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PEDIATRICS Vol. 107 No. 4 April 2001, pp. 768-770
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 Ireland10,11 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 groups22-26 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
humankind32,33 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 TTG45,46 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.
TABLE 1
Research Priorities Identified at the Ninth International Symposium on
Celiac Disease
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.
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.
REFERENCES
This article has been cited by other articles:
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  F. Cerutti, G. Bruno, F. Chiarelli, R. Lorini, F. Meschi, and C. Sacchetti Younger Age at Onset and Sex Predict Celiac Disease in Children and Adolescents With Type 1 Diabetes: An Italian multicenter study Diabetes Care, June 1, 2004; 27(6): 1294 - 1298. [Abstract] [Full Text] [PDF]
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 D. A. Butler and M. T. Lawlor It Takes a Village: Helping Families Live With Diabetes Diabetes Spectr, January 1, 2004; 17(1): 26 - 31. [Abstract] [Full Text] [PDF]
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