What is Alloimmune Implantation Dysfunction

A pregnancy must normally be recognized as different from other maternal body parts to trigger the appropriate immunologic mechanisms. It is as if it has to request the ability to implant. Human Leukocyte Antigen (HLA) compatibility plays an important role in this recognition (HLA-A, B, C, DR, DQ and DP). It is, in effect, the credentials checked by the maternal white blood cells that determine whether or not implantation will be allowed. Simply put, if the father’s HLA markers too closely resemble the mother’s HLA, then permission to implant will not be granted, resulting in a spontaneous abortion or implantation failure. HLA-G is a unique HLA that is expressed by placental cells. The HLA-G identifier is vital to the maternal tolerance of the fetus and functions as immunosuppressive. In other words, HLA-G serves as a defense mechanism to protect the placenta (embryo) from the maternal NK cells. We recently reported that it is now possible to determine the accurate pregnancy potential of each embryo before IVF implantation. The presence of high levels of sHLA-G had a positive predictive value greater than 70% in women under the age of 39, and over 50% in women from 39 to 44 years old.

When the sperm and the woman hosting the pregnancy share several HLA antigens (e.g. HLA- B, C, DR, DQ or DP), there is a breakdown in normal HLA-G related cytokine signaling. As a result, an imbalance occurs between the cytokines called TH-1 and TH-2, with TH-1 cytokines predominating. This often causes progressive or sudden implantation (trophoblastic) failure, most commonly manifesting as recurrent miscarriages and sometimes as unexplained IVF failure.

Therefore a high rate of HLA loci-sharing between the male partner providing the sperm and the female that is the embryo recipient may act to prevent implantation. It is the presenting peptides of the relevant HLA loci (A, B, C, DR, DQ) which come in contact with the partner’s T cells (immune cells in the uterine lining) that initiates the immune response cascade. Most couples will share no more than one locus (out of 10 possible alleles inherited from both parents). Several reports have suggested that genetic similarity, expressed as increased HLA loci sharing, may lead to adverse pregnancy outcome including recurrent pregnancy loss (RPL), low birth weight and pre-eclampsia due to poor implantation. A number of recent studies have also demonstrated a significant excess of HLA sharing among couples failing multiple induction of ovulation/intrauterine insemination and IVF cycles compared to those who conceive.

Two reports support the selective inclusion of DQ alpha/HLA testing in women with unexplained IVF failure and in women with infertility following non-chromosomal RPL. In 1996, one study from the U.S. reported on a positive experience with patients treated using IVIg following recurrent IVF failure. Another recent study reported out of Israel evaluated the efficacy of IVIg treatment in patients with >5 recurrent IVF failures, all of whom shared several matching HLA loci with their husbands. More than 40% of the women went on to have babies following intravenous immunoglobulin (IVIG) therapy. Results from our experience have been similar.

But, alloimmune (DQa/HLA) sharing (“clash”) between the embryo recipient and the sperm provider does not inevitably/always cause reproductive loss due to implantation dysfunction. The fact that there are individuals who have 2 identical DQa genes means that in such cases the parents of that individual must of necessity have shared DQa similarities. So live births can and do on occasion occur, even when the couple shares alloimmune genetic similarities…and here is why:

In cases where an alloimmune clash exists between embryo and decidua, embryos often reach the uterus prior to a point in time where repeated alloimmune exposures precipitate “allo/autoimmune conversion” (i.e. permanent sensitization/activation of NK cells). Should, in such cases a ” competent” embryo reach the uterus very early on in an exposed male-female relationship, before “allo/autoimmune conversion” occurs, such a conceptus can (and in fact often does) escape the full brunt of a NKa-induced rejection and thereupon may progress to a live birth.

We are not suggesting that this is the rule. Rather probably the exception. In fact, most such concepti would elicit a progressive TH-1 cytokinopathy that would lead to miscarriage. Thereupon, depending on the degree of NK cell sensitization, implantation dysfunction would cause repeated miscarriages or total complete implantation failure (perceived as “infertility”).

That is why successful/viable pregnancies that occur in spite of male-female alloimmune clashing usually are ones that are initiated very early on in a new relationship – prior to repeated exposures of the decidua to alloimmune “clashing” causing NK cell sensitization and a sustained NK cell cytokinopathy (i.e “allo-autoimmune conversion). This also serves to explain why many cases where progressive sensitization of NK cells precedes allo-autoimmune conversion begin with a viable pregnancy and progress through a phase of recurrent miscarriages and/or end up with “perceived infertility.”