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Connective-tissue disorders, which are also termed collagen-vascular disorders, have two basic underlying causes. First are the autoantibody-mediated immune-complex diseases in which connective-tissue damage is caused by deposition of immune complexes in specific organ(s) or tissue sites. Because these are manifest by sterile inflammation—predominately of the skin, joints, blood vessels, and kidneys—they are referred to as rheumatic diseases. Many of these immune-complex diseases are more prevalent in women, for example, systemic lupus erythematosus (SLE), rheumatoid arthritis, and a host of vasculitis syndromes. Second are the inherited disorders of bone, skin, cartilage, blood vessels, and basement membranes. Some examples include Marfan syndrome, osteogenesis imperfecta, and Ehlers-Danlos syndrome.

Immune-Mediated Connective-Tissue Diseases

These disorders can be separated into those associated with and those without autoantibody formation. So-called rheumatoid factor (RF) is an autoantibody found in many autoimmune inflammatory conditions such as SLE, rheumatoid arthritis, systemic sclerosis (scleroderma), mixed connective-tissue disease, dermatomyositis, polymyositis, and various vasculitis syndromes. The RF-seronegative spondyloarthropathies are strongly associated with expression of the HLA-B27 antigen and include ankylosing spondylitis, psoriatic arthritis, Reiter disease, and other arthritis syndromes.

Pregnancy may mitigate activity in some of these syndromes as a result of the immunosuppression that also allows successful engraftment of fetal and placental tissues. These changes are discussed in detail in Chapters 4 and 5 (Immunological Functions). One example is pregnancy-induced predominance of T2 helper cells compared with cytokine-producing T1 helper cells (Keeling, 2009). Pregnancy hormones alter immune cells, for example, estrogens upregulate and androgens downregulate T-cell response, and progesterone is immunosuppressive (Cutolo, 2006; Häupl, 2008a; Robinson, 2012).

Some immune-mediated diseases may either be caused or activated as a result of previous pregnancies. To explain, fetal cells and free fetal DNA are detectable in maternal blood beginning early in pregnancy (Simpson, 2013; Sitar, 2005; Waldorf, 2008). Fetal cell microchimerism is the persistence of fetal cells in the maternal circulation and organs following pregnancy. These persistent fetal cells may stimulate autoantibodies, or they may become engrafted in maternal tissues. This raises the possibility that fetal cell microchimerism is related to the predilection of autoimmune disorders for women (Adams, 2004; Lissauer, 2009). Evidence for this includes findings of fetal stem cells engrafted in maternal tissues in women with autoimmune thyroiditis and systemic sclerosis (Jimenez, 2005; Srivatsa, 2001). Such microchimerism has also been described in women with SLE and those with rheumatoid arthritis-associated HLA alleles (Johnson, 2001; Lee, 2010; Rak, 2009a). Similarly, engrafted maternal cells may provoke autoimmune conditions in a woman’s offspring (Ye, 2012). Perhaps related, women with SLE have a 0.6 male:female offspring ratio suggesting excessive male fetal loss in these women (Aggarwal, 2013).

Systemic Lupus Erythematosus

Lupus is a heterogeneous autoimmune disease with a complex pathogenesis ...

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