Autoimmune Disease During Pregnancy and the Microchimerism Legacy of Pregnancy

Abstract

Pregnancy has both short-term effects and long-term consequences. 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.Keywords autoimmune disease; pregnancy; microchimerism; systemic lupus erythematosus; rheumatoid arthritis PREGNANCY IN WOMEN WITH PRE-EXISTING AUTOIMMUNE DISEASEAutoimmune disease may complicate pregnancy in many different ways adding to the immunologic challenges already faced by the mother. The maternal immune system must avoid rejecting a semi-allogeneic fetus, remain immunocompetent to fight infections, and clear abnormal cells (e.g. precancerous) that could be harmful to the mother or fetus. Symptoms of an autoimmune disease could improve, worsen, or remain unchanged when a et al. 1987) In contrast, only a weak association between SLE susceptibility and HLA-DRB1*15 or DRB1*03 has been found in specific ethnic groups; it has been suggested that these associations are instead related to genes in linkage disequilibrium (e.g. gene encoding tumor necrosis factor-alpha with HLA-DRB1*15). (Jacob et al. 1990;Vyse and Kotzin 1998) Sex hormones and the immunologic effects of pregnancy have been investigated in autoimmunity. The well-studied relationship between sex hormones and lupus-like disease in animal models suggests a contributory role for estrogen in disease exacerbation and possibly in disease susceptibility. SLE may occur more frequently in women who have ...

Unique Roles of Infiltrating Myeloid Cells in the Murine Uterus during Early to Midpregnancy

“…In addition, based on studies of women with autoimmune diseases, Th1 immunity appears to be suppressed during pregnancy. For example, rheumatoid arthritis is a chronic systemic inflammatory disorder that is mediated by CD4 + T cells, and its symptoms improve during pregnancy and then deteriorate postpartum (20). In fact, the numbers of maternal suppressive CD4 + Tregs are increased, whereas the proliferation of effector T cells is constrained during pregnancy.…”

Thyroid physiology and autoimmunity in pregnancy and after delivery

“…Therefore, the maintenance of pregnancy is enabled by proper balance of Th1/Th2 immunity, with a slight shift towards Th2 immunity. This physiological state of lowered immune responsiveness in pregnancy results in amelioration of some pre-existing autoimmune disorders, such as rheumatoid arthritis, multiple sclerosis or thyroid autoimmune disease [51]. During the weeks immediately prior to delivery a clear decline in Treg cells occurs.…”

Pregnancy in Myositis: Challenges and Pitfalls

“…Pregnancy is defined as a specific status of high levels of sex hormones and permanent crosstalk between mother and fetus, two major processes being essentially involved in physiological adaptation to pregnancy: (i) the modification of maternal immune system with subsequent conversion of cytokine profile and (ii) the changes of hormonal milieu throughout the course of gestation (Adams Waldorf & Nelson, 2008;Borchers et al, 2010;Gordon C, 2004). …”

“…As patients with autoimmune rheumatic disorders are predominantly young women at childbearing potential (between 20 and 40 years), pregnancy is a major issue with prospective interest regarding the influence of both disease and therapy on pregnancy and, conversely, the effect of pregnancy on disease outcomes (Marker-Herman & Fisher Betz, 2010;Mecacci et al, 2007). The physiological adaptation of the immune system to pregnancy (Th2-type response) potentially affects the course of the immune-mediated rheumatic conditions; equally, autoimmunity may compromise the fetal outcomes (Adams Waldorf & Nelson, 2008;Borchers et al, 2010;Marker-Herman & Fisher Betz, 2010). Besides, systemic autoimmune conditions may be induced as a result of maternal hormonal changes and aberrant function of the immune system during pregnancy (autoimmune rheumatic disorders associated with pregnancy) or as a consequence of materno-fetal microchimerism recognized as the longterm persistence of a small number of cells from a genetically distinct organism (autoimmune rheumatic disorders in post-partum period) (Adams Waldorf & Nelson, 2008;Gordon, 2004;Scott, 2002).…”

“…The physiological adaptation of the immune system to pregnancy (Th2-type response) potentially affects the course of the immune-mediated rheumatic conditions; equally, autoimmunity may compromise the fetal outcomes (Adams Waldorf & Nelson, 2008;Borchers et al, 2010;Marker-Herman & Fisher Betz, 2010). Besides, systemic autoimmune conditions may be induced as a result of maternal hormonal changes and aberrant function of the immune system during pregnancy (autoimmune rheumatic disorders associated with pregnancy) or as a consequence of materno-fetal microchimerism recognized as the longterm persistence of a small number of cells from a genetically distinct organism (autoimmune rheumatic disorders in post-partum period) (Adams Waldorf & Nelson, 2008;Gordon, 2004;Scott, 2002). Over the last decades, most epidemiological studies have focused on pregnancy in systemic lupus erythematosus, anti-phospholipid syndrome and rheumatoid arthritis, with special emphasis on a greater risk of relatively poor fetal outcome than in the general population, particularly with increased disease activity before conception and early in pregnancy (Doria et al, 2004;Doria et al, 2006;Gayed & Gordon, 2007;Mecacci et al, 2007).…”