The protein responsible for the immune response in CD is gluten, which is derived from wheat and similar proteins that are found in rye and barley [15
]. Gliadin peptides, which are derived from gluten, contain the majority of toxic substances and are resistant to degradation by proteases, thereby allowing them to remain intact within the intestinal lumen after ingestion [16
]. In individuals with CD, these peptides then enter the lamina propria, triggering chronic inflammatory changes.
It is notable that gluten peptides in their native form are not toxic. In order for gluten peptides to cause inflammation, they must first be altered by the enzyme tissue transglutaminase (tTG), which is normally involved in tissue remodeling and protein cross-linking. tTG is normally present in nearly all organs and is increased in areas of inflammation. In the submusosa of the intestine, tTG deamidates gluten peptides, changing peptide shape and charge. These altered gluten peptides are then able to bind tightly to HLA-DQ2 and HLA-DQ8 molecules on antigen-presenting cells. This binding triggers an inflammatory reaction causing lymphocyte infiltration, villous atrophy and the production of antibodies to gliadin and tTG ().
While the exact pathogenesis of many of the complications of CD is not fully understood, data supports a direct relationship between both the nutritional deficiencies and inflammatory responses seen in CD, and observed reproductive manifestations. The nutritional deficiencies, which result from malabsorption and, secondarily, to limitations common in the GFD, can directly impact reproductive function. Specifically, zinc, selenium, iron and folate deficiencies have been implicated.
Zinc, an essential element necessary for DNA synthesis, impairs the production and secretion of follicle-stimulating hormone and luteinizing hormone, potentially leading to abnormalities in ovarian development, spontaneous abortions, eclampsia and intrauterine growth retardation [17
]. Similarly, selenium is considered to be another crucial trace element required in adequate amounts for normal reproductive function. Selenium requirements further increase during pregnancy and lactation, and deficiencies have been associated with subfertility and spontaneous abortion in susceptible CD patients. Requirements for folate and iron also increase during pregnancy, and underlying CD may exacerbate the resulting anemia. Insufficient oxygen-carrying capacity in the blood may contribute to complications in pregnancy, and it is well known that folate deficiency is associated with neural tube defects and possible spontaneous abortion [20
Reproductive complications also frequently occur without apparent vitamin or mineral deficiencies, making malabsorption unlikely to be the sole mechanism. Autoimmune factors have been implicated, namely the role of tTG antibodies. It has been illustrated that placental tTG is bound by maternal autoantibody, directly affecting placental function and therefore possibly impairing nutrient exchange [21
]. Alternatively, because tTG may stabilize fragments shed from the syncytiotrophoblast through cross-linking and effective phagocytosis, interference from autoantibodies may also impair phagocytosis and lead to the release of fetoplacental antigens. This would be expected to result in altered recognition of the fetus by the maternal immune system [21
]. This latter theory has yet to be validated, but is an additional possible explanation for aspects of obstetric complications in CD.
Similar to fertility, the effect of CD on BMD is multifactorial. One clear factor is the vitamin D and calcium deficiencies commonly seen in CD patients owing to villous atrophy and dietary restrictions. These nutritional deficiencies may be seen with or without secondarily elevated levels of parathyroid hormone [23
]. Also implicated in decreased BMD is a reduction in IGF, which could be due to decreased zinc absorption [27
It is also likely that the chronic inflammation and proinflammatory cytokines seen in CD contribute to BMD reduction. Specifically, in the context of inflammation, cytokines are released and may affect bone remodeling through local signaling [31
]. Moreno et al.
demonstrated that mutations in IL-1 genes were associated with bone loss in CD [32
]. Finally, a recent study suggested a link between CD and autoantibodies directed towards osteoprotegerin, which inhibits a receptor leading to osteoclast activation and bone resorption. Therefore, the inhibitory effect of osteoprotegerin is blocked and bone loss results. The authors are careful to point out that the pathogenesis of osteoporosis is complex, and the presence of these autoantibodies in CD is probably only one of many factors leading to bone loss [33