There are two (2) forms of immunologic implantation dysfunction. The first and by far the most common is autoimmune implantation dysfunction. This variety is usually easily and successfully remedied through treatment with heparinoids (e.g., Lovenox, Clexane), Intralipid (IL), and corticosteroids. The second variety which is often ignored or overlooked is alloimmune implantation dysfunction.
Autoimmune implantation dysfunction is by far the most common variety. It is believed to be implicated in >90% of cases of immunologic implantation dysfunction and occurs when an immunologic reaction is produced by the individual, to his/her body’s own cellular components. Aloimmune implantation dysfunction on the other hand, arises through the reaction of the uterus to an embryo that shares certain genetic (genotypic) similarities (DQa and other HLA genes)with the recipient’s uterus causing immune cells known as natural killer (NK) cells that populate the uterine lining, to start over-producing “ toxins” known as TH-1 cytokines (TNFa and Interferon gamma). Such activated NK cells (NKa+) attack the cells of the embryo’s “root system” (the trophoblast) damaging it and so compromising implantation. Alloimmune implantation dysfunction, while far less common than the autoimmune variety is considerably more complex, much more poorly understood (even by most RE’s) and far more difficult to treat successfully. It involves a reaction by an otherwise normal uterus to the intrusion of one or more embryos that through the contribution of sperm DNA share certain immunogenetic (genotypic) similarities with the recipient.
For some reason, there is a tendency to consider all couples with alloimmune implantation dysfunction (who share DQa similarities) to be incapable of achieving a viable full term pregnancy. Nothing could be further from the truth.
Let me explain: Each individual has two (DQa’s), one is derived from their mother and the other from their father. The fact that many individuals carry identical DQa's (i.e. both are the same), of necessity means their parents must of necessity have had “matching” DQa’s and yet they were born healthy and normal. The reason is that it is not the “matching” DQa that matters. It is whether upon arriving in the uterus, a DQa “matching” embryo encounters activated uterine natural killer cells (NKa+). These NKa+ release large amounts of TH-1 cytokines that attack and damage the cells of the embryo’s “root system” (trophoblast).It is the extent of such trophoblastic damage that will determine whether such an embryo will immediately “die on the vine” (implantation failure) or “limp along” for some time only to be aborted a few weeks later.
It is important to recognize that NK cell activation only occurs after repeated exposures to DQa-"matching" embryos. This explains why a DQa “matching” embryo that reaches the uterus prior to NK cell activation can and often does implant successfully and then go on to propagate a healthy pregnancy. However, with repeated exposures to DQa "matching" embryos, uterine NK cells will ultimately and inevitably become activated. Such NK cell activity will initially often be limited and accordingly TH-cytokine production will wax and wane (in between exposures), allowing .early implantation (albeit with a damaged embryo) to proceed and even proceed for a limited period of time, only to abort in the first trimester. Ultimately, over time following repeated and successive exposures to DQa-“matching” embryos, NK cell activation will become a permanent feature. Once this happens uterine NK cell activation (as measured by the K-562 target cell test) will exacerbate to the point that as soon as the embryo reaches the uterus implantation will be thwarted and the woman will be considered as being "infertile” when in reality she is experiencing a very early, preclinical miscarriage. .
It is important to understand that DQa “matching” refers to a (genotypic) “match” between the male and female partners…rather than a “match” between sperm and egg. An immature sperm contains 23 pairs of chromosomes”…for a total of 46. With maturation division (following meiosis), the immature sperm divides into two mature sperm each of which comprises 23 chromosomes [including only one (1) DQa gene]. Upon fertilization of the egg by such a sperm this single DQa gene is incorporated into the embryo’s genotype. .If that DQa gene “matches” either of the mother’s two (2) DQa’s, then the potential for NK call activation will arise. It follows that if only one (1) of the husband’s two (2) DQa’ genes “matches” either one (1) of the mother’s DQa’ genes, the potential for the resulting embryo to propagate an embryo that containing a DQa gene that “matches” the recipient will be 50%. On the other hand, if both the husband’s DQa’ genes are the same as any one of the mother’s two DQa’s, (or if the mother and father both identical DQa’s genotypes), then 100% of the embryos will “match” and the propensity to activate uterine NK cells will be markedly increased.
What does all this mean when it comes influencing IVF outcome? …….Well, if we are dealing with a 50% chance of embryo DQa “matching” (see above), and we can successfully down-regulate NKa+ through the administration of Intralipid (IL) or immunoglobulin-G (IVIG) in combination with corticosteroids (e.g. prednisone or dexamethasone), then the transfer of a non-“matching” embryo would theoretically provide the same chance of a successful IVF outcome as in the absence of any DQa “matching” between the partners. On the other hand, when the chance of embryo DQa “matching” is 100% (see above) the ability to down-regulate NKa+ with IL or IVIG is diminished as is the likelihood of a successful pregnancy.
What emerges from all this is that not all DQa “matches” are equal. Outcome following IVF treatment (inclusive of IL/IVIG/corticosteroids) is very much influenced by: a) the presence and severity of uterine NK cell activation, b) whether the DQa genotype of both male and female partners “match” absolutely (i.e. both their pairs of their DQa genes “match”), in which case 100% of the embryos will “match” and the prognosis will be poor, c) whether both the male’s DQa genes are identical, in which case, the of a DQa “match” will again be 100% and the chance of a successful IVF outcome will likely be severely diminished.
It is presently not possible to reliably identify the paternal DQa contribution to the embryo. Also, the exposure of DQa “matching” embryos to the uterus will usually activate uterine NK cells. For these reasons, in cases of a 50% risk of a DQa “match”, I usually recommend transferring only one (1) embryo at a time. The reason is my concern that in transferring more than one embryo, uterine exposure to a DQa-“matching” embryo could, by causing local NK cell activation, compromise implantation of a non-“matching” embryo and so, in the process, reduce the likelihood of its successful implantation. In cases of 100% DQa “matching”, this hardly matters since all the embryos would cause NK cell activation anyway.
In truth, when there is a 100% risk of an embryo-DQa “match” between partners (see above) in association with uterine NK cell activation as measured by the K-562 target cell test, the chance of successful pregnancy is very small. In such cases, in my view seeking the help of a gestational surrogate or resorting to the use of donor sperm (ensuring they do not share DQa similarities with the embryo recipient) will in the final analysis become the treatment of choice.
The recent introduction of comparative genomic hybridization (CGH) to identify and select “competent” embryos for transfer can markedly improve the efficiency by which we are able to manage both alloimmune and autoimmune implantation dysfunction.
Lastly; much has been written about the use of endometrial sampling (biopsy) to measure NK cells and cytokine activity. While this is interesting in concept, there is no supportive clinical data to indicate its value in the clinical management of immunologic implantation failure. Presently the K-562 target cell test remains the gold standard for measuring uterine NK cell activity.
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