Human reproductive failure may be a consequence of aberrant expression of immunological factors during pregnancy. Although the relative importance of immunological factors in human reproduction remains controversial, substantial evidence suggests that human leukocyte antigens (HLA), antisperm antibodies, integrins, the leukaemia inhibitory factor (LIF), cytokines, antiphospholipid antibodies, endometrial adhesion factors, mucins (MUC1) and uterine natural killer cells contribute to reproductive failure. In contrast, fewer data support the roles of anti-trophoblast antibodies, anti-endometrial antibodies, T-cells, peripheral natural killer cells, anti-HLA antibodies, blocking antibodies and suppressor cells in reproductive failure. Although immunological factors involved in reproductive failure have been studied traditionally using assays for antibodies and/or antigens, detailed research on these factors demonstrates conflicting results in humans. Maternal and fetal immunology is also difficult to investigate in humans. For these reasons, molecular assays may serve as a valuable alternative to investigate how the immune system affects reproductive outcome. In Part I of this review, immunological factors involved in human reproductive failure are summarized and critically evaluated. Immunogenetic and interacting factors in human reproductive failure will be summarized and evaluated in Part II.
Studies in humans suggest that reproductive failure may be influenced by immunological factors or by genes encoding immunological factors and regulatory mechanisms controlling immunological expression. Using molecular methods, immunological factors can be clearly studied in an immunogenetic context. One example, the major histocompatibility complex (MHC), known as the human leukocyte antigens (HLA) in humans and MHC in other mammals, affects many different stages of reproduction. Studies in some outbred, and in closely related, human populations indicate that HLA, or HLA-linked, genes and HLA regulatory factors affect gamete development, embryo cleavage, blastocyst and trophoblast formation, implantation, fetal development and survival. Studies in non-human mammals indicate that MHC, or MHC-linked, genes such as the grc complex, Ped/Qa-2, t haplotypes and MHC regulatory factors, have similar reproductive effects. Human reproductive failure may also be a consequence of disruption of interacting factors, including interactions between HLA antigens, cytokines and natural killer (NK) cells. In this review, we highlight the importance of immunogenetic and interacting factors in human reproductive failure. We argue that studies in closely related human populations and animal models may contribute to a better understanding of the ways in which immunogenetic and interacting factors are involved in human reproduction.
Initiation and implementation of nontherapeutic genetic research projects, sponsored by developed countries and conducted in developing countries, requires careful consideration and awareness of procedures that ensure ethical research. This article reviews, and discusses controversies surrounding, the ethical principles established internationally and recommended by institutions in the UK for designing and implementing nontherapeutic genetic research studies. Before project commencement, the researcher should submit proposals to appropriate ethics committees and, wherever possible, seek guidance from experienced researchers. The researcher must also be aware of his/her responsibilities when conducting research with human participants. Responsibilities include respecting autonomy, privacy and confidentiality of participants, respecting social and cultural differences, providing appropriate information to participants, obtaining informed consent and offering appropriate compensation for participation. Finally, researchers involved in human genetics studies must also consider specific issues and public concerns when collecting biological samples. This includes using anonymised samples, considering future use of samples and ensuring confidentiality of results.
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