A potentially hazardous immunological response during pregnancy is more probable when the mother exhibits elevated levels of pbNK cells, facilitating an immunological attack against the fetus. Heightened pbNK cytotoxicity, combined with a propensity for a Th1 proinflammatory response over the favorable Th2 anti-inflammatory counterpart, poses risks for pregnancy. Elevated concentrations and increased activity of cytotoxic pbNK cells, alongside a dominance of the pro-inflammatory Th1 response, have been linked to reproductive immunopathology, including conditions like recurrent spontaneous abortions (RSA), idiopathic infertility, and implantation failure in both natural and assisted reproduction attempts.

A complete reproductive immunology evaluation through the FERTILYSIS Reproductive Immunology Full panel involves the following tests:

✔ NK/Regulatory T-Cell (Tregs) profile

✔ HLA-DQ Alpha matching

✔ NK cell cytotoxicity assay

✔ KIR-HLA-C mismatch

✔ Th1/Th2 cytokine ratio assay

✔ Leukocyte Antibody Detection (LAD)

NK cell profile/ NK cell cytotoxicity

NK cells (Natural Killer cells) are a type of immune cell that play a role in the body's defense against infections and cancer. However, in the context of fertility and pregnancy, elevated NK cell levels in the peripheral blood and, as a consequence, potentially in the uterus, are considered a risk factor for infertility and recurrent miscarriage. Increased, dysregulated NK cell activity in the uterus both in number and toxicity levels may mistakenly attack the developing embryo as a foreign object. This can result in impaired implantation, early pregnancy loss, or recurrent miscarriages.

Th1/Th2 cytokine ratio

The Th1/Th2 ratio relates to the balance between two types of immune cells: Th1 (T-helper 1) and Th2 (T-helper 2) cells. These cells play different roles in the immune system and are involved in regulating immune responses. In the context of infertility, Th1 cells are associated with pro-inflammatory responses and can promote immune reactions that may be detrimental to pregnancy. On the other hand, Th2 cells are associated with anti-inflammatory responses and are involved in promoting tolerance and supporting pregnancy. An imbalance in the Th1/Th2 ratio, with increased Th1 activity and decreased Th2 activity, may create an environment that is less supportive of successful implantation and pregnancy maintenance which may lead to increased inflammation and immune responses that could potentially harm the developing embryo or interfere with implantation.

HLA DQα-1 partner matching

In a healthy pregnancy, the mother's immune system adapts to accept the fetus through active immunological tolerance. This process involves the identification of at least a minimum level of genetic diversity from the father, including diverse human leukocyte antigen (HLA) genes. Studies suggest that fetuses with HLA haplotypes similar to the mother's are more likely to be aborted. Through this test we can predict possible embryo HLA combination and compare to the mother for compatibility.

KIR-HLA-C mismatch

To maintain tolerance, Immune suppressive regulatory T cells (Tregs) and uterine natural killer cells (uNKs) need to regulate the local uterine immunity and prevent rejection of the embryo. The activation of uNKs is facilitated by killer immunoglobulin-like receptors (KIRs), which interact with fetal HLAs. The balance between activating and inhibitory KIRs determines the activation or inhibition of NK cells, crucial for successful pregnancy outcomes. Defective placentation, pre-eclampsia, fetal growth restriction, and recurrent spontaneous abortion are associated with higher frequencies of inhibitory KIRs in women. Specific combinations of maternal KIR and paternal HLA-C genes may indicate a higher risk of infertility. This test allows genotyping of maternal KIR genes and comparison with possible fetal HLA genotypes to predict a possible mismatch.

Lymphocyte Antibody Detection (LAD)

It is a specialized infertility test aimed at assessing immune compatibility between partners. This test is particularly relevant in cases where there are recurrent pregnancy losses or unexplained infertility. During LAD testing, the blood of the female partner is analyzed to detect the presence of antibodies that may react against her partner's lymphocytes. The rationale behind this test is based on the concept of immune-mediated infertility, where the female partner's immune system produces antibodies against the male partner's cells, as a measure of the levels of blocking antibodies and protective antibodies which need to be produced during pregnancy to stop maternal immunological response against the fetus. Overall, LAD interpretation and utility should be evaluated in conjunction with other clinical findings and diagnostic tests.