Celiac disease and endometriosis: what is the nexus?

Abstract

Celiac disease (CD) is a chronic autoimmune disorder [1]. It is an enteropathy of the proximal small intestine characterized by villous atrophy, various degrees of crypt cell hyperplasia and increased numbers of intraepithelial lymphocytes [2–4]. An altered immune response to dietary gluten is crucial for the development of CD in genetically susceptible individuals [2–4]. In CD, gluten induces both adaptive and innate immune responses [5]. CD has been connected with abnormal T helper cell type I (Th1) cytokines production [3]. In particular, it has been suggested a critical role for interleukin-18 (IL-18) and Interferon-c (IFN-c) in inducing and maintaining Th1 responses after gluten exposure [2–4]. It has been shown that IL-18 and IFN-c levels are higher in samples from CD patients compared to healthy controls [2–4]. In this respect, the presence of IL-18 within the epithelium has been related to enterocyte damage [2, 3]. IL-18 is a potent inducer of IFNc [3, 4, 6]. In this regard, it has been shown that in active CD, the early response following gluten intake characterized by high levels of IFN-c levels is driven by IL-18 [2, 3]. IFN-c has been described to play an important role in gut permeability as well as in inflammation in CD [7]. It has been observed that IFN-c secreted by gluten-activated celiac patient T cells, represents the primary effector of increased gluten peptide translocation during active disease [8]. Regarding genetic CD susceptibility, it has been revealed that most celiac patients carry the human leukocyte antigen (HLA)-DRB [18]. CD has been associated with a number of extra-gastrointestinal symptoms including endometriosis [9, 10]. This condition is a benign gynecological disorder defined by the presence of viable endometrial cells and stroma outside the uterus, principally in ovaries and uterosacral ligaments [9, 10]. The main signs are dysmenorrhea, dyspareunia, irregular bleeding and chronic pelvic pain [9]. It has been proved that CD is common and clinically relevant in women suffering from endometriosis [9, 10]. The etiology of endometriosis is not completely defined [11]. Although retrograde menstruation is the most widely accepted pathologic factor, humoral immune abnormalities have been suggested to contribute to the pathophysiology of endometriosis [11]. Similarly to CD, it has been found that endometriosis is linked to chronic local inflammatory process and presence of autoantibodies with the characteristics of an autoimmune disorder [11–13]. In this regard, it has been reported that women affected by endometriosis frequently suffer from autoimmune inflammatory diseases [12, 13]. Endometriosis shares similarities with a number of autoimmune conditions [12, 13]. Concordantly, ongoing chronic inflammation has been proposed as candidate explanation for the positive association between CD and endometriosis [9]. Interestingly, a Th1 imbalance with involvement of IL-18 and IFN-c has also been reported in endometriosis [11]. It has been seen that deep infiltrating endometriosis may be related to a Th1 response pattern [11]. In particular, IL-18 has been described as a key cytokine in developing the pathogenesis of endometriosis [14]. Increased levels of IL18 have been detected in patients with endometriosis in comparison to non-endometriotic controls [14, 15]. What is more, increased expression of IFN-c has also been proved in endometriosis [16]. IFN-c gene polymorphisms have been linked to different stages of endometriosis with R. Mormile (&) Division of Pediatrics and Neonatology, Moscati Hospital, Via A. Gramsci 3, 81031 Aversa, Italy e-mail: raffaellamormile@alice.it; raffaellamormile@libero.it