Anti-Paternal antibodies?

The first question that comes to mind for an immunologist when they hear about paternal antibodies and their (supposed) relationship with recurrent reproductive failure is precisely, what are paternal antibodies? Those of us who work in clinical hospital immunology and perform analytical tests for organ transplantation are used to finding antibodies against HLA molecules in women who have been pregnant, which are different between people. These different molecules are seen by the immune system as foreign, waking it up and activating a response that would limit the success of transplants if it were not for the use of immunosuppressive drugs. Are paternal antibodies HLA antibodies?

Almost 30 years ago, when the methods for detecting these HLA molecules and the antibodies that develop against them were not as well characterized and standardized as they are today, some in vitro studies were carried out that consisted of mixing immune cells (white blood cells or leukocytes) of two different people, previously irradiating those of one of them and analyzing whether the cells of the other person were stimulated. If there was enough activation, the cells would proliferate (multiply) and if not, they would remain unchanged.

This is a brief description of a basic and old experiment in immunology called mixed lymphocyte culture. Well, in the context of reproductive failure, studies were carried out in which the leukocytes of the couple were irradiated and cultured together with the leukocytes of the woman to observe if they stimulated their proliferation sufficiently. In addition, they added to the culture a control that would limit cell growth (serum with antibodies from group O blood, which contains antibodies against groups A and B) and serum (the part of the blood that does not contain cells) from the woman in several dilutions that could block or not the proliferation of the cells. These studies claimed that when proliferation did not occur, it was because there were blocking antibodies in her blood against the couple’s leukocytes and that this would help the mother’s immune system to «tolerate» the embryo (which contains maternal but also paternal molecules that may be different from the mother’s). Thus, these blocking antibodies of the mixed lymphocyte culture, or paternal antibodies (APCA or anti-Paternal cytotoxic antibodies), would help the woman with reproductive failure to tolerate embryos from her partner and achieve a viable gestation.

I have to emphasize that a good part of the reasons why Reproductive Immunology has not progressed as quickly as other areas of Immunology and immunotherapy is the consideration that what happens in blood is what happens in the endometrium. Today we know that the activity of the immune system at the materno-embryonic and materno-fetal interface is very different from the general immune activity, so mixed lymphocyte cultures do not seem to be a very good model to predict what happens during embryonic implantation and gestation.

So much has been abused of this lack of knowledge that even studies have been proposed and carried out in which women with more than 3 miscarriages have been subjected to repeated vaccinations with preparations of leukocytes from the partner with the aim of generating these so-called paternal antibodies and that very probably will be cytotoxic anti-HLA antibodies that not only can make it impossible for the woman to receive an organ from her partner (if she were blood compatible), but would limit the possibility of receiving an organ from other millions of people who share certain similarities with the HLA molecules of the partner but are not exactly the same. Not to mention the possibility of infection during handling, which should be done in sterile compartments called white rooms and of which very few hospitals have.

The study and treatment according to paternal antibodies is based on erroneous premises. The generation of antibodies that are cytotoxic, that is, with the ability to induce in one way or another the death of a target cell to which it adheres, is a mechanism contrary to the tolerance of the immune system, which consists precisely in the opposite, to prevent the activation of the immune system. In addition, even if the APCA antibodies did not turn out to be cytotoxic and only blocking (they do not destroy but do hinder), it has been postulated that their effect would fall on T lymphocytes, thinking in similarities that are not true between pregnancy and organ or bone marrow transplants. As the study of materno-fetal tolerance progresses, T cells seem to contribute less and NK cells more, on which these paternal antibodies would have no effect.

On the other hand, we know that embryos hide the production of class I (A, B) and class II HLA molecules, while only expressing HLA-C molecules. HLA-C molecules are necessary stimuli for KIR receptors, which are necessary for the normal activation of NK uterine cells. This activation is important for the development of implantation and the adaptation of the uterine structures during the first trimester. The fact that embryos hide their HLA molecules (except HLA-C) is already in itself a tolerance mechanism that ensures that the maternal immune system does not «reject» the embryo. Moreover, a recent 2010 study that determines HLA antibodies in a modern way, reveals that the presence of HLA antibodies in women is associated with reproductive failure.

To my surprise, I have observed that articles about this type of vaccination and APCA are still being published, although they attribute the lack of efficacy of the vaccination and the final success of the procedure measured in viable pregnancies and births, to the appearance of anti-phospholipid antibodies that would limit the success of this misnamed immunotherapy; revealing that there are a series of immune-mediated causes that could explain reproductive failure without taking into account the so-called paternal antibodies and for which we do have ample scientific evidence and treatments.