More info on immunological implantation dysfunction-

( Below is some info on the immune issues we are facing- This is really only a glimpse of how it works-We have a kind of complex case, in the sense that we have several auto immune and allo immune factors working against us)

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 own 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 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 to be foolproof would be without precedent in human biology. To argue that this system can never fail is in my opinion, an absurdity, bordering on arrogance. It can and does go wrong in about 15-20% of women with reproductive failure.When it does, it presents either 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 the “body’s own” 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 composed partially of the father’s “foreign” cells), 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 asignal to the pre-pregnancy decidual immune system which thereupon determines whether the embryonic “allograft” should be welcomed as “friend” or be rejected as “foe” 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) evolutionarily adapt and recognize the embryo as friend rather than foe.

Upon reaching the uterine environment, the genetically “competent” embryo hatches and within 12-24 hours starts sending its root system (trophoblast) into the decidua. The trophoblast has both a villous (root-like) and an extravilous (diffuse) component. The extravilous 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 & G)].These HLA genes, (mainly HLA-G) regulate primarily two types of lymphocytes present in the decidua.These are: a) uterine natural killer cells (NK) and b) cytotoxic lymphocytes (CTL). NK cells comprise approximately 75% of decidual lymphocytes and CTL comprise about 10%. They both play a vital role in regulating the normal implantation process by controlling 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 “friend” 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 3 varieties of cytokines, two of which play defining roles in the maintenance of implantation:The first isTH-2 cytokines, which encourage growth and expansion of the trophoblast and promote proliferation of blood vessels (angiogenesis). 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 Implantation Dysfunction

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

This is how alloimmune implantation dysfunction happens:Immunogenetically triggered HLA-G signaling by the 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 determines whether total implantation failure will occur, or whether there remains enough residual trophoblastic activity to 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 often takes several pregnancies for natural killer cell activation to build to the point that a woman with alloimmune implantation dysfunction will present with clinical evidence of implantation dysfunction. Sometimes it starts off with one or two pregnancies surviving to the birth of a baby, whereupon NK cell activity later starts to build, leading to one or more subsequent early miscarriages. Eventually the NK cell/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.

Autoimmune Implantation Dysfunction:

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 initialrecognition of the non-DQ alpha matching embryo as “friend” or “self” sets the stage for the cells/tissues of our bodies 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) diseases (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 calledantiphospholipid antibodies (APAs)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 autoimmune diseases such as lupus erythematosus, Hashimoto’s disease, etc., or reproductive conditions such as endometriosis, is referred to as autoimmune implantation dysfunction. Autoimmune implantation dysfunction is much more common than alloimmuneimplantation dysfunction. In fact, it is probably responsible for more than 85% of reproductive failure attributable to immunologic implantation dysfunction. The most common autoantibodies involved are:

1) antiphospholipid antibodies (APA)

2) antithyroid antibodies (ATA)

3) antiovarian antibodies (AOA)

Since autoimmune implantation dysfunction is often genetically transmitted, it is not surprising that this condition is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as lupus erythematosus, scleroderma, clinical or subclinical hypothyroidism, rheumatoid arthritis, etc. Reactionary (secondary) autoimmunity can occur in conjunction with any medical condition associated with widespread tissue damage. One such gynecologic condition is endometriosis.

As previously stated, autoimmune implantation dysfunction is usually immediately lethal to the implanting embryo and accordingly most often presents as “unexplained “ infertility and/or “unexplained” IVF failure, rather than as miscarriage.This is because NK/CTL activation is present prior to implantation and as such, the embryo’s root system is severely damaged from the get-go. Autoimmune implantation dysfunction isreadily amenable to reversal through timely, appropriately administered, selective immunotherapy (IVIG, Neupogen etc)

Diagnosing Immunologic Implantation Dysfunction:

Whether alloimmune or autoimmune in origin, it is only once specialized immune cells in the uterine lining known as Natural Killer (NK) Cells and Cytotoxic Lymphocytes (CTL), become activated and TH-1 cytokine dominance is established that IID occurs. Thus, a full evaluation of immunologic implantation dysfunction requires that DQ alpha, APA, ATA, as well as NK/CTL activation be evaluated. This involves highly specialized blood testing and possibly also endometrial tests that can only be performed in a handful of reproductive immunology laboratories in the United States.

Alloimmune ID is diagnosed by testing the blood of both the male and female partners for matching DQ alpha genes. A sufficient degree of matching clinches the diagnosis. Since matching DQ alphas will rarely cause reproductive failure unless there is concomitant NK/CTL cell activation, it is important to test the embryo recipient for NK cell activation (the K-562 target cell) test and CTL activation (by a blood immunophenotype and HLA-DR measurement). Some reproductive immunologists might also test blood Treg cell concentration and/or recommend an endometrial biopsy to histolochemically evaluate uterine NK cells or assess the local TH-1/TH-2 balance. The performance of blood TH-1 and TH-2 cytokines to assess for TH-1 dominance is controversial and is of unproven value.