ReviewAutoimmunity in celiac disease: Extra-intestinal manifestations
Introduction
The target organ of celiac disease (CD) is the human proximal small bowel and in the past, symptomatology encompassed mainly small bowel presenting symptoms. Being a constantly changing disease, in the last decades and nowadays, novel features are continuously being unraveled. A lot of new observations and scientific knowledge on its genetic markers, epidemiology, clinical presentations, mode of diagnosis, therapeutic evolvement and high risk conditions were accumulated. Before embarking on its extra-intestinal manifestation (EIM), a background on CD and its shared aspects with other autoimmune diseases (ADs) is presented.
Celiac disease is a life-long autoimmune condition [1] of the enteric tract, targeting mainly the small intestine and systemically multiple extra-intestinal sites, in genetically susceptible individuals. It affects 1–2% of Western populations and its incidence is continuously increasing [2,3]. Gluten is the storage protein of wheat and its alcohol soluble gliadins are the offending toxic molecules of the disease together with structurally related components found in barley, rye and less in oat [4]. Tissue transglutaminase (tTG) is the auto antigen [5,6] and two main auto antibodies: IgA-anti endomysium and IgA-anti tTG are the most frequently used serological markers to screen and diagnose the disease [7,8]. Lately, a new serological marker immerged, targeting neoepitope complexes formed when gliadin docks the tTG enzyme [9]. It appears that compared to the traditional IgA-tTG, the neoepitope tTG out performs and is considered as a reliable diagnostic marker and reflector of the intestinal pathology [10,11]. Interestingly, the microbial transglutaminase (mTG), a heavily used industrial food additive, that imitates functionally the tTG, was recently shown to induce specific antibodies in CD patients [12]. Potentially, it might represent a new environmental player in driving CD autoimmunogenesis [[13], [14], [15]].
The genetic repertoire of CD is expanding, containing more than 50 non-HLA genes but only two of them, HLA-DQ2 and HLA-DQ8 molecules are the most important, predisposing genetic factors [16].
The pathogenesis of the disease is dominated by the intestinal innate and humoral immune systems activation, resulting in enteric inflammation and destruction. In fact, each pathogenetic step: the ingested toxic environmental gluten, the luminal enzyme resistant gluten peptides, their increased intestinal uptake, the increased IL-15 and IFNγ production, tTG gluten deamidation and transamidation (cross linking), TCD4+ cell proliferation and macrophage activation, are crucial events that form the basis for development of future potential therapeutic modalities [17,18].
Since genome-wide association studies became available and performed on various ADs, it appears that there exists an overlap of around 50% of genetic risk factors between those diseases [19]. Some of the shared genes are part of the human leukocyte antigens family that are routinely part of the diagnostic work-up in various ADs [20].
Interesting, regulatory genes, in the intronic, non-coding part of the genome, contain most of those genetic factors. Coming back to CD, the condition is associated with numerous ADs, including rheumatologic (S.L.E, rheumatoid arthritis, juvenile rheumatic/idiopathic, Sjogren's syndrome and connective tissue disease), endocrinal (Type 1 diabetes, Ashimoto thyroiditis, Addison's disease), dermatologic (dermatitis herpetiformis, psoriasis), neurologic, cardiologic, hepatic, pancreatic, gynecologic, gastrointestinal and immunological conditions [[21], [22], [23]]. In recent surveys, Hashimoto thyroiditis, type 1 diabetes, psoriasis, Sjogren's syndrome, autoimmune hepatitis, IBD and biliary ADs were the most frequently associated conditions with CD [24,25]. While the effect of gluten free diet is controversial in non-celiac ADs, the duration of the disease is considered a risk factor for polyautoimmunity [25]. It can be argued that shared genetics and environment are at the basis of the polyautoimmunity in CD patients or their family members [26]. More so, multiple screenings identified common genes shared between various ADs, supporting the autoimmune trait as part of the autoimmune tautology [[23], [24], [25], [26], [27]]. In a recent study, the following risk factors were identified for polyautoimmunity in CD patients: female gender, CD associated serology, family history of ADs, insufficient vitamin D levels, having high antinuclear antibody titer, and associate musculoskeletal conditions [28].
Conversely to the old notions upgrading genetics as the most influential, the impact of environmental exposure on autoimmune risk development, is paramount [29]. Multiple environmental factors are similarly shared between ADs. The recently coined term “autoimmune ecology” is the cross relation between us and the surrounding environment, that induce the breach of immune tolerance resulting in one or multiple ADs in an individual [29,30]. Chemicals, organic solvents, physical factors, surgery, nutrients, processed food additives, drugs and sex hormones, heavy metals, infectious agents, dysbiota, vitamins' deficiencies, smoking, alcohol, coffee, life style and stress, socioeconomic status and vaccines are some of them [13,23,29,30]. Notably, CD share some of them. Virus like enterovirus, EBV, CMV, HBV, HCV, rotavirus, reovirus, Microbes like tuberculosis, Bacteroides species, Campylobacter jejuni, pneumococcus, Helicobacter pylori, microbiotic composition and diversity, microbial transglutaminase, first year feeding pattern and antibiotic consumption, mode of delivery, amount and timing of gluten consumption, processed food additives and physical or emotional stress [4,13,14,23,31] were suggested as environmental components that influence CD induction, development or behavior. However, association and not causality was shown, except for gluten consumption in CD.
The title: “Our environment shapes us” [32], set the stage for the additional evolving topic, positioned in-between genetics and environment, meaning epigenetics. In fact, growing evidences are constantly accumulating for the pivotal role of epigenetics in driving autoimmunity. It is not only a loss of tolerance [33], since abnormal epigenetic modifications can present biomarker for ADs and be involved in multiple ADs pathogenic progression [34], CD not excluded [35,36]. Interestingly, most recently the microbiota memory was suggested to govern diseases by epigenetic regulation [37].
After mentioning the shared genes, clustering of ADs in the patients, the shared epigenetic events and environmental factors, the autoimmune trait resulting in familial coaggregation of ADs, the stage is set for extra-intestinal features of CD, shared by numerous ADs.
Section snippets
Extra-intestinal manifestations (EIM) of celiac disease
The scientific and medical literature is rich in comprehensive reviews describing EIM in CD populations. As can be expected, the list is expanding rapidly since the 90th [38] to the present [[39], [40], [41]]. Fig. 1 describes the multiple faces of the disease. The octopus intend to show that the CD arms can reach and affect any tissue/organ in the human body and many of the contemporary presenting symptoms of the disease are included. It goes without saying that patients' complains and
Nutrition
The pivotal place played by nutrients, shaping human physiology and pathology, not just only in the intestinal compartment, is increasingly appreciated. In fact, the nutritional effects are irradiated peripherally to remote organs [69,70] and even to the brain [71]. Some of their effects are channeled by the microbiome, some affect intestinal permeability and many are direct by their digested and absorbed metabolites. Two aspects, related to CD, that might drive systemic autoimmunogenesis, are
Conclusion
Multiple non-intestinal organs and tissues are affected in CD and present an end-organ disease, associated with the enteric one [21,39,41,92]. The gut originated autoimmune inflammatory network spreads peripherally and contributes to the EIM in CD population. Nutrients, bugs, chemical modifications, gut leakage, intestinal wall components like the immune, neuronal, endocrine, endo-mesodermal, hematological and vascular systems, gather together, in a very coordinated way, to initiate and
Acknowledgment
The authors would like to thank Mr. Neu Alf for the figure design and to Dr. Neidhöfer Sandra, Dr. Ramesh Ajay and Mrs. Wusterhausen Patricia for the editing and reviewing the manuscript.
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