Immune Systems and Human Intrauterine Development

 

 

 

 

 

 

Itzhak Zusman, D.V.M., Ph.D., D.B.Sc.,

Professor

Koret School of Veterinary Medicine,

Faculty of Agricultural, Food and Environmental Quality Sciences,

The Hebrew University of Jerusalem, Rehovot,

Israel

 

Pavel Gurevich, M.D., Ph.D., D.M.Sc.,

Professor

Laboratory of Experimental Medicine,

Rabin Scientific Park, Rehovot,

Israel

 

Herzel Ben-Hur, M.D.,

Department of Gynecology and Obstetrics,

Assaf Harofeh Medical Center, Beit-Dagan;

Head, Laboratory of Experimental Medicine,

Rabin Scientific Park, Rehovot,

Israel

 

 

                                                            Contents

 

Preface

 

Introduction

 

Chapter 1. Morphological Characteristics and Functions of the Immune Systems

1.1) Components of the nonspecific immune protection

1.2) Components of the specific immune protection

  1.2.1)  Cellular components of the common immune system

     1.2.2)  Humoral components of the common immune  system

  1.2.3)  The secretory (mucosal) immune system

  1.2.4)  The secretory immune system in the barrier structures

 

Chapter 2.  Immune Protection of the Process of Fertilization and Preimplantation Embryos. Early Development of the Secretory Immune System

            2.1)   Protection of the fertilization process 

            2.2)   Protection of preimplantation embryos

            2.3)  Components of the secretory immune system in human embryos and  early   fetuses in the first trimester of pregnancy 

 

Chapter 3.  Immune Protection of Vitally Important Organs and Cells in Human  Embryos and Early Fetuses

3.1)  Immune components in fetal endocrine glands and their precursors

3.2)  Immune components in the developing myocardium

3.3)  Immune protection of the developing brain

3.3.1)   Secretory immune components in the developing brain

         3.3.2)   Types of barrier protection  of the developing brain

3.4)   Immune protection of gonads and genital tracts

     3.4.1)  Immune protection of gonads and genital tracts in adults

               3.4.1-1)  Immunoprotective components in the female genital tract,

                            ovaries and oocytes

3.4.1-2)  Immunoprotective components in the testes and male genital tract

      3.4.2)   The secretory immune system in the developing gonads and genital tracts

3.4.2-1)     Secretory immune components in the developing genital tracts

3.4.2-2)     Secretory immune components in the developing female gonads

3.4.2-3)     Secretory immune components in the developing male gonads

 

Chapter 4.  Immune Protection of Embryos and Fetuses in Normal Pregnancy and Under Pathological Conditions

                 4.1)  Mononuclear phagocytes in embryos and fetuses under normal

                             and pathological conditions of gestation

                 4.2)  Immunoprotective role of the trophoblast

     4.3)  Apoptosis in the embryonic cells and its consequences 

                 4.4) Pathology of the immune organs  in growth-retarded or low-weight fetuses  and newborns under antigen-induced influences                       

        

 

 

 

Chapter 5.  Mother-Embryo Immune Conflict as a Reason for Recurrent

                       Spontaneous  Early Abortions

5.1)            Possible reasons for the immune conflict

5.2)            Humoral and cellular mechanisms of the immune conflict

5.3)            Pathological changes in  the placental barrier as a reason for spontaneous early abortions

 

Chapter 6.    The Fetal Immune Systems in Normal Development and under

                        Pathological Effects

         6.1)  The common immune system in fetuses

               6.1.1)  Immune components in experimental fetal pathology

               6.1.2)  The immune system in human fetal pathology

6.2)  The secretory immune system  in human fetuses

               6.2.1)  Lymphoid-epithelial components of the secretory immune system    in self-protection of human fetuses 

6.2.2)      Components of the secretory immune system in fetal membranes and decidua

 

Chapter 7.   The Secretory Immune System  and the Placental Barrier

             7.1)   The placental barrier: its morphology, function and pathology

 7.2) The role of the secretory component and J chain in maternal  immunoglobulin  transport   through the placental barrier 

             7.3)   The secretory immune system as part of the placental barrier

 

Chapter 8.   Immune Systems in the Pathogenesis of RhD-Hemolytic Disease

                   of Fetuses and Newborns  (HDN)

                8.1)   Immune response of fetuses and newborns in RhD-conflict

    8.2)   Immune antigen-antibody complexes in RhD-HDN

 8.3)   Mechanism of immune destruction of erythrocytes in RhD-HDN

           

Chapter 9.   Pathology of the Immune System in Fetuses and Newborns  Affected by Infectious Diseases

9.1)            Nucleolar organizer regions in the lymphoid cells in fetuses and newborns with pneumonia and sepsis

9.2)            Intraorganic immunity of fetuses and newborns with pneumonia and sepsis

9.3)            Insufficiency of the immune system in fetuses and infants with sepsis

Chapter 10. Clinically Oriented Extrinsic and Intrinsic Factors in Etiology of Fetal                                   Growth  Restriction

      10.1)   Geographic peculiarities of immunoglobulins in FGR

     10.2)   Changes in the placenta as a reason for  FGR

10.2.1)   Morphological aspects

10.2.2)   Biochemical aspects

                     10.2.3)   Transport across the trophoblast in FGR

    10.3)   Maternal environment and FGR

            10.3.1)   Effects of mother's diet

            10.3.2)   Effects of mother's diseases

            10.3.3)   Effects of mother's smoking

            10.3.4)   Effects of mother's alcohol consumption

            10.3.5)   Effects of drinking water

            10.3.6)   Effects of socioeconomic factors

            10.5.7)   Genetic predisposition to FGR

            10.3.8)   Racial effects on FGR

        10.4)   Effects of FGR on postnatal growth and development  

 

Preface

In recent years it has come to be generally recognized that, directly or indirectly, immunology intrudes into nearly every aspect of human reproduction. The discovered importance of the natural transfer of immunity from mother to offspring, the ontogeny of the immune response, and the recognition of pregnancy as an  example of the mother-embryo interaction, are only a few components of the multifaceted field known as the immunology of reproduction. In this book, we have compiled material, obtained in our laboratories and gleaned from the modern publications  illustrating ongoing research in the field of reproductive immunology on the immune system in human  intrauterine development. Many new approaches have been postulated and published in recent years, enough to warrant bringing them together in one place. In this book, we focus our attention mainly on the application of humoral and cellular changes that describe the role of immune systems in human intrauterine development. A substantial area of the reproductive immunology deals with the issue of the maternal-fetal conflict and the survival of the embryo/fetus as an allograft. Although much efforts has been invested in describing different aspects of this problem, relationships between the pregnant mother and her developing fetus are not yet fully understood from an immunological point of a view. The role of the fetal immune system in its survival and in the maintenance of pregnancy have only been scanty studied, especially with respect to the secretory immune system. General skepticism has been developed regarding the diagnosis and treatment of recurrent spontaneous abortions. In our research, we have described changes in the secretory immune system of the embryo/fetus and mother as   possible reasons for such abortions and we hope that these findings will yield a better understanding of the mechanism underlying this phenomenon.

 

For many years, our laboratories have been studying the pathology of fetuses and the immune response of their lymphoid systems to experimentally induced disorders in laboratory animals (mice and rats) and under some diseases in humans, such as hemolytic disease of fetuses and newborns, sepsis of fetuses, and others. In the last decade, we have concentrated our efforts on studying the immune protection of human embryos and fetuses under non-antigen and antigen-induced diseases, studying the secretory (mucosal) immune system. The changes in the different types of immune systems in the intrauterine-developing organism in normal pregnancy, under non-infectious pathology and under infectious effects as well as under mother-fetus immune conflict are discussed in this book. The protective role of mononuclear phagocytes and the non-villous infiltrating trophoblast  is analyzed. The pathological morphology of some immune and inflammatory processes, including massive apoptosis of embryonic cells, is also discussed.  We hope that the problems described in this book will be of interest to people with various professional orientations, such as physicians and researchers in the field of obstetrics and gynecology, reproductive immunology and intrauterine human development, as well as medical students. For the clinician and scientists in other areas of medicine, pregnancy provides an area in which many immunological ideas can be tested. This is particularly true now that the impact of pregnancy impacts on the maternal immune system is becoming better understood.

 

 

Introduction

One of the most intriguing phenomena in immunology is the exemption  of the semi-allogenic embryo (or allogenic embryo in surrogate mothers) to be exempt from immunological rejection (1). Why a pregnancy sometimes  runs successfully to full- term, while in other cases it is interrupted without any visible or recognizable cause, remains a mystery.  The exact frequency of spontaneous abortions in the general population is unknown: it has only been suggested that pregnancy loss is common affecting 10% to 15% and even to 20% of all pregnancies (2,3). Our lack of knowledge in this field is reflected by the fact that the real causes of spontaneous early abortions (in humans, before  week  9 of pregnancy, i.e., in the embryonic period of intrauterine development) are unknown in 50% of the cases (4).

One opinion holds that the uterus possesses some immune "privileges", that allows it to develop a tolerance to the implanting embryo and sustain its survival  and normal development (5). But because some other organs, such the brain and eyes, have the similar  immune  privileges  (6),  it seems more plausible to suggest  that the trophoblast cells which come into contact with the immunocompetent cells of the decidua  do  not  contain  the major histocompatibility complex (MHC)  responsible for inducing the cell-rejection reaction.  The immunological rejection of an embryo is also prevented also by the presence of immunosuppressive regulatory molecules in the placenta, such as progesterone (7), prostaglandin E2 (8) and early pregnancy factor (9).

Some studies in the field of reproductive immunology have focused on the postulate of the mother-embryo conflict as a transplanting graft, a conception which was published in the 1950s by Dr. Peter Medavar. Howwever, many aspects of immunological relationships between a mother and her developing fetus remain unclear, and some of them are discussed in this book. Molecules of human leukocytes antigens (HLA) expressed by trophoblast and placenta cells, play an important role in the immune relationships between the pregnant mother and her fetus. Promising are studies of the role of the cytokine cascade and regulation of cytokine gene expression in the processes of fertilization and implantation, as well as mechanisms regulating the invasion of the trophoblast into the endometrium, which as a result ensures adequate levels of fetoplacental complex development. The role of apoptosis process in fetal intrauterine development is especially interesting. Undoubtedly, studies into the molecular-cellular specificities of different fetal tissues in cases of habitual miscarriages, will yield important information.

One of the hypotheses that is analyzed in this book is that disturbances in maturation and activation of the fetal immune system are related to the onset of preterm labor (9).    The question of whether activation of the fetal immune system and preterm labor occur as a consequence of the bi-directional trafficking of fetal and maternal cells is discussed. Increased fetal-maternal HLA compatibility may lead to interactions between maternal and fetal cells which in turn lead to activation of the fetal immune system and preterm labor (10).

Although many research efforts have been devoted to the detailed study of the early intrauterine development of human embryos, the role of the embryos and fetuses themselves and their immune system in normal and pathological development are less known. For many years now we have studied the pathology of intrauterine human development in different diseases and the role of the fetal immune system in this process. Results of these studies are analyzed in this book and compared with up-to-date data from the literature. Our groups are studying the immune mechanisms  underlying fetal protection against infection and other antigenic effects. Our main focus has been on evaluating the functions of mononuclear phagocytes in embryos and early fetuses and the protective role of the secretory immune system and its different variances.

 

This book describes tha protective mechanisms of the secretory immune system and its components (secretory component (SC), joining (J)  chain, immunoglobulins (Igs), Fc receptors, etc.) in normal development, under noninfectious pathologies, and antigen-induced infectious  pathologies; the protective role of mononuclear phagocytes as well as of the non-villous trophoblast in early embryos; the pathological morphology of some immune and inflammatory processes, including the massive apoptosis of embryonic cells in response to the described pathogenic effects. Separate chapters in the book describe the role of  mother-embryo immune conflict as an a frequent reason for recurrent spontaneous early abortions; a role for the placental barrier in normal pregnancy and in those complicated by inflammation; a role of the secretory immune system in growth-retarded fetuses under antigen-induced influences. The last chapter analyzes the role pf clinically oriented environmental factors as etiologies of restriction in the fetal growth.

 

 

References

 

 

1.  Sargent, I.L., Borzychowski, A.M., and Redman, C.W.,  2006, Immunoregulation in normal pregnancy and pre-eclampsia: an overview, Reprod. Biomed. Online, 13, 680.

2. Kutteh, W.H., 1999, Recurrent pregnancy loss: an update, Curr. Opin. Obstet. Gynecol., 11, 435.

3. Adolfsson, A., and Larsson, P.G., 2006, Cumulative incidence of previous spontaneous abortion in Sweden in 1983-2003: a register study, Acta Obstet. Gynecol. Scand., 85, 741.

4. Sargent, I.L., 1993, The placenta and recurrent early pregnancy loss. In: The Human Placenta. A Guide for Clinicians and Scientists, C.W.G. Redman, I.L. Sergant and P.M. Sturkey (Eds.), Blackwell Sci. Publ., Oxford, 414.

5. Niederkorn, J.Y., and Wang, S., 2005, Immune privilege of the eye and fetus: parallel universes? Transplantation, 80, 1139.

6. Streilein, J.W., and Stein-Streilein, J., 2000, Does innate immune privilege exist? J. Leukoc. Biol., 67, 479.

7. Piccini, M.P., Gindizi, M.G., Biagiotti, R., Beloni, L., Gianarini, L., Sampogriardo, S., Parronchi, P., Manetti, R., Annunziato, F., Livi, C., Romagnani, S., and Magi, E.,   Progesterone favours the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clones, 1995,  J. Immunol., 155, 128.

8. Abe, N., Katamura, K., and Shintakci, N., Prostaglandin E2 and IL4 provide naïve CD4+ T cells with distinct inhibitory signals for priming of IFN