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Fertil Steril. Author manuscript; available in PMC 2017 September 01. Published in final edited form as: Fertil Steril. 2016 September 1; 106(3): 497–498. doi:10.1016/j.fertnstert.2016.07.1090.
Reproductive Immunology: Checkered Past and Bright Future Steven L. Young, M.D., Ph.D. University of North Carolina at Chapel Hill, Department of Obstetrics and Gynecology, 4005 Old Clinic Building (CB #7570), Chapel Hill, North Carolina 27599-7570 Steven L. Young: [email protected]
Author Manuscript
Abstract The immune system plays a critical role in pregnancy establishment and maintenance, but application of immunological principles to the treatment of infertility and pregnancy loss has had a checkered past. Improving knowledge in this area hold great promise for improving the treatment of subfertile patients.
Author Manuscript
Immune function is the result of a highly complex system of cellular and soluble components, working in intricate parallel and competing pathways to defend the host from invasive pathogens and destroy harmful or senescent cells of the host, while avoiding chronic production of potentially harmful inflammatory factors. These systems must adapt to the prolonged exposure of the semi-allogeneic embryo, in ways not yet fully understood. Furthermore, cells and molecules evolved to function in the immune system have, in mammals, been evolutionarily adapted for reproductive functions, comprising critical components of fertilization, embryo implantation, pregnancy health, and parturition. It is striking that a recent paper identified immune system genes as among the most recruited into endometrial expression during the evolution of placentation (1). Not suprisingly, then, immune system dysfunction has been identified as a likely contributor to endometriosis, infertility, recurrent pregnancy loss, preeclampsia, and preterm delivery.
Author Manuscript
However, the amazingly complex nature of immune system function, confusing nomenclature, intricate adaptations to placentation, and the plethora of competing, abstract, conceptual models among immunologists make reproductive immunology an incredibly difficult field to understand, for clinicians and scientists, leading to skepticism and misinterpretation of data. Clinical skepticism is further fueled by a history of clinical therapies that have failed to withstand careful scrutiny. These therapies have often been based on poorly validated diagnostic testing, highly premature clinical application of animal model findings, and/or small, poorly constructed, observational trials. Despite previous failures of the application of reproductive immunological findings to clinical care, the immune system plays an irrefutable role in normal fertility and successful
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Young
Page 2
Author Manuscript
applications of immunology (e.g. heparin therapy for anti-phospholipid antibody-associated recurrent pregnancy loss) have become standard part of evidence-based clinical practice. Given its importance to reproduction, the field of reproductive immunology will clearly be a future source of significant improvement in the prevention and treatment of many reproductive disorders. Thus, our aim in this News and Views, is to prime the immunologically naive reader with understandable reviews of topics that are or will be relevant to reproductive medicine.
Author Manuscript
The authors of these News and Views articles cover a wide range of topics that should be of interest to reproductive medicine clinicians and have done an outstanding job reviewing current data and explaining and translating the relevant immunology for the reproductive specialist. In the first review, Drs. Hyde and Schust examine the role of maternal responses and adaptations to “foreign” molecules carried by sperm, placenta, and a microchimeric mother as compared to maternal responses to pathogenic or commensals microbes. The authors’ combined use of historical context and up-to-date information allows an accessible and rigorous account of the immunological mechanisms involved in maternal adaptation to pregnancy. This approach and the perspective of Dr. Schust’s significant history of contributions to the field provide an excellent introductory resource to both clinicians and scientists. Drs. Roberston and Sharkey contribute a review on a very different subject, the immunology of maternal reproductive tract responses to seminal fluid and potential consequences on fertility and pregnancy outcome. Dr. Robertson has been a pioneering leader in this area, which has the potential to improve ART pregnancy rates as well as maternal-fetal health.
Author Manuscript
Drs. Riley and Jungheim examine the role of inflammation in reproduction with specific examination of dietary factors that can modify inflammation in polycycstic ovarian disease and obesity. Dr. Jungheim and her collaborators have previously contributed very interesting animal data suggesting a potent role of obesity-linked inflammation on reproduction. In this review, the authors review the state of the field, outlining what is known and what remains to be clarified. Further understanding of the role of these nutritional factors could be rapidly applied to improved care for obese infertile women, at minimal cost. This exciting area of research has great potential.
Author Manuscript
These three reviews give only a very partial introduction to current research in reproductive immunology. The data presented here and elsewhere combined with the critical roles that immune factors play in reproduction highlight the need fo further study of relevant immune mechanisms. Given further study, it is certain that we can develop new evidence-based, immunological diagnostic tests and therapies to improve our care of the infertile couple.
References 1. Lynch VJ, Nnamani MC, Kapusta A, Brayer K, Plaza SL, Mazur EC, Emera D, Sheikh SZ, Grützner F, Bauersachs S, Graf A, Young SL, Lieb JD, DeMayo FJ, Feschotte C, Wagner GP. Ancient transposable elements transformed the uterine regulatory landscape and transcriptome during the evolution of mammalian pregnancy. Cell Reports. 2015; 10:551–61. [PubMed: 25640180]
Fertil Steril. Author manuscript; available in PMC 2017 September 01.
Fertil Steril. Author manuscript; available in PMC 2017 September 01. Published in final edited form as: Fertil Steril. 2016 September 1; 106(3): 497–498. doi:10.1016/j.fertnstert.2016.07.1090.
Reproductive Immunology: Checkered Past and Bright Future Steven L. Young, M.D., Ph.D. University of North Carolina at Chapel Hill, Department of Obstetrics and Gynecology, 4005 Old Clinic Building (CB #7570), Chapel Hill, North Carolina 27599-7570 Steven L. Young: [email protected]
Author Manuscript
Abstract The immune system plays a critical role in pregnancy establishment and maintenance, but application of immunological principles to the treatment of infertility and pregnancy loss has had a checkered past. Improving knowledge in this area hold great promise for improving the treatment of subfertile patients.
Author Manuscript
Immune function is the result of a highly complex system of cellular and soluble components, working in intricate parallel and competing pathways to defend the host from invasive pathogens and destroy harmful or senescent cells of the host, while avoiding chronic production of potentially harmful inflammatory factors. These systems must adapt to the prolonged exposure of the semi-allogeneic embryo, in ways not yet fully understood. Furthermore, cells and molecules evolved to function in the immune system have, in mammals, been evolutionarily adapted for reproductive functions, comprising critical components of fertilization, embryo implantation, pregnancy health, and parturition. It is striking that a recent paper identified immune system genes as among the most recruited into endometrial expression during the evolution of placentation (1). Not suprisingly, then, immune system dysfunction has been identified as a likely contributor to endometriosis, infertility, recurrent pregnancy loss, preeclampsia, and preterm delivery.
Author Manuscript
However, the amazingly complex nature of immune system function, confusing nomenclature, intricate adaptations to placentation, and the plethora of competing, abstract, conceptual models among immunologists make reproductive immunology an incredibly difficult field to understand, for clinicians and scientists, leading to skepticism and misinterpretation of data. Clinical skepticism is further fueled by a history of clinical therapies that have failed to withstand careful scrutiny. These therapies have often been based on poorly validated diagnostic testing, highly premature clinical application of animal model findings, and/or small, poorly constructed, observational trials. Despite previous failures of the application of reproductive immunological findings to clinical care, the immune system plays an irrefutable role in normal fertility and successful
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Young
Page 2
Author Manuscript
applications of immunology (e.g. heparin therapy for anti-phospholipid antibody-associated recurrent pregnancy loss) have become standard part of evidence-based clinical practice. Given its importance to reproduction, the field of reproductive immunology will clearly be a future source of significant improvement in the prevention and treatment of many reproductive disorders. Thus, our aim in this News and Views, is to prime the immunologically naive reader with understandable reviews of topics that are or will be relevant to reproductive medicine.
Author Manuscript
The authors of these News and Views articles cover a wide range of topics that should be of interest to reproductive medicine clinicians and have done an outstanding job reviewing current data and explaining and translating the relevant immunology for the reproductive specialist. In the first review, Drs. Hyde and Schust examine the role of maternal responses and adaptations to “foreign” molecules carried by sperm, placenta, and a microchimeric mother as compared to maternal responses to pathogenic or commensals microbes. The authors’ combined use of historical context and up-to-date information allows an accessible and rigorous account of the immunological mechanisms involved in maternal adaptation to pregnancy. This approach and the perspective of Dr. Schust’s significant history of contributions to the field provide an excellent introductory resource to both clinicians and scientists. Drs. Roberston and Sharkey contribute a review on a very different subject, the immunology of maternal reproductive tract responses to seminal fluid and potential consequences on fertility and pregnancy outcome. Dr. Robertson has been a pioneering leader in this area, which has the potential to improve ART pregnancy rates as well as maternal-fetal health.
Author Manuscript
Drs. Riley and Jungheim examine the role of inflammation in reproduction with specific examination of dietary factors that can modify inflammation in polycycstic ovarian disease and obesity. Dr. Jungheim and her collaborators have previously contributed very interesting animal data suggesting a potent role of obesity-linked inflammation on reproduction. In this review, the authors review the state of the field, outlining what is known and what remains to be clarified. Further understanding of the role of these nutritional factors could be rapidly applied to improved care for obese infertile women, at minimal cost. This exciting area of research has great potential.
Author Manuscript
These three reviews give only a very partial introduction to current research in reproductive immunology. The data presented here and elsewhere combined with the critical roles that immune factors play in reproduction highlight the need fo further study of relevant immune mechanisms. Given further study, it is certain that we can develop new evidence-based, immunological diagnostic tests and therapies to improve our care of the infertile couple.
References 1. Lynch VJ, Nnamani MC, Kapusta A, Brayer K, Plaza SL, Mazur EC, Emera D, Sheikh SZ, Grützner F, Bauersachs S, Graf A, Young SL, Lieb JD, DeMayo FJ, Feschotte C, Wagner GP. Ancient transposable elements transformed the uterine regulatory landscape and transcriptome during the evolution of mammalian pregnancy. Cell Reports. 2015; 10:551–61. [PubMed: 25640180]
Fertil Steril. Author manuscript; available in PMC 2017 September 01.
