PEDIATRICS Vol. 107 No. 4 April 2001, pp. 768-770

COMMENTARY:
Celiac Disease: The Past, the Present, the Future

Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten-containing grains (ie, wheat, barley, and rye) in susceptible individuals. Both in vivo challenges and in vitro immunologic studies support the possibility that oat (once considered toxic for CD patients) can be safely ingested.¹ However, because of uncontrolled harvesting and milling procedures, a cross-contamination of oat with gluten is a concern. It is the gliadin fraction of wheat gluten, and similar alcohol-soluble proteins in other grains, that are the environmental factors responsible for the development of the intestinal damage. The disease is associated with human leukocyte antigen (HLA) alleles DQA1*0501/DQB1*0201, and in the continued presence of gluten the disease is self-perpetuating.² The typical intestinal damage characterized by loss of absorptive villi and hyperplasia of the crypts completely resolves on elimination of gluten-containing grains from the patients' diet. CD represents a common cause of malabsorption in western countries with apparent geographic variation in incidence.

THE PAST

In the second century AD, Aretaeus from Cappadocia described what is believed to be the first report of a gastrointestinal condition resembling CD.³ Approximately 1700 years later, the connection between the ingestion of certain cereals and the onset of gastrointestinal symptoms typical of CD was established.⁴ For the past 18 centuries, CD has been perceived as a disease whose clinical presentation was quite uniform. The case identification was entirely based on the search for symptoms such as chronic diarrhea, abdominal distension, and weight loss (or poor weight gain) occurring in young children a few weeks/months after the introduction of solid food to their diet. Therefore, early epidemiologic studies targeted the pediatric population experiencing this typical clinical presentation of the disease. In the past 5 decades, a substantial number of epidemiologic studies have been conducted in Europe to establish the frequency of CD, and interesting controversies have arisen. One of the oldest epidemiologic studies on CD conducted in 1950 established that the cumulative incidence of the disease in England and Wales was 1/8000, while an incidence of 1/4000 was detected in Scotland.⁵ The diagnosis at that time was entirely based on the detection of typical symptoms and confirmed by complicated and sometimes nonspecific tests. The awareness of the disease greatly increased in the 1960s when more specific tests for malabsorption and the pediatric peroral biopsy technique became available.⁶ Consequently, an elevated incidence of the disease (that in the middle 1970s reached peaks of 1/450-500) was reported in studies from Ireland,⁷ Scotland,⁸ and Switzerland.⁹ This increased incidence of CD urged changes in the dietary habit, based on the hypothesis that delayed exposure to gluten could prevent the onset of the disease. For the first time in 25 years a decrease in the incidence of CD was reported in the United Kingdom and Ireland^10,11 after a late introduction of gluten in the infants' diet. Unfortunately, this decrease was deceptive, because subsequent screening studies demonstrated that the reduction of typical cases in infants was counterbalanced by the increase of atypical forms of CD with the onset of the symptoms occurring in older children or in adults.¹²

THE PRESENT

In the past 10 to 15 years, we learned that the clinical expression of CD is more heterogeneous than previously thought.¹³ Besides the classical gastrointestinal form, a series of other clinical manifestations of the disease have been described, thanks to the advent of innovative serologic screening tests such as antigliadin and antiendomysium (EmA) antibodies assays. The combined use of serum antigliadin immunoglobulin G (highly sensitive) and immunoglobulin A (highly specific) and the confirmation with the EmA test resulted in a reliable screening algorithm to study the epidemiology of CD.¹⁴ Based on the use of these new tools, we have learned that the clinical presentation of CD is more protean then previously thought, including previously unrecognized atypical and asymptomatic forms. Moreover, these studies demonstrated that CD is not limited to the pediatric population, but the disease may become clinically apparent during adulthood after years of silent disease. The European experience taught that, despite common genetic and environmental factors, the clinical presentation of CD in neighboring countries may greatly diverge and could justify the different prevalence of the disease previously reported.^15-19 A similar explanation seems to account for the rare prevalence of CD previously reported in the United States.^20,21 Recent studies conducted by using more appropriate experimental designs and powerful screening tools demonstrated that CD in the United States is as frequent as in Europe in both risks groups^22-26 and the general population.^26,27 Similar results were obtained in Africa,²⁸ South America,²⁹ and Asia,^30,31 continents where CD was considered a rare disorder. Combined together, these studies revealed that CD is one of the most frequent genetically-based diseases of humankind^32,33 occurring in 1 out of every 100 to 300 individuals in the general population worldwide.^26,27,34

Major progress has also been achieved on the pathogenesis of the disease. It is now evident that CD is the result of an inappropriate T-cell mediated immune response against ingested gluten. Under physiologic circumstances, the intestinal epithelium with its intact intercellular tight junctions (TJs) serves as the main barrier to the passage of macromolecules such as gluten. During this healthy state, quantitatively small but immunologically significant fractions of antigens cross the defense barrier. These antigens are absorbed across the mucosa along 2 functional pathways. The vast majority of absorbed proteins (up to 90%) crosses the intestinal barrier through the transcellular pathway, followed by lysosomal degradation that converts proteins into smaller, nonimmunogenic peptides. The remaining portion of peptides is transported as intact proteins, resulting in antigen-specific immune responses. This latter phenomenon uses the paracellular pathway that involves a subtle but sophisticated regulation of intercellular TJ that leads to antigen tolerance. When the integrity of the TJ system is compromised, such as in CD,^35,36 an immune response to environmental antigens (ie, gluten) may develop. The upregulation of zonulin, a recently described intestinal peptide involved in TJ regulation,³⁷ seems to be responsible, at least in part, for the increased gut permeability characteristic of the early phase of CD.³⁸ This zonulin-dependent increased permeability may also be responsible for the increased incidence of autoimmune disorders reported in untreated CD patients³⁹

Another important factor for the intestinal immunologic responsiveness is the major histocompatibility complex. HLA class I and class II genes are located in the major histocompatibility complex on chromosome 6. These genes code for glycoproteins, which bind peptides, and this HLA-peptide complex is recognized by certain T-cell receptors in the intestinal mucosa.^40,41 Susceptibility to at least 50 diseases, including CD, has been associated with specific HLA class I or class II alleles. The primary HLA association in CD is to the HLA-DQA1*0501, DQB1*0201 genes encoding DQ2 molecules.² Interestingly, it seems that non-HLA genes together contribute more to genetic susceptibility than do the HLA genes, but the contribution from each single, predisposing non-HLA gene appears to be modest.⁴² Dieterich et al⁴³ have recently demonstrated that the target of the EmA is the tissue transglutaminase (TTG). The deamidating activity of this enzyme seems to generate gliadin peptides that bind to DQ2 to be recognized by disease-specific intestinal T cells.⁴²

Because TTG is the target of a specific autoimmune response,⁴² this enzyme has also been used to develop innovative diagnostic tools. The routine use of the EmA assay is limited by elevated costs, the time-consuming protocols unsuitable for testing large numbers of samples, and the use of the esophagus of an endangered species (such as the monkey) as the substrate for the immunofluorescent analysis. Even if this last issue has been resolved by using the human umbilical cord as a valid alternative to the monkey esophagus,²⁷ it has been reported that the subjective interpretation of the EmA assay may lead to unacceptable variability among laboratories that perform this test.⁴⁴ Therefore, major effort has been placed on the development of a TTG-based enzyme-linked immunosorbent assay, using either the commercially-available guinea pig TTG^45,46 or human recombinant TTG.^47,48

THE FUTURE

A multidisciplinary research effort to understand the pathogenesis of CD is currently taking place worldwide. This effort is fueled by the appreciation that CD represents a unique example of an autoimmune disease in which the environmental factor(s) that induces the immune response has been identified. Therefore, scientists view CD as a model to tackle key questions on the pathogenic mechanisms involved in other autoimmune diseases (ie, multiple sceloris, diabetes mellitus, rheumatoid arthritis, etc) whose environmental triggers are still unknown. Future directions in CD research have been clearly identified and recently discussed at the Ninth International Symposium on Celiac Disease that was held August 10-13 in Baltimore, Maryland⁴⁹ (Table 1). Although some of these goals are in an advanced state of development (ie, engineering gluten-free grains), others (ie, the search for the CD genes) are extremely challenging and will require an international task force to generate meaningful data. Nevertheless, the appreciation that CD is a global problem affecting not only Europe, but also continents, such as North and South America, Africa, and Asia, where it was historically considered an extremely rare condition, is catalyzing the scientific attention of new generations of investigators that will surely contribute to achieve these challenging targets.

ACKNOWLEDGMENTS

I thank the American celiac community which, with its generosity and unconditioned support, has made possible some of the scientific achievements discussed in this commentary. I am also deeply indebted with Pamela King and Robert Levy for their personal commitment to the Center for Celiac Research.

Alessio Fasano, MD
Center for Celiac Research and Division of Pediatric Gastroenterology and Nutrition
University of Maryland Hospital for Children
Baltimore, MD 21201

FOOTNOTES

Received for publication Aug 3, 2000; accepted Aug 3, 2000.

Reprint requests to (A.F.) Center for Celiac Research, University of Maryland School of Medicine, 685 W Baltimore St HSF Bldg, Rm 465, Baltimore, MD 21201. E-mail: afasano{at}umaryland.edu

ABBREVIATIONS

CD, celiac disease; HLA, human leukocyte antigen; EmA, antiendomysium antibodies; TJ, tight junction; TTG, tissue transglutaminase.

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