ALLO Immune info- HY restricting HLA's, Matches and more-



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 confrontedby 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) signalingthrough 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.






At Braverman IVF & Reproductive Immunology we have long recognized the important contributions made by HLA genes to unexplained infertility and recurrent miscarriage. A recent publication by a group of scientists from the Netherlands has now further advanced our understanding of this important area of reproductive immunology. This publication demonstrated that females carrying certain copies (called alleles) of an HLA gene called HLA-G are predisposed to both primary (no history of a live birth) and secondary (prior live birth) recurrent miscarriage.
This same study also found that females with a history of a firstborn boy are susceptible to secondary recurrent miscarriage and to giving birth to boys with a low birth weight when they have certain other HLA alleles known as HY-restricting HLA (HYrHLA) alleles. These HYrHLA alleles can specifically alert the mother's immune system to the presence of male-specific proteins (HY antigens) encoded by genes on the Y chromosome of a male fetus. In some women this can lead to the development of a dangerous immune reaction to the fetus mediated through T cells and HY antibodies produced by B cells.
While this study specifically looked at the effects of HLA-G and HYrHLA alleles in patients with primary and secondary recurrent miscarriage, we believe that these genes are also likely to be important in the development of primary and secondary unexplained infertility.
Here at Braverman Reproductive Immunology, we are already testing our patients for HYrHLA alleles and we are actively developing new tests that will soon allow us to detect HLA-G alleles and HY antibodies. These new tests will not only expand our ability to diagnose specific immunological issues, but also to further personalize and tailor therapeutic approaches for each of our patients.

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