DQ alpha/HLA Sharing: Does It Always Lead To Reproductive Failure?

23 Oct
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It is not unusual for couples who share DQ alpha/HLA similarities to first give birth to a healthy baby only to subsequently develop infertility, recurrent IVF failure or recurrent pregnancy loss. Such couples find it hard to comprehend how after having experienced an often uncomplicated pregnancy and birth they could then go on to develop immunologic implantation dysfunction. Hopefully, this brief article will serve to explain how and why DQ alpha/HLA sharing between the embryo recipient (female partner) and the sperm provider (male partner) does not inevitably lead to implantation dysfunction and reproductive loss.

When DQ alpha and/or HLA sharing exists between a female and male it will usually require repeated embryo exposures for the host’s uterine natural killer cells to become sufficiently activated to cause damage to the embryo’s root system (trophoblast). Once natural killer cells become activated, they begin to over-produce substances known as TH-1 cytokines which attack the trophoblast and so damage it that the embryo is promptly rejected. Sometimes, the effect is not immediately lethal and the pregnancy “limps along,” only to miscarry, usually in the first trimester. If, in spite of there being DQ-alpha/HLA sharing between the male and female partners, a “competent” embryo reaches the uterus prior to the advent of NK-cell activation (NKa+) it would escape severe damage to its root system and, provided that NKa+ does not subsequently ensue the pregnancy will usually go on to full term. On the other hand, should NKa+ occur, such a pregnancy would likely miscarry. Thus, outcome very much depends on the level and timing of NK cell activation.

The bottom line: In cases of alloimmune implantation dysfunction, it is the frequency and number of embryo-NK cell exposures over time that will determine the absence, presence and degree of NKa+ and so determine the fate of the pregnancy. This serves to explain why successful pregnancies are usually the ones that occur early in the male-female relationship and why subsequently with a progressive build up of NKa+ a successful pregnancy will often be followed by a series of miscarriages and eventually by a complete failure to conceive (i.e. “perceived infertility”).

30 Comments

  • E daffodils says:

    Hello,

    We have a healthy daughter 3.5 yrs old.

    Since 2012, I’ve had 3 chemicals, one mmc after a faint heartbeat and an ectopic.

    We have no class 2 HLA mismatches according to my doc. Last we checked NK cells were in normal range. Tumor Necrosis alpha was high while I was miscarrying ectopic. I had a lap removing Endo stage 2 and ectopic blockage.

    Now I’m a cycle past and ready to try again. Going to try IUI paired w femara, IL, lovenix and prednisone.

    Any thoughts on my situation? All blood tests good except HLA.

    • Geoffrey Sher says:

      I would first carefully reevaluate for NK cell activation. Remember this has nothing to do with NK cell concentration. Rather it has to do with NK cell toxicity as measured by the K-562 target cell test.

      Geoff Sher

      • E daffodils says:

        Do you think that having no HLA CLASS 2 mismatches could be causing my losses?

        I’m wondering if it was the Endo which was removed. Or the HLA issue. Doc wants to treat me with neupogen.

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