DQ alpha Matching: Its Effect on Reproduction and IVF Outcome
In my personal practice, I find myself treating an ever increasing number of desperate women with REPEATED, unexplained IVF failure (often in spite of having had numerous good quality embryos transferred), and women with unexplained recurrent pregnancy loss (RPL). In a large percentage of such cases, I find that the cause is hitherto undetected immunologic implantation dysfunction (IID).
In May 2011 I posted 2 articles in which I pointed to the fact that there are two varieties of IID. The first, autoimmune implantation dysfunction comprises the majority of such cases. It is readily treated successfully with selective immunotherapy such as Intralipid (IL) or intravenous gamma globulin (IVIG) and steroids (e.g. Prednisone and Dexamethasone). The second, alloimmune implantation dysfunction, while far less common, is much more difficult to address and treat successfully. This article focuses on a discussion of alloimmune dysfunction.
Alloimmune implantation dysfunction occurs when there is matching (between the reproductive partners) of genes known as “DQ-Alpha” (DQa) in association with activation of uterine NK cells (NKa). A couple may have either a partial DQa match [DQa (p)] or a total DQa match [DQa (t)]. The former is far more common than the latter and readily amenable to immunotherapy treatment, while [DQa(t)] is usually refractory to such treatment, requiring the use of a gestational surrogate or donor sperm. This post is intended to help those so affected gain a better understanding of this rather complex and very poorly understood problem.
What are DQa Genes? Each individual has two DQa genes, one derived from their mother and the other from their father. Usually, since the immunologic make-up of people is unique and distinct, most reproductive partnering involves two individuals with differing DQa expression. This is an essential prerequisite for normal healthy implantation to occur. However, in some cases the partners will have one or both DQa genes in common (DQa matching) When the woman (host) shares but a single DQa gene with her sperm provider, we refer to this as “partial” DQa matching [DQa(p)]. In a very small percentage of cases, the partners share both DQa genes. This is referred to a total DQa matching [DQa(t)].
With DQa(p), one out of every two embryos will express the DQa trait contributed by the husband’s sperm. A total DQa match or DQa(t) infers that every single embryo will express matching DQa genes between the host and the sperm provider. In either case, when a DQa matching embryo reaches the uterus of a woman who, in addition, has activated natural killer cells, implantation will be compromised and the woman will either not conceive, or will generally miscarry in the 1st trimester. With DQa matching, the outcome has nothing to do with DQa matching between egg and sperm. Rather, it has to do with the embryo expressing the DQa that matches that of the host (embryo recipient) and the male partner’s sperm. That is why the use of an egg donor does NOT bypass the problem.
The Role of Uterine Natural Killer (NK) Cells: Repeated exposure of the woman’s uterine lining to one or both matching DQa genes will, over time, provoke the activation of predominating uterine immune cells, known as natural killer (NK) cells. These NK cells play an important role in promoting healthy implantation of the embryo’s trophoblast (“root” system) into the uterine lining and subsequent development of its “lifeline,” the placenta.
When NK cells become exposed to an embryo that carries a DQa trait that matches that of the host’s uterus, they become provoked. They might not at first react fully, but after repeated exposures (perhaps taking a number of years) they become activated (NKa) and begin releasing an excess of “toxins” known as TH-1 cytokines that attack the embryo’s trophoblast. Sometimes, this totally destroys the embryo, such that the woman loses the pregnancy before even being aware that she was pregnant (a so called “mini-miscarriage”). In other cases, the embryo’s roots are damaged but not destroyed, such that the conceptus starts to run out of essential life-support and is lost as a miscarriage.
Partial DQa Matching: Since a partial DQa match means that 1 out of 2 sperm will contain a matching DQa , it follows that 1 of 2 embryos will express that sperm’s DQa trait. If such an embryo were to reach the uterus of a host who also tests positive for NKa, it would be highly unlikely to implant successfully (even if IL or IVIG had been administered in advance, to down-regulate activated uterine NK cells). In order for a viable pregnancy to occur, that embryo should not express the matching husband-derived DQa. Moreover, the transferred embryo should be chromosomally normal, and Intralipid should have been infused 7-14 days prior to embryo transfer. Once the blood hCG rises (indicating that implantation has started) the IL infusion should be re-administered every 2-4 weeks through the 24th week of pregnancy.
With partial DQa matching (+NKa), one out of two embryos are likely to have a DQa match with the host. Since it is presently not possible to selectively detect paternal DQa expression in the embryo, it is my opinion that multiple embryos should not be transferred at the same time. Rather, a single blastocyst should be transferred. The reason is that, in my opinion, if more than one embryo is transferred, there is a strong possibility that one of those reaching the uterus will express the matching paternal DQa , resulting in local activation of uterine NK cells and failed implantation of ALL the transferred embryos.
Since in cases with NKa and partial DQa match, the chance of successful per-embryo implantation will invariably be half that of the otherwise expected rate, I routinely recommend a detailed chromosomal assessment of all such embryos using comparative genomic hybridization (CGH) and thereupon selectively performing single blastocyst transfers (SBT). The remaining blastocysts are vitrified and banked for subsequent SBTs. Since the baby rate following the SBT of a CGH-normal embryo would ordinarily be about 60%, it follows that by doing this in cases of DQa(p) matching (+ NKa), those women receiving Intralipid or IVIG would have a baby rate half of 60% (i.e. 30%).
Since a CGH abnormal blastocyst would have a much lower baby rate because of undetected chromosomal numerical irregularities, this consideration becomes even more relevant when SBT’s are done using embryos derived from the eggs of older women whose embryos are progressively more likely to be aneuploid and to have reduced implantation potential.
Total DQa Matching: With combined total DQa matching +NKa, the likelihood of successful implantation is very low, regardless of whether measures are taken to down-regulate NKa with Intralipid or IVIG. This is because every embryo will carry a DQa trait that clashes with that of the host. The only way to bypass that eventuality is to use a gestational carrier that does not have a DQa genotype that clashes with the sperm provider. If the biological mother-to-be wants to carry the baby, non-DQa matching sperm (from a sperm donor) should be used. In the latter case, however, the host would still need to undergo NKa down-regulation with IL or IVIG
It is important to bear in mind that in the absence of uterine NK cell activation, the implantation potential of DQa matching embryos is not compromised. This is the reason why a woman who conceives with embryos that bear matching paternal DQa will usually be able to carry the baby without difficulty. It is only after repeated exposures to DQa matching embryos that uterine NK cells become activated. Activation of uterine NK cells can thus take several years to become established, whereupon the woman will develop implantation dysfunction which can manifest as recurrent pregnancy loss (RPL) or infertility. This explains why in many cases of DQa(p) and DQa(t) matching, the woman will present with infertility or recurrent pregnancy loss only after having had one or more prior successful pregnancies.