Celiac disease results from the interplay of genetic, environmental, and immunologic factors. An understanding of the pathophysiology of celiac disease, in which the trigger (wheat, rye, and barley) is known, will undoubtedly reveal basic mechanisms that underlie other autoimmune diseases (eg, type 1 diabetes) that share many common pathogenic perturbations. This review describes seminal findings in each of the 3 domains of the pathogenesis of celiac disease, namely genetics, environmental triggers, and immune dysregulation, with a focus on newer areas of investigation such as non-HLA genetic variants, the intestinal microbiome, and the role of the innate immune system.
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Celiac disease results from the interplay of genetic, environmental, and immunologic factors.
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HLA-DQ2 and HLA-DQ8 are the strongest and best-characterized genetic susceptibility factors in celiac disease, although recent genome-wide association studies have identified additional susceptibility variants, many involved in the immune system and overlapping with other immune-mediated disease.
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Environmental factors implicated in disease pathogenesis include gluten, commensal and pathogenic microorganisms, timing of gluten introduction, mode of delivery, and duration of breastfeeding; however, the mechanisms underlying these associations are incompletely understood.
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Both the adaptive and innate immune systems are dysregulated in the pathophysiology of celiac disease.
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Improved understanding of the pathophysiology of celiac disease will help uncover new potential therapeutic targets and provide insight into disease mechanisms relevant to other immune-mediated disease such as type 1 diabetes.
Introduction
Celiac disease is an intestinal inflammatory disease that is triggered by dietary gluten, a protein found in wheat, barley, and rye, in genetically susceptible individuals. Descriptions of a celiac disease–like phenotype can be traced back to the Greek physician Aretaeus in the first and second century ad (reviewed in Ref. ). Gluten was identified as the culprit of celiac disease by Dutch physicians who observed that, during the 1944-1945 famine when wheat and rye were scarce, celiac children symptomatically improved. Subsequent studies characterized many features of celiac disease, and while disease pathogenesis and pathophysiology remain incompletely understood, the disease is thought to arise from the interplay of genetic, environmental, and immunologic factors ( Fig. 1 ). An understanding of the pathophysiology of celiac disease, in which the trigger (wheat, rye, and barley) is known, will undoubtedly reveal basic mechanisms that underlie other autoimmune diseases (eg, type 1 diabetes) that share many common pathogenic perturbations. This review describes seminal findings in each of the 3 domains of the pathogenesis of celiac disease, namely genetics, environmental triggers, and immune dysregulation, with a focus on newer areas of investigation such as non–human leukocyte antigen (HLA) genetic variants, the intestinal microbiome, and the role of the innate immune system.
Genetics
Celiac disease has a strong hereditary component. Epidemiologic studies show that up to 20% of first-degree relatives are affected by the disease, with concordance rates of 75% to 80% in monozygotic twins and 10% in dizygotic twins. The strongest and best-characterized genetic susceptibility factors in celiac disease are the HLA class II genes known as HLA-DQ2 and HLA-DQ8, molecules responsible for presentation of antigens to immune cells. However, although HLA-DQ2 or -DQ8 are necessary for disease to develop, they are not sufficient thus implicating other genetic or environmental factors in disease development. Approximately 25% to 30% of individuals of European descent carry HLA-DQ2 susceptibility, but only about 4% of these individuals will develop celiac disease in their lifetime, underscoring the role of additional factors. Recent large-scale genetics studies known as genome-wide association studies (GWAS) have identified several common non-HLA genetic factors (many in genes involved in immunity) associated with celiac disease which, on their own, contribute a small amount to overall risk but have great potential in discovering important and novel pathways involved in disease pathogenesis.
HLA-DQ2 and HLA-DQ8 Genetics and Disease Risk
HLA is the name of the major histocompatibility complex (MHC) in humans. These genes reside on chromosome 6 and are divided into 3 classes (I–III) ( Fig. 2 ). HLA-DQ is a class II molecule on chromosome 6p21.3 responsible for presentation of peptides from outside cells (compared with class I molecules that present peptides from within cells and class III molecules that encode complement proteins). HLA-DQ is composed of an αβ heterodimer encoded by HLA-DQA1 and HLA-DQB1 genes, respectively. The αβ heterodimer is a cell-surface receptor located on antigen-presenting cells (APCs).
