Microchimerism in Human Health and Disease

During pregnancy some cells traffic between the fetus and the mother. Recent investigative work indicates a low level of fetal cells commonly persists in the maternal circulation for years, or even indefinitely, after pregnancy has been completed. The term microchimerism refers to one individual harboring DNA or cells at a low level that derive from another individual. Chronic graft-versus-host disease (cGvHD) shares similarities with some autoimmune diseases and is an iatrogenic form of chimerism, occurring as a complication of hematopoietic stem cell transplantation. The HLA genes of the donor and the host are known to be of central importance to the development of cGvHD. When also considered in light of the female predilection to autoimmunity, these series of observations led to the hypothesis that microchimerism and HLA genes of host and non-host cells are involved in some autoimmune diseases. The hypothesis can also apply to men, children, and women who have not been pregnant because there are other sources of microchimerism. Persistent microchimerism can follow a blood transfusion, or can occur from transfer between twins in utereo. Additionally, maternal cells have recently been found to persist in her immune competent progeny. A number of studies have investigated a potential role of microchimerism in human diseases including systemic sclerosis (SSc), primary biliary cirrhosis (PBC), Sjögren's syndrome, polymorphic eruption of pregnancy, myositis, and thyroid disease. While some studies lend support to the concept that microchimerism is involved in the pathogenesis of selected autoimmune diseases, studies also indicate microchimerism is not uncommon in other human conditions and in healthy individuals.     

Microchimerism in autoimmune disease: more questions than answers?

Recent studies indicate cell traffic occurs between the fetus and mother during pregnancy and that low numbers of fetal cells commonly persist in the maternal circulation for years thereafter. Microchimerism refers to a small number of cells or DNA from one individual harbored in another individual. Autoimmune diseases are more common among women and often increase in incidence following reproductive years. Chronic graft vs. host disease is an iatrogenic form of chimerism with similarities to some autoimmune diseases for which the HLA relationship of donor and host are of central importance. When considered together, these observations led to the hypothesis that microchimerism and HLA relationships of host and non-host cells are involved in autoimmune disease. The hypothesis is applicable to men, children and women without pregnancies because there are other sources of microchimerism, including from a twin, the mother or a blood transfusion. Microchimerism has now been investigated in a number of different diseases with some results supporting a potential role in disease pathogenesis. However, fetal and maternal microchimerism are also found in organs affected by non-autoimmune conditions. Moreover, microchimerism is commonly detected in the peripheral blood of healthy individuals raising the intriguing question of whether these cells are simple remnants of pregnancy or whether they might also have beneficial effects for the host.     

Autoimmune disease during pregnancy and the microchimerism legacy of pregnancy

Pregnancy has both short-term effects and long-term consequences on the maternal immune system. For women who have an autoimmune disease and subsequently become pregnant, pregnancy can induce amelioration of the mother's disease, such as in rheumatoid arthritis, while exacerbating or having no effect on other autoimmune diseases like systemic lupus erythematosus. That pregnancy also leaves a long-term legacy has recently become apparent by the discovery that bi-directional cell trafficking results in persistence of fetal cells in the mother and of maternal cells in her offspring for decades after birth. The long-term persistence of a small number of cells (or DNA) from a genetically disparate individual is referred to as microchimerism. While microchimerism is common in healthy individuals and is likely to have health benefits, microchimerism has been implicated in some autoimmune diseases such as systemic sclerosis. In this paper, we will first discuss short-term effects of pregnancy on women with autoimmune disease. Pregnancy-associated changes will be reviewed for selected autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus and autoimmune thyroid disease. The pregnancy-induced amelioration of rheumatoid arthritis presents a window of opportunity for insights into both immunological mechanisms of fetal-maternal tolerance and pathogenic mechanisms in autoimmunity. A mechanistic hypothesis for the pregnancy-induced amelioration of rheumatoid arthritis will be described. We will then discuss the legacy of maternal-fetal cell transfer from the perspective of autoimmune diseases. Fetal and maternal microchimerism will be reviewed with a focus on systemic sclerosis (scleroderma), autoimmune thyroid disease, neonatal lupus and type I diabetes mellitus.     

Autoimmune Disease During Pregnancy and the Microchimerism Legacy of Pregnancy

Pregnancy has both short-term effects and long-term consequences on the maternal immune system. For women who have an autoimmune disease and subsequently become pregnant, pregnancy can induce amelioration of the mother's disease, such as in rheumatoid arthritis, while exacerbating or having no effect on other autoimmune diseases like systemic lupus erythematosus. That pregnancy also leaves a long-term legacy has recently become apparent by the discovery that bi-directional cell trafficking results in persistence of fetal cells in the mother and of maternal cells in her offspring for decades after birth. The long-term persistence of a small number of cells (or DNA) from a genetically disparate individual is referred to as microchimerism. While microchimerism is common in healthy individuals and is likely to have health benefits, microchimerism has been implicated in some autoimmune diseases such as systemic sclerosis. In this paper, we will first discuss short-term effects of pregnancy on women with autoimmune disease. Pregnancy-associated changes will be reviewed for selected autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus and autoimmune thyroid disease. The pregnancy-induced amelioration of rheumatoid arthritis presents a window of opportunity for insights into both immunological mechanisms of fetal-maternal tolerance and pathogenic mechanisms in autoimmunity. A mechanistic hypothesis for the pregnancy-induced amelioration of rheumatoid arthritis will be described. We will then discuss the legacy of maternal-fetal cell transfer from the perspective of autoimmune diseases. Fetal and maternal microchimerism will be reviewed with a focus on systemic sclerosis (scleroderma), autoimmune thyroid disease, neonatal lupus and type I diabetes mellitus.     

Maternal microchimerism—Allogenic target of autoimmune disease or Normal Biology?

Chimerism is the state of cells from two distinct individuals living within one body. Fetal cells pass into a mother during pregnancy, where they may persist at low levels for years, creating a state of fetal microchimerism. At the same time, maternal cells pass into the fetus, leading to maternal microchimerism that can persist into adulthood. Hematopoietic stem cell transplantation also creates a state of chimerism, and can lead to a complication of chronic multi-organ inflammation called graft-versus-host disease, (GVHD). The similarities between GVHD and some autoimmune diseases like scleroderma, lupus and myositis suggest that chimerism may be involved in the pathogenesis of both. Maternal and fetal microchimerism in the blood and in tissues have been associated with autoimmune diseases. However, many healthy individuals harbor maternal and fetal cells. Human and animal studies have begun to elucidate the mechanisms for normal tolerance to maternal and fetal microchimeric cells, and how this tolerance may be broken in states of chronic inflammatory disease.     

Possible roles and determinants of microchimerism in autoimmune and other disorders

Microchimerism is the presence of a low level of non-host stem cells or their progeny in an individual. The most common source of microchimerism is pregnancy. During pregnancy, bi-directional trafficking of hematopoietic cells occurs through the placenta and these microchimeric cells persist for decades after childbirth. A possible role of microchimerism in the pathogenesis of some (systemic sclerosis, systemic lupus erythematosus, primary biliary cirrhosis, autoimmune thyroid diseases and juvenile myositis) but not all autoimmune diseases has been suggested by recent studies. Contradictory reports exist regarding HLA allelic associations with persistent T lymphocyte microchimerism. Although much of the focus of past studies has been on microchimerism in the effector arm of the immune system, increasing evidence suggests that microchimeric cells may differentiate into many lineages in different tissues raising additional possible roles for these cells. The possibility of microchimerism in many organs should induce an exploration of how persistent mixtures of cells of different genetic backgrounds throughout the body may influence diverse physiologic processes during life. In the present review, we discuss possible influencing factors and roles of all forms of microchimerism in autoimmune and non-autoimmune diseases. A better understanding of the immune mechanisms, along with the identification of environmental and genetic risk factors, is crucial for further deciphering the many possible implications of maternal-fetal and fetal-maternal cell trafficking in health and disease.     

Fetal-maternal microchimerism: impact on hematopoietic stem cell transplantation

Reciprocal cell traffic between mother and fetus during pregnancy gives rise to postpartum fetal-maternal lymphohematopoietic microchimerism, which is frequently detected in blood or tissue from healthy individuals. Although such microchimerism has been implicated in the pathogenesis of autoimmune diseases and tissue repair, recent clinical experiences have suggested the association of microchimerism with acquired immunologic hyporesponsiveness to non-inherited maternal HLA antigens (NIMAs) or inherited paternal HLA antigens (IPAs); T cell-replete HLA-haploidentical hematopoietic stem cell transplantation from a microchimeric IPA/NIMA-mismatched donor confers relatively lower incidence of severe graft-versus-host disease. The underlying mechanisms by which fetal-maternal microchimerism contributes to IPA/NIMA-specific tolerance are still elusive, although emerging experimental evidence suggests an involvement of the central deletion of IPA/NIMA-reactive T cells, the induction of peripheral regulatory T cells, and affinity-dependent modulation of NIMA-reactive B cells.     

Fetal microchimerism and autoimmune disease

Microchimerism is defined by the presence of circulating cells, bi-directionally transferred from one genetically distinct individual to another. The acquisition and persistence of fetal cell microchimerism, small numbers of genetically disparate cells from the fetus in the mother, is now a well-recognized consequence of normal pregnancy. Some of the autoimmune diseases that show a predilection for women in their child-bearing years and beyond are linked to fetal microchimerism from previous pregnancies. Microchimerism has been investigated in different autoimmune disorders, such as systemic sclerosis, systemic lupus erythematosus, autoimmune thyroid diseases, and primary biliary cirrhosis. Recent data have demonstrated the promising role of microchimeric cells in the maternal response to tissue injuries by differentiating into many lineages. Therefore, further understanding of fetal-maternal microchimerism may help in anticipating its implications in disease as well as in more general women's health issues.     

Microchimerism in Endocrine Pathology

Chimerism in an individual refers to the coexistence of cells arising from two distinct organisms. It can arise iatrogenically via transplant or blood transfusion, and physiologically via twin to twin transfer, or from trafficking between mother and fetus during pregnancy. Many of the diseases associated with microchimerism affect the endocrine system (e.g., autoimmune thyroid disease and diabetes mellitus type 1). Microchimerism is relevant to endocrine pathology because (a) it is associated with pregnancy, a condition of complex endocrine physiology; (b) materno-fetal and feto-maternal cellular migration must involve the placenta, itself an endocrine organ; and (c) in some species, chimerism results in states of intersexuality, a condition intimately involved with endocrine physiology. Studies of feto-maternal microchimerism in the thyroid have documented the presence of fetal cells in association with Hashimoto thyroiditis, Graves’ disease, thyroid adenoma, and papillary thyroid carcinoma. Studies of materno-fetal microchimerism have documented the presence of maternal cells in juvenile diabetes and other pediatric conditions. Microchimerism plays a potential role in the repair of diseased thyroid and pancreatic tissues.     

Fetal-cell microchimerism, lymphopoiesis, and autoimmunity

During all human and murine pregnancies, fetal cells enter the maternal circulation and tissues and may persist there for decades. The immune consequences of this phenomenon have been explored for many years as a potential origin of autoimmunity or protection from cancer in women after pregnancy. The leading hypothesis, suggesting that semi-allogenic fetal T cells may trigger a graft-versus-host type of disease, has been supported by several studies showing an increased frequency of fetal-cell microchimerism (FMc) in women affected with systemic sclerosis. However, a large proportion of healthy women or women affected with non-immune disorders also display fetal T cells, challenging the direct pathogenic role of such cells. In addition, recent evidence showing the transfer of various fetal progenitor cells to the mother during gestation has shed new light on the interpretation of microchimerism in autoimmunity. This review discusses the functional capacity of fetal hematopoietic progenitors to form T and B cells in maternal hematopoietic tissues, where they undergo an educational process probably resulting in tolerance to maternal antigens. Therefore, hypotheses other than the transfer of fetal cells to the mother’s circulation should be considered in explaining the observed association of FMc and autoimmune disorders.     

Fetomaternal cell trafficking: A new cause of disease?

Isolation of fetal cells from maternal blood is under active investigation as a noninvasive method of prenatal diagnosis. In the context of studying cell surface antigens expressed on fetal cells we discovered that fetal cells from a prior pregnancy also could be detected. This led to the appreciation of the persistence of fetal cells in maternal blood for as long as 27 years postpartum, and the realization that following pregnancy, a woman becomes a chimera. Quantitative polymerase chain reaction analyses have shown that a term pregnancy is not required for the subsequent development of fetal cell microchimerism. As many as 500,000 fetal nucleated cells are transfused following an elective first trimester termination of pregnancy. The relationship between fetal cell microchimerism and maternal disease is currently being explored. During pregnancy, fetal cells in the maternal skin are related to polymorphic eruptions of pregnancy and increased fetomaternal trafficking is detectable in cases of preeclampsia. After delivery, more male DNA of presumed fetal origin is present in the blood and skin of women with scleroderma as compared with healthy controls. Scleroderma is of particular interest because it shows a strong female predilection and it is an autoimmune disease with clinical similarities to graft‐versus‐host disease. Fetomaternal cell trafficking provides a potential explanation for the increased prevalence of autoimmune disorders in adult women following their childbearing years. Am. J. Med. Genet. 91:22–28, 2000. © 2000 Wiley‐Liss, Inc.     

The implications of autoimmunity and pregnancy

There are multiple epidemiological studies that document the potential adverse affects of autoimmunity on nearly every aspect of reproduction, even in the absence of clinically manifest autoimmune disease. Two decades ago, it was suggested that women with autoimmune diseases avoid pregnancy due to inordinate risks to the mother and the child. In contrast, newer epidemiological data demonstrated that advances in the treatment of autoimmune diseases and the management of pregnant women with these diseases have similarly improved the prognosis for mother and child. In particular, if pregnancy is planned during periods of inactive or stable disease, the result often is giving birth to healthy full-term babies without increased risks of pregnancy complications. Nonetheless, pregnancies in most autoimmune diseases are still classified as high risk because of the potential for major complications. These complications include disease exacerbations during gestation and increased perinatal mortality and morbidity in most autoimmune diseases, whereas fetal mortality is characteristic of the anti-phospholipid syndrome (APS). In this review, we will discuss these topics, including issues of hormones, along with potential long-term effects of the microchimerism phenomenon. With respect to pregnancy and autoimmune diseases, epidemiological studies have attempted to address the following questions: 1) Is it safe for the mother to become pregnant or are there acute or chronic effects of pregnancy on the course of the disease? 2) Does the disease alter the course and/or the outcome of a pregnancy and thereby represent an inordinate risk for the fetus and infant? And do new therapeutic and management approaches improve the pregnancy outcomes in women with autoimmune diseases? 3) Does passage of maternal autoantibodies represent a risk to the child? 4) Do pregnancy, parity, or other factors influencing hormonal status explain the female predominance of many autoimmune diseases, and is the pregnancy effect related to microchimerism? Answering these questions has taken on additional importance in recent decades as women in western countries now frequently choose to delay pregnancies and have some or all of their pregnancies after disease onset. In this paper, we primarily focus on APS, systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), and type 1 diabetes (T1D).     

Fetomaternal cell trafficking: a new cause of disease?

Isolation of fetal cells from maternal blood is under active investigation as a noninvasive method of prenatal diagnosis. In the context of studying cell surface antigens expressed on fetal cells we discovered that fetal cells from a prior pregnancy also could be detected. This led to the appreciation of the persistence of fetal cells in maternal blood for as long as 27 years postpartum, and the realization that following pregnancy, a woman becomes a chimera. Quantitative polymerase chain reaction analyses have shown that a term pregnancy is not required for the subsequent development of fetal cell microchimerism. As many as 500,000 fetal nucleated cells are transfused following an elective first trimester termination of pregnancy. The relationship between fetal cell microchimerism and maternal disease is currently being explored. During pregnancy, fetal cells in the maternal skin are related to polymorphic eruptions of pregnancy and increased fetomaternal trafficking is detectable in cases of preeclampsia. After delivery, more male DNA of presumed fetal origin is present in the blood and skin of women with scleroderma as compared with healthy controls. Scleroderma is of particular interest because it shows a strong female predilection and it is an autoimmune disease with clinical similarities to graft-versus-host disease. Fetomaternal cell trafficking provides a potential explanation for the increased prevalence of autoimmune disorders in adult women following their childbearing years.     

Remission of rheumatoid arthritis during pregnancy and maternal-fetal class II alloantigen disparity.

Rheumatoid arthritis (RA) is an autoimmune disorder known to be associated with specific class II genes. Although it has been known since 1938 that the majority of women with RA experience disease improvement or remission during pregnancy, the reasons remain unknown. Pregnancy represents an immunologic challenge and maternal immune recognition of the semi-allogeneic fetus occurs as part of normal pregnancy. We hypothesized that maternal immune response to fetal HLA antigens might be associated with the effect of pregnancy on arthritis activity. To test this hypothesis, we studied HLA antigens in mother-child pairs comparing maternal-fetal HLA antigen sharing for pregnancies where arthritis improved with those where disease was active. No significant difference was observed in the two groups for class I HLA antigens. Fetal-maternal disparity for HLA-DR and HLA-DQ antigens was observed significantly more frequently in pregnancies with remission or improvement compared with those in which disease was active. These observations suggest that maternal immune response to fetal paternally-inherited class II HLA antigens may be important in RA remission observed during pregnancy.     

The tripartite immune conflict in placentals and a hypothesis on fetal-->maternal microchimerism

There is a two-way traffic of immune cells through the placenta; and fetal immune cells are often present in the maternal body even long after giving birth. We present an adaptationist theory to interpret fetal-->maternal microchimerism and the diverse set of concomitant medical phenomena. We handle fetal, maternal, and paternal adaptive interests separately and in interaction with one another. Fetuses may benefit from immunological information gathered by migrant cells in the maternal body, and also from improved maternal defence. However, they may be jeopardized by a selfish maternal usage of fetal-->maternal microchimerism - i.e., some mothers get pregnant only to improve their immune system and then to abort. The use of microchimeric cells by the maternal immune system may contribute to the adaptive benefits of female choosiness and polyandry. While fathers may enjoy an indirect benefit from enhanced fetal and maternal health, they also face the risk of wasting sexual efforts due to selfish pregnancies of cheating females. Paternal alleles acting via clones of microchimeric cells in the maternal body could launch an immunological attack against the non-kin sperm in the female genitalia, or against the non-kin fetus in the womb. Furthermore, an intraspecific version of Zahavi's Mafia Hypothesis could explain a potential interaction between the abortion of fetuses and a subsequent rise of an autoimmune disease. We suggest that males may be capable to provoke microchimerism-induced autoimmune-like diseases in the mother in revenge of selfish pregnancies. This hypothetic paternal threat could increase the maternal costs associated to selfish pregnancies. From a medical point of view, we propose new interpretations for autoimmune-like diseases, infertility, miscarriage, and also for the prevailing connections among them. Specifically, we argue that miscarriages may cause autoimmune diseases, a reversed causality as compared to the currently accepted one.     

Male microchimerism in peripheral blood from women with multiple sclerosis in Isfahan Province

Multiple sclerosis (MS) is referred to as an organ‐specific T‐cell‐mediated autoimmune disease of the central nervous system (CNS). Different genetic and environmental factors increase the risk of developing MS. In recent years, microchimerism (Mc) has been widely studied in autoimmune diseases, although the exact role of this phenomenon in human health is not known well. Microchimerism is the low level presence of DNA or cells from one individual into the tissue or circulation of another individual. In the current study, we evaluated the association of fetal microchimerism (FMc) with MS in Isfahan province. In this study, we enrolled 68 women in four groups. Two groups were MS patients with or without a pregnancy for a son, and the other two groups were MS‐negative patients with or without a pregnancy for a son. The presence of the male genome assessed and compared in these groups. Four millilitres of peripheral blood were collected from all subjects in the tube containing EDTA and DNA was extracted. Real‐time PCR assay was used for the DAZ (deleted in azoospermia) region Yq 11.23 as a marker for male microchimerism in all subjects. Our results showed that the percentage of DAZ (male genome)‐positive women was significantly higher in MS‐positive women given birth to a son in comparison with the other three groups. Our results also revealed no significant correlation between the percentage of DAZ‐positive women and Expanded Disability Status Scale (EDSS) score and age of onset in the patients’ group. For future studies, we suggest enrolling subjects who MS diagnosis occurred before and after pregnancy with a son. Comparing FMc in these two groups might provide a better understanding of the possible role of FMc in later development of MS.     

HLA class II transgenic mice as models of human diseases

Summary: Predisposition co develop Various autoimmune disorders has been associated with certain HLA class II molecules but there is a lack of information on che pathophysiological rule of HLA genes in conferring susceptibility Various experimental animal models of autoimmune disease have been studied to address the role of immune response genes. To study the interactions involved between class II molecules (DQ and DR) and define the immunologic mechanisms in various diseases, we generated HLA-DR and DQ transgenic mice that lacked endogenous class II molecules. The HLA molecules in these mice arc expressed on the cell surface and can positively select CD4+ T cells expressing Various Vβ T-cell receptors (TCR). A peripheral tolerance is maintained co transgenic HLA molecules thus indicating that these molecules act as self, Mouse co stimulatory and accessory molecules can interact with the HLA-peptide-TCR complex leading to efficient T-cell activation. In this review, we describe immunogenetic models for human diseases using these transgenic mice. Our studies show that HLA class II transgene-restricted T cells recognize the immunodominant antigens and peptide epitopes, similar to HLA class II-restricted human T cells. Thus these mice provide powerful tools to understand the role of HLA class II molecules in predisposition and onset of human diseases and to develop immunotherapy and vaccines.     

Chimerism in health and potential implications on behavior: A systematic review

In this review, we focus on the phenomenon of chimerism and especially microchimerism as one of the currently underexplored explanations for differences in health and behavior. Chimerism is an amalgamation of cells from two or more unique zygotes within a single organism, with microchimerism defined by a minor cell population of <1%. This article first presents an overview of the primary techniques employed to detect and quantify the presence of microchimerism and then reviews empirical studies of chimerism in mammals including primates and humans. In women, male microchimerism, a condition suggested to be the result of fetomaternal exchange in utero, is relatively easily detected by polymerase chain reaction molecular techniques targeting Y‐chromosomal markers. Consequently, studies of chimerism in human diseases have largely focused on diseases with a predilection for females including autoimmune diseases, and female cancers. We detail studies of chimerism in human diseases and also discuss some potential implications in behavior. Understanding the prevalence of chimerism and the associated health outcomes will provide invaluable knowledge of human biology and guide novel approaches for treating diseases.     

Linkage disequilibrium between human leukocyte antigen (HLA) class II and HLA-G--possible implications for human reproduction and autoimmune disease

A line of investigation indicates that one or several genes in the human major histocompatibility complex (MHC) influences reproductive success. Studies have revealed associations between human leukocyte antigen (HLA) class II genes and risk of recurrent spontaneous abortion (RSA) and pre-eclampsia. However, these genes are not expressed at the feto-maternal interface. Furthermore, associations between polymorphisms in the nonclassical HLA class Ib gene, HLA-G, and reproductive outcome have been demonstrated. HLA-G is expressed by extravillous trophoblast during pregnancy, making it a more obvious candidate gene for a possible influence on pregnancy outcome. HLA-G has immunomodulatory functions. We have studied linkage disequilibrium between HLA class II genes, primarily HLA-DRB1 alleles, and HLA-G alleles in women with RSA and their partners (n = 103) and in control women and their partners (n = 92). We found a significant linkage disequilibrium between HLA-DR3 and HLA-G*010102 in both the RSA and control populations. For all four studied HLA loci, the alleles in the haplotype HLA-DRB1*03.DQA1*05.DQB1*02.G*010102 was in clear linkage disequilibrium. This HLA haplotype has repeatedly been associated with different autoimmune diseases but also with RSA. The G*010102 allele includes a 14-bp sequence polymorphism in the 3' untranslated region of the gene, which has been associated with differences in HLA-G mRNA alternative splicing and stability. This 14-bp polymorphism has also been associated with RSA, pre-eclampsia, and outcome of in vitro fertilization. Implications of HLA polymorphism--and other polymorphic genes in the MHC for pregnancy outcome--and for autoimmune diseases during pregnancy are discussed.     

Interaction of pregnancy and autoimmune rheumatic disease

During pregnancy, the fetus represents a natural allograft that is not normally rejected. While the maternal immune system retains the ability to respond to foreign antigens, tolerance mechanisms are up-regulated to protect the fetus from immunologic attacks by the mother. The profound immunologic adaptations during and after pregnancy do influence maternal autoimmune rheumatic diseases in several ways. One is triggering the onset of a rheumatic disease in the post partum period, the other influencing disease activity of established rheumatic disease. The review will discuss the mechanisms of increased susceptibility of rheumatoid arthritis (RA) in the first year post partum with a specific emphasis on the role of fetal cells or antigens persisting in the maternal circulation (so called microchimerism). Furthermore, the different influences of pregnancy on established rheumatic diseases will be highlighted. A marked beneficial effect of pregnancy is observed on RA whereas several other rheumatic diseases as ankylosing spondylitis (AS) and systemic lupus erythematosus (SLE) show either no particular effect or an aggravation of symptoms during pregnancy. Differences emerging in regard to modulation of disease symptoms during pregnancy seem related to response to hormones, the type of cytokine profile and immune response prevailing as well as further downstream interactions of molecular pathways that are important in disease pathogenesis.