In 15-20% of women who have infertility or RPL, the cause will be immunologic implantation dysfunction (IID). Accordingly, all women who have predisposing factors such as endometriosis, unexplained infertility/repeated failed IVF, RPL, or have a personal/family history of primary autoimmune conditions, should be evaluated and treated appropriately. By doing so, we as physicians will not only be promoting a safer journey from “Infertility to family” but by promoting better implantation, will enhance placentation and prenatal development with the ultimate objective of optimizing the quality of life after birth.

Immunologic acceptance of the implanting embryo by the uterus of the mother is both highly complex and magnificent. Not only is it essential for pregnancy to occur, but it also sets the scene for our body’s own cells, tissues, and organs to be shielded from attack by our immune systems. For a moment, consider how, when confronted by foreign proteins (bacteria viruses, foreign tissue grafts/transplantation), the body’s immune system goes on the attack but yet an embryo that is partially derived from proteins that come from another individual (the sperm or paternal antigen), usually safely implants in the pre-pregnancy uterine lining and then grows into a healthy baby. This phenomenon has come to be referred to as the “immunologic riddle of pregnancy.”

For such a complex arrangement never to fail would be without precedent in human biology. To argue to the contrary is, in my opinion, an absurdity, bordering on arrogance. It can and does go wrong in about 15–20% of women with reproductive failure and when it does, it sometimes presents as failed implantation (presumed by the patient to be infertility), as miscarriage, or (much less frequently) as placental failure and compromised fetal development or intrauterine death. It all depends on the timing, nature, and severity of the immune assault.

It is well known  that  the reason the implanting  normal  embryo thrives in the womb is that unique immunologic adjustments convert the pre-pregnancy uterine lining (decidua) into a “privileged site” where the embryo and the fetus come to be regarded as “bodies own” (“self ”) and as such are protected from immune attack. This initial acceptance of the embryo as “self ” or “friend” rather than “non-self ” or “foe” (in spite of it being a semi-allograft) is one of the miraculous adaptations of nature and is in large part responsible for our survival as a species.

As soon  as  implantation  begins, the  paternal  genetic  contribution to the embryo (so called DQ alpha genes) initiates a signal to the pre-pregnancy decidual immune system which thereupon determines whether the embryonic allograft should be welcomed (i.e., be accepted as “friend”) or be regarded as “foe” and be rejected through immune attack. The process is referred to as “alloimmune recognition.” Given that with the exception of monozygotic twins, interpersonal differences in genotype are inevitable, it follows that maternal and paternal DQ alpha gene combinations will usually also differ in the vast majority of cases. Thus, preservation of the human species required that in spite of such immunogenetic dissimilarities, the immune system of the pre-pregnancy endometrium (decidua) adapt and recognize the embryo as “self” or “friend” rather than as “non-self ” or “foe.”

Upon reaching the uterine environment, the “genetically competent” embryo, hatches and thereupon, within 12–24 hours starts sending its root system (trophoblast) into the decidua. The trophoblast has both villous (root-like) and extravilous (diffuse) components.  The extravillous trophoblast, which diffusely permeates the decidua expresses several so-called major histocompatibility complex (MHC) class 1 genes [e.g., histocompatibility leukocyte antigen (HLA-) C, E, and G]. These HLA genes, (primarily HLA-G) regulate primarily two types of lymphocytes present in the decidua. These are uterine natural killer (NK) cells and cytotoxic lymphocytes (CTL). NK cells comprise approximately 75% of decidual lymphocytes and CTL comprise about 10%. They both likely play a vital role in regulating the normal implantation process by control- ling the penetration and functioning of the trophoblast.

The recognition of proteins as “self” (“friend”) or “non-self” (“foe”) is propagated by highly specialized immune lymphocytes known as regulatory T-cells. These so-called Treg cells can “turn off” immune reactions even once they have been started by conventional immune cells. They play a pivotal role in the immune system’s ability to prevent rejection of an embryo whether due to an autoimmune or alloimmune response. Other immune cells known as dendritic cells, introduce antigenic proteins to these Treg cells, whose concentration increases when the antigen is recognized as “self” and decreases when recognized as “foe.” MHC (primarily HLA-G) signaling, through the Treg lymphocyte mechanism working in combination with other regulatory proteins, influences the production and release of so-called cytokines by the NK and CTL cells. There are three varieties of cytokines, two of which play defining roles in the maintenance of implantation: The first is TH-2 cytokines, which encourage growth and expansion of the trophoblast and promote proliferation of blood vessels (angiogenesis). The second, TH-1 cytokines, promote destruction (cytolysis) of trophoblastic cells and also cause blood to clot (procoagulant effect). A balance between TH-1 and TH-2 cytokines is essential for normal implantation and development of the placenta (placentation).

Over-activity (dominance) of TH-1, the hallmark of NK cell and CTL activation, leads to damage of the trophoblast, implantation dysfunction, and reproductive failure.

Alloimmune Causes

Every human being has two DQ alpha genes. One is contributed by the father and the other by the mother. When (albeit in a small percentage of patients undergoing IVF) paternal-maternal DQ-alpha gene similarities occur, it will, following repeated exposures to such genetically matching embryos, provoke activation of the decidual immune system. Usually, this will, through the mechanisms described above, ultimately lead to NK/CTL activation and reproductive failure (i.e., infertility, and pregnancy loss) in most cases. We refer to this phenomenon as alloimmune implantation dysfunction.

This is how alloimmune implantation dysfunction happens: Immunogenetically triggered HLA-G signaling on the part of the implanting embryo leads to a reduction in Treg cells and eventually to a destabilization of NK/CTLs with domination of TH-1 over TH-2 activity. The severity with which this occurs is an important determinant of whether total implantation failure will occur or whether there would remain enough residual trophoblastic activity that would allow the pregnancy to limp along until the nutritional supply can no longer meet the demands of the pregnancy, at which point miscarriage or pregnancy loss occurs.

With paternal-maternal DQ alpha matching it will often take the passage of several pregnancies for NK cell activation to build to the point that woman with alloimmune implantation dysfunction will present with clinical evidence of implantation dysfunction. Sometimes it starts off with one or two pregnancies surviving to birth of a baby, whereupon NK/CTL cell activity starts to build, leading to one or more early miscarriages. Eventually the NK /CTL activity is so high that subsequent pregnancies can be lost before the woman is even aware that she was pregnant at all. At this point she is often diagnosed with secondary, “unexplained” infertility and/or “unexplained” IVF failure. The case report below illustrates the interplay of factors involved in Alloimmune IID.

Autoimmune Causes

With autoimmune implantation dysfunction, NK cell activation is already well established by the time the embryo reaches the uterus. Accordingly, in such cases the pregnancy is usually lost before its presence can be established by a blood pregnancy test or an early ultrasound examination (i.e., it presents as a negative pregnancy test or a chemical gestation).

So how is autoimmune implantation dysfunction established? The initial recognition of the non-DQ alpha matching embryo as “friend” or “self” sets the stage for the cells/tissues of our tissues not coming under immune attack. However under certain circumstances, genetic, infective, toxic, and degenerative influences can result in our own body’s proteins coming to be regarded as “non-self” (“foe”). When this happens the immune system starts to produce antibodies that are directed against our body’s own proteins. These so-called autoantibodies then start attacking the body’s own cells/tissues/organs creating pathologic states (diseases) such as can be seen with certain  (autoimmune)  disease states—e.g., lupus  erythematosus,  autoimmune  hypothyroidism  (Hashimoto’s disease), and rheumatoid arthritis.

There are also certain reproductive diseases such as endometriosis, where cell membrane phospholipids are often altered by the disease process and then combine with proteins to evoke the production of so-called antiphospholipid antibodies (APA). Certain types of APAs can both directly damage the trophoblast and can also lead to a reduction of Treg lymphocytes, culminating in activation of NK/CTLs. This type of reaction—albeit due to a predisposition to auto-immune diseases such as lupus erythematosus, Hashimoto’s disease, or reproductive conditions such as endometriosis—is referred to as autoimmune implantation dysfunction. Autoimmune implantation dysfunction is much more common than alloimmune implantation dysfunction. In fact, it is responsible for more than 85% of reproductive failure due to immunologic implantation dysfunction. The three most common types of autoantibodies involved are antiphospholipid antibodies (APA), anti-thyroid antibodies (ATA), and possibly, antiovarian antibodies (AOA).