Connective-tissue disorders, also referred to as collagen-vascular disorders, cause a variety of generalized clinical findings and are characterized by autoantibody-mediated connective-tissue abnormalities. These are also called immune-complex diseases because many involve deposition of immune complexes in specific organ or tissue sites. Some of these disorders are characterized by sterile inflammation, especially of the skin, joints, blood vessels, and kidneys, and are referred to as rheumatic diseases. For inexplicable reasons, many rheumatic diseases primarily affect women. Another major category of connective-tissue diseases includes inherited disorders of bone, skin, cartilage, blood vessels, and basement membranes. Examples include Marfan syndrome, osteogenesis imperfecta, and Ehlers-Danlos syndrome.
Relative to future pregnancies, hemopoietic stem-cell transplantation is becoming accepted therapy for severe autoimmune diseases that include systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, and vasculitis. According to Marmont (2008), randomized clinical trials have been launched by the European Group of Blood and Marrow Transplantation (EBMT). At this time, however, even tentative conclusions are not yet available.
Although the pathogenesis has not been elucidated, immune-mediated disorders can be separated into those clearly associated with and those without autoantibody formation. So-called rheumatoid factor is an autoantibody found in many autoimmune inflammatory conditions. Those associated with rheumatoid factor include systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis (scleroderma), mixed connective-tissue disease, dermatomyositis, polymyositis, and a variety of vasculitis syndromes. In contrast, the seronegative spondyloarthropathies do not display rheumatoid factor, but are strongly associated with the presence of the HLA-B27 antigen (Benjamin and Parham, 1992; Moll, 1994). These include ankylosing spondylitis, psoriatic arthritis, Reiter disease, and likely the arthritis syndromes associated with ulcerative colitis and Crohn disease.
Because renal involvement is common and often adversely affects pregnancy, a search for coexisting renal involvement is paramount. Hypertension likewise is common, and exacerbation during pregnancy frequently forces early delivery (Wolfberg and colleagues, 2004). In some of these immune-mediated diseases, antiphospholipid antibodies are formed that can cause injury to maternal vasculature and to the placenta.
The immune system is designed to protect cells, tissues, and organs perceived as self, and to attack and destroy foreign or nonself antigenic material by the production of antibodies. This protection has two phases. The first is the innate phase, which is broad and rapid and is mediated through neutrophils, macrophages, and complement. The second is the adaptive phase, which is precise and is caused by antigen-specific reactions through T and B lymphocytes that result in memory for future exposures (Parkin and Cohen, 2001).
For some as yet unknown reason, the immune system may be stimulated to begin producing antibodies directed against self or normal tissues. These “misdirected” antibodies are called autoantibodies. The stimulus responsible for their production is unknown, but may be due to bacterial or viral injury to genetically susceptible tissues.
Autoantibodies induce destruction by at least two mechanisms. The cytotoxic mechanism involves direct antibody attachment to a specific surface antigen, which results in cell injury or destruction. The immune-complex mechanism results in tissue damage when an antigen-antibody complex attaches to a susceptible tissue. The complex may then incite a complement response or cascade, resulting in the release of chemotactic substances that attract polymorphonuclear cells.
The major histocompatibility complex (MHC) is a series of 40 to 50 genes located on the short arm of chromosome 6, and is known as the human leukocyte antigen (HLA) complex. These genetic loci code for distinct cell-surface glycoproteins, including transplantation antigens, and are involved in self and nonself recognition. Class I antigens include HLA-A, -B, and -C. Class II antigens include HLA-DR, -DQ, and -DP. Through complex interactions that include T- and B-cell stimulation and interaction with immunoglobulins and the complement system, nonself antigens or, in the abnormal state, self antigens in normal tissue are destroyed.
Immune-Mediated Disease and Pregnancy
Very few immune disorders arise only during pregnancy. Maternal isoimmunization from fetal red cell or platelet antigens is the most common (see Chap. 29, Isoimmunization). Some theories of the causes of preeclampsia-eclampsia (see Chap. 34, Etiopathogenesis) and recurrent abortion (see Chap. 9, Immunological Factors) implicate an immunological basis.
Some pregnancy-induced immune alterations may modulate connective-tissue disorders (see Chap. 5, Immunological Functions). For example, one considered important is the predominance of T2 helper cells over the cytokine-producing T1 helper cells (Keeling and Oswald, 2009). Although it is generally thought that these immunological changes have negligible effects on immune-mediated collagen-vascular disorders, the effects of large amounts of estrogen, progesterone, and prolactin must be considered. For example, estrogens upregulate and androgens downregulate T-cell response, and a number of cytokines are regulated by sex hormones (Häupl and associates, 2008a; Refojo and colleagues, 2003). Progesterone is an immunosuppresive (Cutolo and co-workers, 2006). In addition, given that autoimmune rheumatic diseases mostly affect women, Lockshin (2002) postulates a modulating effect of hormones rather than a causative role. Østensen and Villiger (2007) suggest that the hormonal and immunological alterations in pregnancy may correct the altered immunoregulation in rheumatoid arthritis.
Fetal Cell Microchimerism
Fetal cells and DNA are present in maternal blood starting in the first trimester (Sitar and associates, 2005; Waldorf and Nelson, 2008). Fetal cell microchimerism is an intriguing phenomenon that has been used to help explain the predilection of autoimmune disorders for women (Adams and Nelson, 2004). By this putative mechanism, persistent fetal cells in the maternal circulation stimulate the production of autoantibodies that underlie some autoimmune conditions. In this scheme, fetal cells such as thymocytes become engrafted in maternal tissues, and “immortal” long-lived lymphocytes circulate. Lupus may therefore represent a chronic graft-versus-host response to transplacentally acquired fetal cells, which is also suggested for some thyroid diseases and systemic ...