Where is the critical paternal antigen and how is the female organism exposed to the paternal HLA message

The exact way by which the female organism is exposed to the paternal HLA message is uncertain.

Koelman et al. (2000) demonstrated the presence of soluble class I HLA molecules in seminal plasma representing a potentially straightforward way of endometrial exposure. Interestingly, soluble HLA molecules have also been demonstrated to induce apoptosis in human cytotoxic T cells (Zavazava and Kronke, 1996), and induction of apoptosis may be a mechanism for inducing specific tolerance against a partner's HLA cell membrane molecules. An alternative model, proposed by Clark (1993, 1994), states that the genital tract has unusual T cells with yd rather than ab type receptors for antigen. He suggested that these T cells respond to antigens in the vagina and uterus without the usual requirement for simultaneous binding to an HLA-A, -B, -C, or -D type antigen on the antigen-presenting cells (APC). Such a mechanism would pave the way for recognition of human trophoblast lacking classical HLA surface antigens.

However, based on his study of pregnancies after intra-uterine insemination, Smith et al. (1997) suggested that the protective factor is on the spermatozoa themselves and not in the seminal fluid. This was strongly supported by a subsequent study by Wang et al. (2002). They used a very elegant model to confirm the protective effect of previous sperm exposure and to analyse whether or not this protection is conveyed by sperm cells or seminal plasma. These authors looked at outcomes in pregnancies following Intra-Cytoplasmatic Sperm Injection (ICSI), where fertilization is achieved by injecting the sperm into the oocyte plasma. ICSI is used initially in cases where there are severe semen defects, including azoospermia. In some patients it is necessary to obtain sperm surgically. Couples in which the male partner has azoospermia and where sperm cells are obtained surgically provide an ideal ''model'' to test the protective partner-specific immune-tolerance conveyed by sperm cells. The model allows independent analysis of what may be present in seminal fluid, since in these couples there is no exposure of the female genital tract to sperm cells during intercourse, while exposure to seminal fluid is unaffected. Altogether, 1621 deliveries conceived after standard IVF, ICSI using sperm cells obtained by masturbation, and ICSI using surgically obtained sperm cells were analyzed; 195 (12.0%) had gestational hypertension, and 67 of them (4.1%) had pre-eclampsia. The risk of gestational hypertension was doubled, while the risk of pre-eclampsia was tripled in ICSI using surgically obtained sperm compared with standard IVF and ICSI using sperm obtained by masturbation. This study clearly confirms that previous exposure to the actual sperm cells must convey a major part of the protection, since women in the ICSI group using sperm cells obtained by transcu-taneous surgical methods had not experienced any previous contact with their partner's sperm cells — and it was only in this subset of patients with longstanding infertility that the increased incidence of both pre-eclampsia and gestational hypertension was seen.

Hall et al. (2001) came to different conclusions. These investigators examined the outcomes of pregnancies of women who conceived by donor insemination, as compared with women who conceived after IVF with their partner's spermatozoa. This was a retrospective cohort study of 218 women attending an IVF clinic, 45 of whom conceived with donor insemination and 173 of whom conceived with their partner's spermatozoa. Cases were identified from the IVF unit and data were extracted from patients' notes by blinded observers. Analysis showed no difference between the groups, with 22% of women who conceived with donor spermatozoa and 24% who conceived with partner spermatozoa developing some form of hypertensive disease of pregnancy. Insemination with their partner's spermatozoa was not associated with a reduction of hypertensive disease, and neither was donor spermatozoa insemination associated with an increased incidence. It should be noted that (a) this is a very small study, and (b) the incidence of pregnancy-induced hypertensive disorders is very high in both groups. We feel, however, that Hall et al. (2001) made one significant error that can explain their contrasting findings. The group of women requiring IVF using their partner's sperm cells almost certainly had additional fertility limiting factors when compared with the group who conceived with donor sperm. As mentioned earlier, Basso et al. (2003) found that some factors delaying clinically recognized conception might also be in a causal pathway for pre-eclampsia.

In summary, sperm exposure does provide some protection against developing pre-eclampsia. Actual exposure to the sperm cells appears to be the important factor. Deposition of semen in the female genital tract provokes a cascade of cellular and molecular events that resemble a classic inflammatory response. The critical factor appears to be seminal vesicle-derived transforming growth factor b (TGFb). Seminal vesicle-derived TGFb is secreted predominantly in a latent form.

Seminal plasmin and uterine factors transform the latent form into bioactive TGFb (Tremellen et al., 1998). Intra-uterine insemination of TGFb in vivo results in an increase in granulocyte—monocyte colony stimulating factor (GM-CSF) production that is sufficient to initiate an endometrial leuko-cytosis comparable with that seen following mating (Robertson, 2002). The introduction of TGFb into the uterus, in combination with paternal ejaculate antigens, favors the growth and survival of the semi-allogenic fetus, as evidenced by a significant increase in fetal and placental weight in animal studies. This is believed to be facilitated in two ways. First, by initiating a post-mating inflammatory reaction, TGFb increases the ability to sample and process paternal antigens contained within the ejaculate. Another important role of TGFb and the subsequent post-coital inflammatory response, is the initiation of a strong type 2 immune deviation. The processing of an antigen by antigen-presenting cells in an environment containing TGFb is likely to initiate a Th2 pheno-type within these responding T-cells (Robertson, 2002). By initiating a type 2 immune response toward paternal ejaculate antigens, seminal TGFb may inhibit the induction of type 1 responses to the semi-allogenic conceptus that are thought to be responsible for poor placental and fetal development. Decidual macrophages, present in an immune-suppressive phenotype from the moment of implantation, may inhibit NK cell lytic activity through the release of molecules such as TGF, interleukin-10 (IL-10) and prostaglandin-E2 (PGE2). Under the influence of the local cytokine environment, antigen-presenting cells (such as macrophages and dendritic cells) may take up, process and present ejaculate antigens (sperm, somatic cells, and soluble antigens) to T cells in the draining lymph nodes (Tremellen et al., 1998). In mice, uptake of sperm mRNA encoding for paternal HLA by decidual antigen-presenting cells has been shown to occur. There is subsequent translation of this sperm mRNA encoding paternal MHC class I within these maternal antigen-presenting cells. These antigen-presenting cells traffic from the uterus to the draining lymph nodes during the post-coital inflammatory response. It is unknown whether or not this fascinating mechanism is operative in humans. HLA-G is certainly not involved here, since human sperm cells do not have mRNA for HLA-G (Hiby et al., 1999; Watson et al., 1983). Since HLA-G is monomorphic it would also be a very unlikely candidate to represent the paternal HLA specificity. Classic HLA-A and HLA-B are also very unlikely since these are not expressed by trophoblast.

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