta flooding maternal‐fetal interface and in maternal circulation throughout the pregnancy 15,57 . Immunologically a successful pregnancy can be divided into alternate phases of pro (1 st and 3 rd ) and anti‐inflammation (2 nd ) for implantation, parturition and for fetal growth respectively, 58 This immunological shift during gestation is mediated by HLA‐G 47 . HLA‐G works via various mechanisms like it induces tolerogenic dendritic cells (DC‐10) and other regulatory cells via interaction with ILT‐2 and/or ILT‐4 receptor to produce anti‐inflammatory cytokine like interleukin‐10 59 .…”

Tumour necrosis factor inhibitor combined with intravenous immunoglobulin and heparin for treatment of recurrent spontaneous abortion: A two‐centre, retrospective, cohort study

“…The upregulation of inflammatory cytokines (such as TNF-α) in RSA patients compared to controls has been reported, indicating the potential underlying mechanism of these cytokines in RSA pathogenesis. 18,19 Recently, TNFi has been indicated in treating RSA patients for rescuing pregnancy management, while these findings are conflicting.…”