Gluten-sensitive enteropathy (GSE), also known as celiac disease or celiac sprue, is characterized by inflammatory injury to the mucosa of the small intestine after ingestion of gluten in genetically predis-posed individuals. The inciting agent is gluten, a storage protein commonly found in wheat. More specifically, GSE is caused by T-cell-mediated recognition of glia-din, an alcohol-soluble fraction of gluten. Removal of gluten from the diet has been found to result in significant regression of the inflammatory lesion and symptoms seen with the disease.
For some time, GSE was thought to be rare, as its often nondescript clinical pre-sentation masked its true prevalence. How-ever, the advent of new serologic tests has allowed for more accurate diagnosis in the general population. Currently, it is thought to affect as many as 1 in 100 to 250 individ-uals worldwide – predominantly affecting Caucasians and people mainly in North America, Europe, and South America. GSE has also been observed among populations in North Africa, Iran, and India, which attests to the widespread occurrence of the disease.
Genetics plays a major role in the patho-genesis of GSE. Individuals expressing the MHC haplotypes -DR3, -DR5, -DR7, and, more importantly, -DQ2 or -DQ8 are at increased risk of developing GSE. The dis-ease tends to cluster in families, and the monozygotic twin concordance rate of 75 percent further emphasizes the strong genetic component. Less is known about the involvement of non-HLA (human leu-cocyte antigen) genes, which can modify the clinical expression of the disease. GSE has been associated with a region on the long arm of chromosome 5 (5q31 – 33), which is where other candidate suscep-tibility genes that have been implicated in Crohn’s disease and asthma are also located. It has been speculated that there is some involvement of the gene that encodes the negative co-stimulatory mol-ecule, cytotoxic T-lymphocyte antigen-4 (CTLA-4).
The myriad of symptoms associated with GSE has made detection of disease especially difficult. It was once thought to occur only in childhood, but GSE can manifest at any age. Patients commonly present with malabsorption, steatorrhea, and weight loss relating to the flattening of proximal small intestinal villi. Diarrhea is not usually present unless the distal small bowel, in addition to the proximal portion, is affected. Some patients do not present with any gastrointestinal symptoms, but with effects secondary to malabsorption of vitamins such as iron, folate, and calcium. These patients may only present with anemia and osteoporosis, respectively. In addition, there is a strong association between GSE and autoimmune disease. Some individuals with GSE also present with dermatitis herpetiformis (DH), a pru-ritic vesicular rash that commonly presents on the extensor surfaces and the scalp. Most DH patients have GSE, whereas all individuals with GSE do not have DH. These lesions improve with the removal of gluten from the diet. Dapsone can help expedite the healing process.
Immune responses to gliadin occur in two places: the LP and the epithelium. At a low pH, tissue transglutaminase (tTG, a calcium-dependent enzyme), deamidates glutamine on gliadin, rendering these pep-tides more capable of binding HLA-DQ2 and HLA-DQ8. After CD4+ LP T cells rec-ognize the gliadin epitope presented by DQ2 and DQ8, they are thought to secrete interferon-γ (IFN-γ), which then causes the destructive lesions seen in GSE. The expansion of IELs (predominantly CD8+) that occurs is more controversial and difficult to understand, but may relate to the reduction of IL-15 by IECs in the presence of gliadin. However, the development of lymphoma in individuals with refractory sprue has been shown to consist of a clonal expansion of CD8+ T cells, implicating the IELs as a possible source. However, as glia-din-specific IELs have not been identified, this has led to the conclusion that expan-sion of CD8+ T cells is secondary to the CD4+ T-cell response to gliadin. But this same expansion of CD8+ T cells does not occur in other inflammatory disorders of the GI tract such as IBD and autoimmune enteropathy, where CD4+ T cells are also activated.
A mechanism to explain this incon-sistency may involve the expression of nonclassical MHC class I molecules such as major histocompatibility class I chain related (MIC) and human leucocyte anti-gen E (HLA-E), which are induced by stress and IFN-γ. Natural killer receptors NKG2D and CD94 present on IELs are up-regulated by IL-15 and can recognize MIC and HLA-E on damaged cells. Up-regula-tion of IL-15 could cause the uncontrolled activation of IELs and villous atrophy. In this situation, IELs do not have to recognize gliadin peptides directly. These data have laid the groundwork for an alternate ther-apy for GSE, using antibodies against IL-15 in refractory sprue because IL-15 activates IELs and promotes the development of lymphoma.
An ongoing controversy has been whether gliadin is acting as an immuno-logic trigger for an adaptive (CD4+ T-cell) response or whether gliadin fractions are directly toxic to the epithelium, initiating the disease process. Several groups have shown that gliadin peptide can cause the lysis of certain epithelial cell lines. More recently, newer studies have supported both sides of the argument. A major glia-din fragment possesses two activities: (1) a T-cell epitope in the N terminus and (2) a fragment that is rapidly taken up by epithe-lium and subsequently subepithelial cells, inducing the production of IL-15 (an innate immune response). The combination of both activities accounts for the CD4+ T-cell acti-vation, CD8+ IEL lymphocytosis, and IFN-γ secretion. The ability or inability to gener-ate the complete response may account for some of the disease heterogeneity.
The gold standard for the diagnosis of GSE is a small-bowel biopsy. Histologically, GSE is characterized by a triad of villous atrophy, hyperplastic crypts, and intraepi-thelial lymphocytosis. Empiric therapy with a trial of gluten-free diet should be avoided as this will alter the small-bowel biopsy findings. In addition, serologic tests are useful for the diagnosis and manage-ment of GSE as they allow for a noninvasive means of monitoring adherence to diet and the identification of individuals who are at high risk for the disease who otherwise might not have been detected. IgA anti-bodies to endomysium, tTG, and gliadin are typically identified. Even though tTG is the autoantigen recognized by endomysial antibodies, there is not always concordance between antibodies against endomysium and tTG. Detection of GSE is optimized by looking for both antibodies. Interestingly,
antibodies to tTG do not alter the function of this enzyme. The presence of antibodies against endomysium is 100 percent specific for the diagnosis of GSE. IgA deficiency occurs in about 1.7 percent to 2.6 percent of patients with GSE, a rate that is ten- to sixteenfold higher than the general popula-tion. In these instances, it is acceptable to look at IgG antibodies to endomysium, tTG, and gliadin instead of IgA. The detection of both IgA and IgG antibodies requires indi-rect immunofluorescence with either mon-key esophagus or human umbilical cord as the substrate or tTG by enzyme-linked immunosorbent assay.
The only disease-controlling action is the removal of all gluten from the diet for life. The major limiting factor in healing is noncompliance especially in adoles-cents with GSE. In cases in which there is poor clinical improvement, continued ingestion of gluten is the most likely cause. Poor control is thought to be a major factor in the development of IEL lymphomas.