Recent Advances in the Understanding of Celiac Disease

Pediatr Drugs 2006; 8 (6): 375-388REVIEW ARTICLE 1174-5878/06/0006-0375/$39.95/0

© 2006 Adis Data Information BV. All rights reserved.

Recent Advances in the Understanding ofCeliac DiseaseTherapeutic Implications for the Management of Pediatric Patients

John H. Kwon1 and Richard J. Farrell2

1 Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland, USA2 Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3751. Epidemiology and Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376

1.1 Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3761.2 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377

2. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3782.1 Gluten Processing and Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3782.2 Gluten Antigen Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3792.3 Adaptive and Innate Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380

3. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3813.1 Endoscopy and Small Intestinal Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3823.2 Serologic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382

4. Current Therapy and Therapeutic Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3835. Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3846. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385

Celiac disease (CD) is an autoimmune condition occurring in genetically susceptible individuals character-Abstractized by inflammatory injury to the mucosa of the small intestine after the ingestion of wheat glutens or relatedbarley and rye products. Originally thought to be highly prevalent only in Northern European populations,growing evidence indicates a much higher prevalence in many other regions, including the US as well as SouthAmerica, North Africa, and Asia. The growing awareness that pediatric patients may present with quite diverseand protean manifestations and the significant impact of CD on childhood development has prompted efforts toincrease CD awareness for the early diagnosis and treatment of this disease. The current diagnostic criteria forCD requires characteristic histologic findings in small bowel biopsies and clinical remission when placed on agluten-free diet. Serologic testing for CD can provide additional support for the diagnosis of CD or a means toassess efficacy and adherence to a gluten-free diet. The mainstay of treatment remains the institution of agluten-free diet. However, patients with refractory CD may require treatment with immunosuppressant medica-tions. With the increased identification of specific gluten epitopes and understanding of the pathogenesis of CD,future therapies may rely on genetically altering gluten proteins, immunization techniques, or therapies focusedon either the development of specific immune tolerance or regulation of mucosal inflammation.

Celiac disease (CD) has been described in the literature as tion.[1,2] It is an autoimmune condition characterized by inflam-celiac sprue, celiac syndrome, gluten-sensitive enteropathy, matory injury to the mucosa of the small intestine after thenon-tropical CD, idiopathic steatorrhea, and primary malabsorp- ingestion of wheat glutens or related barley and rye proteins.[3]

376 Kwon & Farrell

Historically, CD was first recognized as a clinical entity by 1. Epidemiology and Clinical PresentationAretaeus the Cappadocian in the first century A.D.[4] However, the

classic clinical manifestations were first published by Samuel 1.1 Clinical Presentation

Gee[5] in 1888. Both adult and pediatric patients were noted toThe age of diagnosis of CD ranges from 4 months to >60

have similar symptoms and at that time the diet was recognized asyears.[9,10] The clinical manifestations of CD depend upon a num-

the main etiologic factor for the disease. However, it was not until ber of factors including the age at diagnosis, duration and extent ofWorld War II when Karel Dicke, a Dutch pediatrician, observed an disease, and the presence of extra-intestinal manifestations (seeimprovement in childhood CD during rationing of cereals and table I).

The classic symptoms associated with pediatric CD relate tobread in The Netherlands that wheat products were specificallyinfants presenting at <2 years of age.[11] These patients tend to doimplicated.[6] In 1950, he and his colleagues conclusively demon-well during the first few months of life. However, with thestrated the relationship between wheat protein ingestion and CD.[7]

introduction of cereals, they begin to fall off their respectiveWe now know that CD occurs in genetically predisposed individu-

growth curves and present with symptoms related to malabsorp-als and is caused by the ingestion of prolamins (alcohol-soluble tion, including failure to thrive, anorexia, hypotonia, apathy, irrita-proteins rich in glutamine and proline) found in wheat, barley, and bility, and diarrhea or constipation. The diarrhea is often describedrye. It results in histologic changes within the duodenum and as voluminous, pale, watery to semi-formed, and foul smelling. On

physical examination, the infant often appears pale with musclejejunum characterized by crypt hyperplasia, villous atrophy, andwasting, abdominal distention, decreased subcutaneous fat, andlymphocytic infiltration within the lamina propria and epithelium.short stature.

CD affects both pediatric and adult populations. Classically,While the classic pediatric patient with CD is still seen in the

CD presents in childhood after weaning as failure to thrive,clinical setting, there has been a recent shift in our understanding

diarrhea, and abdominal distention between the ages of 4 and 24 of how patients with CD present. Most importantly, recent epide-months. While adults with CD may classically present with diar- miologic data indicate that the floridly symptomatic patients re-rhea, abdominal distention, and nutritional deficiencies, the major- present only the tip of the ‘celiac iceberg’ and that the majority of

patients with CD have either subclinical disease or present later inity of adults present with extra-intestinal manifestations (see sec-life with primarily extra-intestinal manifestations. This was firsttion 1.1). CD has been described throughout the world but isnoted in Finland, by Maki et al.,[12] and has also been observed ingenerally considered a disorder affecting people in Western Eu-other countries including Scotland, England, Canada, Spain, and

rope and countries to where they have emigrated.the US.[13-16]

CD had previously been thought to be less prevalent in North Reported extra-intestinal manifestations of CD include muscu-America.[8] However, recent epidemiologic studies have chal- loskeletal, cutaneous, hematologic, reproductive, and neurologic

symptoms (see table I).[1]lenged our traditional views towards the prevalence and clinicalAttention should also be directed toward the diagnosis andpresentation of CD. In addition, these data as well as advances in

management of associated diseases, including insulin-dependentour understanding of its pathogenesis have brought about a signifi-diabetes mellitus, hypothyroidism, systemic lupus erythematosus,

cant change in our approach to the screening, diagnosis, andSjogren syndrome, polymyositis, Down syndrome, and IgA ne-

management of CD. phropathy as well as primary biliary cirrhosis, sclerosing cholangi-The purpose of this review is to outline these advances and the tis, inflammatory bowel disease, and interstitial lung diseases. In

particular, the association between type 1 diabetes and CD is wellimplications regarding the current and future diagnosis and man-established, with a prevalence of 1.1–16.4%.[17-20] In addition, anagement of CD. Relevant literature was screened and reviewedassociated long-term complication of CD is the development offrom a MEDLINE search (1966 to present) with the keywordsmalignancies, including enteropathy-associated T-cell lymphoma,

‘celiac sprue,’ ‘celiac disease,’ ‘coeliac sprue,’ and ‘coeliac dis-melanoma, adenocarcinoma of the small intestine, and squamous

ease’ alone or in combination with the keywords ‘epidemiology,’ cell carcinomas of the esophagus, mouth, and pharynx.[21-24]

‘prevalence,’ ‘serology,’ ‘pathogenesis,’ ‘treatment or therapy,’ The presentation of CD has changed over the last 30 years; the‘pediatric,’ and ‘diagnosis.’ Relevant articles listed in the primary reasons for the trend towards a later and more protean presentationliterature were also reviewed. may be multifactorial, including the increased use of serologic

© 2006 Adis Data Information BV. All rights reserved. Pediatr Drugs 2006; 8 (6)

Recent Advances in Celiac Disease 377

Table I. Clinical manifestations of celiac disease

Clinical presentation and associated conditions Possible associated conditions Complications

General Addison disease Refractory sprueFailure to thrive, low birth weight, short stature Autoimmune hepatitis Enteropathy-associated T-cellBehavioral Congenital heart disease lymphomaDepression, impaired school performance, irritability Cystic fibrosis Carcinoma of the oropharynx,Cutaneous Fibrosing alveolitis esophagus, and small bowelAlopecia, dermatitis herpetiformis, follicular keratosis Inflammatory bowel disease Ulcerative jejunoileitisGastrointestinal/hepatic Lung cavities Collagenous sprueAbdominal distention, autoimmune thyroiditis, diarrhea, Myasthenia gravishypertransaminasemia, nausea/vomiting, microscopic colitis, recurrent Melanomaabdominal pain, steatohepatitis, steatorrhea PolymyositisHematologic Primary biliary cirrhosisFolate deficiency anemia, hyposplenism, iron deficiency, anemia, Pulmonary hemosiderosisthrombocytopenia, thrombocytosis Recurrent pericarditisMusculoskeletal SarcoidosisArthropathies, arthralgias, dental enamel defects, myopathy, Schizophreniaosteopenia, osteoporosis Systemic lupus erythematosisNeurologic VasculitisCerebellar ataxia, dementia, epilepsy, occipital calcifications, peripheralneuropathy, seizuresReproductiveDelayed puberty, female infertility, male infertility, recurrentmiscarriagesOtherDown syndrome, IgA deficiency, IgA nephropathy, rheumatoid arthritis,Sjogren syndrome, vitamin B12 deficiency, vitamin K deficiency

testing and the increased recognition of CD prevalence in many diagnosis of CD in patients with overt and subclinical disease ispopulations. However, it has also been hypothesized that an in- important to improve their well-being and to prevent potentiallycreased emphasis on breast feeding and alterations in recommend- irreversible complications.ed dietary practices have resulted in a greater complexity ofmanifestations.[25] However, conflicting data have been reported 1.2 Epidemiologyand the role of breast feeding and dietary changes on CD has notbeen fully determined.[26-30] In 1992, Richard Logan[37] suggested that symptomatic patients

with classic gastrointestinal symptoms (see section 1.1) represent-Considerable evidence indicates that, if diagnosed earlyed only the tip of the iceberg, with the majority of patients with CDenough, the institution of a gluten-free diet reverses many of thehaving clinically undetected disease (‘silent’ or ‘latent’ disease).intestinal and extra-intestinal manifestations of CD. Furthermore,Silent CD is defined as patients with biopsy-proven CD butit has become readily apparent that patients with presumed asymp-without symptoms and latent CD is defined as patients with atomatic CD report a marked improvement in well-being after thenormal small intestine on a normal diet but who either in the pastinstitution of a gluten-free diet. Many children often exhibit catch-developed or in the future will develop morphologic changesup growth, characterized by a height velocity above the statisticalresponsive to gluten withdrawal. With the increased appreciationlimits of normality, once the gluten-free diet is commenced.[31]

of the protean nature of CD manifestations and advances inNotably, bone mineral density in children with CD is often mark-serologic testing, this concept of a ‘celiac iceberg’ has becomeedly reduced.[32] This deficit in bone mineral density is oftenwidely accepted.corrected within 1 year of institution of a gluten-free diet.[32,33] In

addition, early diagnosis and institution of a gluten-free diet ap- Because we are uncertain of the exact depth and breadth of thepears to have an effect on the incidence of cancer and mortality. celiac iceberg, the true prevalence of CD is currently not known.Growing evidence indicates that patients diagnosed with CD in However, it is clear from serologic studies that the prevalence ofchildhood do not have a higher risk of malignancy or mortality, in CD is much greater than original estimations that were based oncontrast to adults diagnosed with CD.[34-36] Therefore, the early populations of European patients presenting with classical clinical


378 Kwon & Farrell

symptoms and biopsy-confirmed CD. In 1950, the incidence of found a prevalence of anti-endomysial antibodies of 1 : 133CD in England and Wales was reported as 1 : 8000, while in among 4126 not-at-risk individuals.Scotland the reported incidence was 1 : 4000.[38] Current screen- Epidemiologic data have also supported the ‘celiac iceberg’ing studies estimate the prevalence of CD in Celtic populations to hypothesis. For example, in the study by Maki et al.,[12] none of thebe as high as 1 : 122.[39] Similar prevalence rates have been noted 56 Finnish school children with the combination of serologicin Italy, Sweden, Finland, and southeastern Austria.[40-43] Most positivity and HLA-DQ2/HLA-DQ8 haplotype was previouslyrecently, Maki et al.[12] screened blood samples of 3654 Finnish diagnosed with CD. Only ten were diagnosed during the periodschool children for both anti-endomysial and tissue trans- between serum sample collection and blood analysis. Furthermore,glutaminase (tTG) antibodies and estimated that the prevalence of 27 of 36 individuals without a CD diagnosis had biopsy-provenbiopsy-proven CD among Finnish school children was 1 : 99 CD. Upon answering a questionnaire, 13 reported manifestationswhile the prevalence of schoolchildren who carried the HLA-DQ2 attributable to CD, including abdominal pain, intermittent diar-or HLA-DQ8 haplotypes, which are strongly associated with CD, rhea, constipation, fatigue, and cutaneous manifestations. Resultsand who were also antibody positive was 1 : 67. A similar study indicate that the ratio of symptomatic to unrecognized CD inpublished in 1996 involving 17 201 Italian school children using Italian school children is 1 : 7.[51] This highlights the likelihoodless sensitive and less specific anti-gliadin antibodies reported an that many cases of ‘silent’ CD are, in fact, unrecognized, sympto-overall prevalence of 1 in 184 individuals.[44] matic CD and reinforces the necessity for increasing our general

awareness of CD prevalence.[39]Originally, CD was considered a disease of northern EuropeansBecause of the protean manifestations of CD and the widewith the highest reported prevalence in Ireland, Scotland, Scandi-

range of ages in which CD has been diagnosed, there is a currentnavia, and Italy.[16,39,41,42] However, the emigration of northerndebate as to whether all cases of CD begin in childhood regardlessEuropeans to other regions and the utilization of gluten-containingof the age of actual diagnosis. Bingley et al.[52] and other groupsgrains have resulted in an increased prevalence in countries wherehave determined that the prevalence of childhood CD is similar toCD was once thought to be exceedingly rare. For example, whilethat in the adult population, indicating that the incidence of CDthe predominantly rice-eating areas of southern India rarely reportdoes not increase with age.[53,54] However, recent studies haveCD, an increasing prevalence has been noted in the Punjab prov-provided evidence that patients diagnosed with CD during child-inces of northwest India where wheat rather than rice comprises ahood appear to have a lower prevalence of autoimmune diseasesmajor portion of the diet.[1] Similarly, South America, Northsuch as type 1 diabetes and thyroiditis compared with patientsAfrica, and Asia are becoming increasingly recognized as areasdiagnosed in adulthood.[51,55] It remains to be determined whetherwhere CD is under-diagnosed.[45-48]

childhood CD is identical in pathogenesis to adult CD.This trend towards an increasing prevalence of CD has alsobeen seen in the US. In 1993, Rossi et al.[49] reported the preva-

2. Pathogenesislence of CD in children with chronic diarrhea, short stature, orinsulin-dependent diabetes in the western New York region, New The exact mechanism by which the ingestion of wheat glutensYork to be 1 : 5464, using anti-endomysial antibodies. In a retro- results in villous atrophy in the proximal small intestine remainsspective community-based, case-finding study, Talley et al.[8] esti- uncertain. Research into the pathogenesis of CD has focused onmated the prevalence of CD in 1991 in Olmstead County, Minne- the identification of the antigenic epitopes within wheat gluten, thesota to be 1 : 4857. However, both studies were performed prior to identification of antigen-presenting molecules binding to thoseour understanding of the protean nature of CD manifestations. In epitopes, and the elucidation of downstream adaptive and innate1998, a study of 2000 healthy blood donors reported a prevalence immune responses resulting in characteristic pathologic changes inof anti-endomysial antibodies in 1 : 250 individuals.[13] In addi- CD. Each of these research foci bears significant therapeutiction, a large study has indicated the likelihood that the prevalence implications.of CD in the US is comparable to that in European populations.[50]

Fasano et al.[50] determined the prevalence of anti-endomysial 2.1 Gluten Processing and Functionantibodies in >13 000 at-risk and not-at-risk American individualsand found the prevalence of anti-endomysial antibodies to be Wheat proteins are classified into four main groups, the alco-1 : 22 and 1 : 39 among first- and second-degree relatives of hol-soluble gliadins, the glutenins (partially soluble in dilute acidindividuals with CD, respectively. A prevalence of 1 : 56 was or alkali), the globulins, and the albumins.[2] The glutens comprisedocumented among patients with gastrointestinal symptoms of CD the gliadins and glutenins. The gliadins are 32–58 kDa proteinsor associated disorders. Of most significance, these investigators comprised predominantly of glutamine and proline residues. They



belong to a general class of alcohol-soluble proteins called pro- Shan et al.[69] identified a 33 amino acid peptide corresponding tolamines, which include the secalins from rye, hordeins from bar- amino acids 57–89 that was resistant to lumenal digestion byley, and avenins from oats. Prolamines from other cereals tend to gastric, pancreatic, and intestinal brush border proteases but reac-have immunologic cross-reactivity with each other.[56,57] The glia- tive to tTG. This peptide was also capable of T-cell activation.dins are further subdivided into α, β, γ, and ω gliadins, depending Similarly, Matysiak-Budnik et al.[70] demonstrated that both theon their electrophoretic mobility. All four subfractions of gliadin 31–49 and 57–89 peptides are resistant to digestion by lumenalhave been shown to independently exacerbate CD in vitro and in enzymes but completely degraded in the epithelial cells of healthyvivo. individuals and patients with treated CD. However, both peptides

were able to breach the epithelial barrier in patients with active CDUsing synthetic peptides generated from α-gliadin, severaland were identified in the serosal compartment of duodenal biopsyregions appear to significantly influence and reflect the complexi-samples obtained from patients with active CD, allowing for thety of the pathogenesis of CD. In organ cultures, the peptideincreased potential for stimulation of the immune response charac-corresponding to amino acids 31–49 has been shown to be toxic toterizing CD. The mechanism of resistance to lumenal digestionthe intestinal mucosa via recruitment of intraepithelial lympho-and increased permeability of these toxic gliadin peptides incytes and induction of epithelial lesions.[58] Interestingly, peptidepatients with CD has yet to be determined.31–49 does not activate intestinal CD4+ T cells from patients with

Interestingly, the studies mentioned in this section were allCD in vitro and a related peptide corresponding to amino acidsconducted using tissues obtained from adults with CD. However,31–43 is capable of inducing epithelial cell apoptosis and activat-recent work using CD tissues obtained from both adult and pedi-ing macrophages, indicating a likely role in the innate immuneatric patients has introduced another layer of complexity regardingresponses in CD pathogenesis.[59,60] Of note, peptide 31–43 doesresponsiveness to specific gluten peptides in the pathogenesis ofappear capable of activating peripheral CD4+ T cells isolated fromCD. Vader et al.[65] recently demonstrated that both adult andpatients with CD.[61] Recently, Gianfrani et al.[62] reported that thepediatric patients with CD respond to a diverse repertoire of glutenα-gliadin-derived peptide corresponding to amino acids 123–32 ispeptides. In particular, they demonstrated that native gluten pep-recognized by CD8+ T lymphocytes from patients with CD and istides and non-deaminated peptides were often found to result inassociated with cytotoxic activity. Furthermore, the peptide corre-the stimulation of T cells isolated from small bowel biopsies ofsponding to amino acids 57–68 appears to function in adaptivepediatric patients and to a much lesser extent from small bowelimmunity via the stimulation of intestinal T cells in most patientsbiopsies from adults. The authors hypothesized that CD resultswith CD.[63-65] This peptide does not appear to be directly toxic tofrom a multiple step process of inter- and intra-molecular epitopethe intestinal mucosa of patients with CD in vitro.spreading. With disease progression, an increased release of intra-While specific peptide regions of α-gliadin appear importantcellular tTG may lead to a progressive deamidation of glutens andfor CD, the protein digestion of the wheat glutens appears to be aan enhancement of a demonstrated gliadin-specific response. Fur-key step in CD pathogenesis. Glutens, in general, contain relative-ther longitudinal studies assessing the responses to gluten epitopesly few negatively charged amino acids that may interact withare necessary to confirm this hypothesis and these results willantigen-presenting molecules. The deamidation of glutamine resi-likely have a great impact on future treatment strategies.dues into glutamic acid introduces negative charges, which favor

binding. It has been demonstrated that a ubiquitous intracellularenzyme, tTG, plays a key role in this process.[66,67] tTG is ex- 2.2 Gluten Antigen Presentationpressed in the brush border and subepithelial area as well as at thesurface of activated macrophages. It normally catalyzes transami- A major breakthrough in our understanding of CD as andation and deamidation of specific peptides and is upregulated in autoimmune disease was the discovery of its association with theCD. At the brush border of the proximal intestine, the pH of 6.6 MHC class II HLA. The HLA genes encode glycoproteins thatappears to promote deamidation over transamidation.[68] This bind peptides to form HLA-antigen complexes that are recognizeddeamidation of gliadin residues depends on the relative position of by certain T cells. CD has been most commonly associated withproline residues, with a preferential sequence of Gln-X-Pro.[68] HLA-DQ haplotypes.[71,72] Subsequently, Sollid et al.[73] reportedMolberg et al.[67] subsequently demonstrated that the selective that >90% of northern European patients with CD shared thedeamidation of gluten proteins by tTG increased their stimulating HLA-DQ2 (α1*0501/β1*02) heterodimer, specific for CD4+ T-effect on gluten-sensitive T cells from patients with CD. cell activation. In southern Europe, the HLA-DQ2 is also the

Specific peptide regions also appear to confer resistance to major CD susceptibility genotype, while HLA-DQ8 (α1*0301/enzymatic breakdown to allow for potential antigen presentation. β1*0302) comprises a smaller group.[74]


380 Kwon & Farrell

We now know that tTG deamidates gliadin peptides, which gen-presenting cells. The presentation of antigen to CD4+ T lym-facilitates the high affinity binding of resultant negatively charged phocytes in the lamina propria results in T-cell activation and theglutamic acid residues in key positions on gliadin peptide T-cell subsequent release of interferon-γ (IFNγ), and B-cell proliferationepitopes to HLA-DQ2 and HLA-DQ8 molecules.[66,67] Gjertsen and immunoglobulin production. The release of IFNγ results inet al.[61] demonstrated that HLA-DQ2 was able to present the epithelial cell damage via the direct epithelial cell injury or the31–49 peptide to and stimulate CD4+ T cells from the peripheral activation of macrophages and release of proinflammatoryblood of patients with CD. cytokines.[78] Cytokines that have been shown to be increased in

active CD include IFNγ, interleukin (IL)-2, tumor necrosis factor-While there are very strong associations between HLA-DQ2α, IL-6, and transforming growth factor-β (TGFβ).[79-82]and HLA-DQ8 with CD, evidence indicates that other heritable

factors most likely play a role in CD pathogenesis. Concordance There is substantial evidence for the role of humoral immunitybetween CD and HLA is approximately 70% in monozygotic in the pathogenesis of CD. In untreated CD, the number of B cellstwins and only 35–40% in HLA identical siblings.[3] In addition, within the lamina propria are markedly increased.[83] Furthermore,HLA-DQ2 occurs in 20–25% of the normal population, indicating antibodies to purified gliadin and gliadin fractions can be detectedHLA-DQ2 alone does not result in CD. It remains to be deter- in the sera of most patients with CD.[84-86] However, patients withmined why only a small overall proportion of HLA-DQ2 individu- CD also have increased levels of serum antibodies to other non-als develop CD. Other HLA molecules that have been associated specific food proteins, including ovalbumin, casein, and β-lacto-with CD include HLA-B8, HLA-DR3, HLA-DR4, and HLA- globulin.[87] It is likely that anti-gliadin antibodies reflect a non-DRA.[3,75,76] specific response to the passage of food antigens across an abnor-

Recently, Gianfrani et al.[62] demonstrated that the peptide mally permeable intestinal epithelium.[88,89]

corresponding to amino acids 123–132 is selectively recognized The major breakthrough regarding the humoral response in CDby the MHC class I antigen HLA-A201. The binding of this pathogenesis was the discovery that the target of IgA anti-endo-peptide to HLA-A201 results in the activation of CD8+ T lympho- mysial antibodies is tTG.[90] Subsequently, tTG has been found tocytes isolated from patients with CD. These results indicate that have numerous functions in CD pathogenesis. In addition to itsboth MHC class I and II molecules play a role in antigen presenta- role in deamidation of gliadin proteins, tTG has been shown to betion and downstream activation of CD8+ and CD4+ T lympho- essential for the bioactivation of TGFβ and subsequent epithelialcytes. differentiation.[91,92] Local tTG autoantibody production may play

a role in the decreased epithelial differentiation noted in activeCD.2.3 Adaptive and Innate Immunity

While the mechanisms that trigger the humoral and cell-medi-ated adaptive immune responses are not understood, it has beenThe massive infiltration of lymphocytes into the small intesti-hypothesized that an activated innate immune response to gliadinnal mucosal epithelium and the lamina propria is a characteristicmay play a key role.[60] This activated innate immune response isfeature of CD. In active CD, the predominant lymphocyte popula-thought to occur in the setting of an immune regulatory defect ortion in the intraepithelial layer is CD8+, while the lymphocytes ofenvironmental factor (i.e. viral or bacterial infection). However,the lamina propria are predominantly CD4+. The specific T-cellspecific regulatory defects or environmental factors have yet to bepopulations within the epithelial layer and the lamina propria areconclusively identified. Viral infections have been implicated inquite distinct and may reflect their relative roles in the adaptivethe pathogenesis of CD. α-Gliadin appears to share homology withimmune responses in CD (figure 1). Adaptive immunity refers tothe 54kD E1b protein coat of adenovirus 12, suggesting that CDthe part of the immune system responsible for remembering previ-may result from molecular mimicry with viral proteins.[93] This isous encounters with antigens and capable of adapting to futuresupported by evidence that patients with CD have a significantlyencounters with the same antigen.[77]

higher prevalence of adenovirus 12 infections compared withPart of the adaptive immunity in CD is hypothesized to occur ascontrol individuals.[94]an orchestrated activation of the lamina propria CD4+ T lympho-

cytes to gliadin epitopes. Briefly, aberrant proteolysis of gluten IL-15 appears to be a key molecule in bridging the innate andproteins results in the accumulation of immunostimulatory gliadin adaptive immune responses in CD pathogenesis.[78] As stated inpeptides in the intestinal submucosa. The pH of the proximal small section 2.1, the 31–49 peptide is capable of inducing epithelial cellintestine, favoring deamidation of glutamine residues by tTG, lesions and intraepithelial lymphocyte recruitment in the absenceresults in the formation of negatively charged gliadin epitopes of CD4+ T-cell activation. Maiuri et al.[60] demonstrated that thiswhich favorably bind HLA-DQ2/HLA-DQ8 molecules on anti- peptide activated macrophages in organ cultures from duodenal



Fig. 1. Pathogenesis of celiac disease (CD). Aberrant proteolysis of gliadin results in the accumulation of immunostimulatory peptides in the intestinalsubmucosa. Peptide 123–132 is selectively recognized by the MHC class I antigen HLA-A201 resulting in the activation of CD8+ T lymphocytes in theintraepithelial layer (IEL). Deamidation of glutamine residues to glutamic acid on the peptide corresponding to amino acids 57–89 by tissue trans-glutaminase (tTG) results in binding to HLA-DQ2/8 molecules on antigen-presenting cells (APC). Subsequent CD4+ T-lymphocyte activation results in therelease of interferon-γ (IFNγ) as well as B-lymphocyte proliferation and immunoglobulin production. The release of IFNγ results in epithelial damage viadirect epithelial injury or the activation of macrophages and release of cytokines. Macrophage activation by IFNγ or peptide 31–49 results in interleukin(IL)-15 production. Surface IL-15 expression is also increased in enterocytes of patients with active CD. IL-15 induces direct epithelial injury viamechanisms relating to IFNγ, enhances the capacity of dendritic cells to function as APC, and regulates intraepithelial lymphocyte homeostasis bypromoting migration and preventing apoptosis. It has been hypothesized that an environmental trigger, such as a viral infection, may activate the innateimmune response and result in molecular mimicry resulting in an immunologic response to gliadin. TCR = T-cell receptor; TGFβ = transforming growthfactor-β; TNFα = tumor necrosis factor-α.

biopsies of patients with CD. This macrophage activation resulted villous atrophy and remain elevated after histologic resolution on agluten-free diet.[96-98] Their expansion appears to be regulated inin COX-2 production, p38 mitogen-activated protein (MAP) kin-part by IL-15.[99] While the function of the γδ+ T cells is unknown,ase activation, and IL-15 production. Surface IL-15 expression isit has been hypothesized that they may act as ‘sentinels’ moderat-also increased in enterocytes of patients with active CD anding immune responses to epithelial damage.[78] The levels of αβ+refractory CD.[95] IL-15 is capable of inducing direct epithelial cellT cells in the epithelial layer correlate with CD activity, suggestinginjury by specifically inducing the expansion of clonal abnormalthat the reactivity to gliadin proteins resides in this cell population.intraepithelial lymphocytes that characterize refractory CD andThis is supported by the discovery that CD8+ T-cell responses intriggered their secretion of IFNγ, which is cytotoxic to intestinalintra-epithelial lymphocytes are modulated via gliadin binding toepithelial cells.[95] In relation to adaptive immunity, IL-15 regu-the MHC class I HLA-A2.lates intraepithelial lymphocyte homeostasis by promoting migra-

tion, preventing apoptosis, and enhancing the capacity of dendritic3. Diagnosiscells to function as antigen-presenting cells.[60]

In active CD, both CD8+ T-cell receptor αβ+ and T-cell Increasing our capability to diagnose CD in the general popula-receptor γδ+ intra-epithelial lymphocytes are increased in number. tion is essential to not only fully understanding the true prevalenceHowever, the γδ+ T-cell levels increase prior to the onset of of this disease, but also to identifying patients at risk and providing


382 Kwon & Farrell

early intervention. In addition, increased awareness of the high the diagnosis of CD.[3] The revised diagnostic criteria requireprevalence of subclinical, atypical, or silent CD and the implica- characteristic histologic findings on a small intestinal biopsy fol-tions of subjecting patients to a life-long gluten-free diet has lowed by an obvious clinical remission while on a gluten-free diet.increased the necessity for highly sensitive and specific tests. In contrast to a diagnostic small intestinal biopsy, positive serolo-Recent goals regarding diagnostic testing for CD have focused on gy at the time of diagnosis was considered supportive rather thanclarifying the indications for invasive testing and improving the essential for the diagnosis of CD. This considerably eased thesensitivity and specificity of serologic tests. burden on the patient and gastroenterologist with only one set of

small intestinal biopsies required to establish the diagnosis. Incontrast to the earlier diagnostic criteria proposed by the ES-3.1 Endoscopy and Small Intestinal BiopsyPGHAN in 1970, the use of a second set of biopsies to demonstratehistologic improvement on a gluten-free diet and a third set toThe gold standard for the diagnosis of CD remains the smallconfirm histologic relapse after a gluten challenge is no longerintestinal biopsy. While the endoscopic diagnosis of CD may berequired.suggested by the presence of several macroscopic features includ-

While most children can avoid additional biopsies or a glutening scalloping of duodenal folds, visible vasculature, and reducedchallenge, additional biopsies should be considered in childrenduodenal folds, recent studies indicate that the sensitivity andwith suspected CD diagnosed before 2 years of age. However, aspecificity of endoscopic features for CD is quite low in thegluten challenge should be avoided prior to 6 years of age orpediatric population.[100,101] Furthermore, these findings are lessduring periods of rapid growth. Other patients who should belikely to be present when the duodenal biopsy reveals only partialconsidered for a gluten challenge or additional biopsies are pa-rather than total villous atrophy.[102] It is uncertain whethertients with a questionable diagnosis such as those who initiatechromoendoscopy increases the sensitivity of the endoscopic diag-gluten withdrawal in advance of a diagnostic small intestinalnosis of CD. Because of the low sensitivity of direct endoscopicbiopsy or those who wish to discontinue their gluten-free diet. Invisualization, routine duodenal biopsies are recommended in chil-addition, patients with symptoms attributable to possible non-dren undergoing upper endoscopy for symptoms of dyspepsia,compliance to their gluten-free diet may be considered for addi-abdominal pain, or anemia. Biopsy samples should be obtainedtional biopsies.from at least three regions from the distal duodenum (second or

third part) using ‘jumbo’ forceps. While some pediatric gastroen-terologists still utilize a suction-guillotine biopsy capsule (i.e. 3.2 Serologic TestingWatson or Crosby-Kugler capsule) most biopsies in children arenow performed during upper endoscopy.[2] Several serologic tests for CD have been utilized in clinical

practice. These serologic tests have utility in screening patientsCharacteristic features on histology include villous atrophy,with symptoms suggestive of CD, patients with atypical extra-crypt hyperplasia, and lymphocytic infiltration of the laminaintestinal manifestations of CD, and asymptomatic patients with apropria and the surface epithelium. The degree of villous damagefirst-degree relative with CD. In addition, the serologic testscan range from mild blunting to total atrophy. The progression oftypically become negative after several months as patients respondCD from lymphocytic infiltration to total villous atrophy has beento a gluten-free diet, providing a means to assess efficacy andproposed to occur in stages. Marsh[103] proposed that stage 0adherence to a gluten-free diet.comprises histologic findings of a pre-infiltrative lesion with

normal mucosal architecture. Stage 1 is defined as an inflammato- Clinical studies have assessed the presence of several antibo-ry lesion with normal mucosal architecture but with villous epithe- dies related to CD: the IgA anti-endomysial antibody, the IgA anti-lium markedly infiltrated by intra-epithelial lymphocytes. Stage 2 tTG antibody, the IgG anti-tTG antibody, the IgA anti-gliadinis characterized by crypt hyperplasia in addition to increased antibody, and the IgG anti-gliadin antibody. The approximatevillous intra-epithelial lymphocytes. Stages 3 and 4 are associated sensitivities and specificities of these tests are listed in table II.with varying degrees of villous atrophy. The degree of involve- While the IgA anti-endomysial antibodies are highly sensitivement of CD may range from patchy disease within the duodenum and specific, the utilization of human umbilical cord or monkeyand jejunum to fulminant disease involving the entire small intes- esophageal smooth muscle for the indirect immunofluorescencetine. study make this test very costly and difficult to perform. There-

With the advent of more sensitive and specific serologic test- fore, because tTG has been recognized as the main autoantigen foring, in 1990, the European Society for Paediatric Gastroenterolo- the anti-endomysial antibody and the ELISA for IgA tTG is agy, Hepatology and Nutrition (ESPGHAN) revised the criteria for technically more reliable and easier test to perform, the IgA tTG



Table II. Sensitivity and specificity and positive and negative predictive values of serologic tests for untreated celiac disease

Serologic test Sensitivitya (%) Specificitya (%) Positiveb predictive Negativeb predictivevalue (%) value (%)

IgA anti-tTG antibody ELISA (using guinea-pig tTG) 95–98 94–95 91–95 96–98

IgA anti-tTG antibody dot blot test (using human tTG) 93 99 99 93

IgG anti-tTG antibody ELISAc 99 99

IgA/IgG anti-tTG antibody immunochromatograph stick 83–97 99–100

IgA anti-tTG/IgA antigliadin antibody immunochromatograph stick 83–89 99–100

IgA antiendomysial antibody indirect immunofluoresence assay 85–98d 97–100d 98–100 80–95

IgA antigliadin antibody test 75–90 82–95 28–100 65–100

IgG antigliadin antibody test 69–85 73–90 20–95 41–88

a There are wide variations in the sensitivity and specificity of these tests among different laboratories.

b These high positive and negative predictive values reflect the high disease prevalence of celiac disease among the population studied.

c Studied in IgA-deficient individuals.[104] Other studies report reduced diagnostic efficacy.[105,106]

d Sensitivity and specificity for tTG.

tTG = tissue transglutaminase.

antibody test has become more widely available.[105,107] Wide what defines a gluten-free diet remains quite controversial. Debatevariations in the reliability of the ELISA for IgG tTG have been continues regarding the minimal amount of gluten allowed in areported.[104-106] Regardless, the ELISA for IgG tTG has been gluten-free diet. The Natural Food Authority recently defined aconsidered useful for the 1–3% of patients with CD who have a gluten-free diet as containing no gluten and a ‘low-gluten’ diet ascoexisting selective IgA deficiency.[108,109] In addition, an immu- containing 0.02% gluten.[11] The Codex Alimentarius standardnochromatographic stick for IgA and IgG tTG and another stick allows for 0.05g of nitrogen content per 100g of cereal grain.[117]

for IgA tTG and IgA anti-gliadin have been developed and demon- Clearly, there is currently no established standard for the classifi-strate results comparable to the ELISA.[110] cation of gluten-free foods.

The anti-gliadin antibody tests have a generally poor, positive Maintenance of a gluten-free diet requires a vast knowledge ofpredictive value.[111,112] However, the IgA anti-gliadin antibody foods, additives, and preservatives containing wheat, barley, andremains useful in symptomatic children aged <2 years. Further- rye. While numerous books and websites[118] provide comprehen-more, like the IgG tTG ELISA, the test for the IgG anti-gliadin sive information on gluten-containing foods, the list of foods hasantibody has been useful in diagnosing CD in patients who have a become quite extensive. Because wheat flour is used as an inex-coexisting selective IgA deficiency.[113] In practice, the serum IgA pensive filler for many commercially produced foods, a vast arraylevel should always be checked in patients with suspected CD who of foods must be avoided. Wheat flour has been found in icehave a negative IgA tTG or IgA endomysial antibody test to cream, pasta, sausages, cheese spreads, fish fingers, salad dress-exclude a false-negative test. ings, soups, instant coffee, ketchup, mustard, candy bars, sauces,

and mixed seasonings.[1] Further complicating matters, a large4. Current Therapy and Therapeutic Implications range of pharmaceutical products, including prescription medica-

tions, vitamins, and mineral supplements also contain inactiveThe mainstay of treatment for CD has been the gluten-free diet,ingredients, which contain varying levels of gluten.with 70% of patients demonstrating symptomatic improvement in

The maintenance of a gluten-free diet requires caution when itas little as 2 weeks.[114] While the clinical response may be quitecomes to oats. All foods containing oats should be avoided initial-dramatic, it has been estimated that between 7% and 30% ofly and only once the patient’s symptoms have resolved on apatients do not respond to a gluten-free diet.[115] Histologic im-

provement typically lags behind clinical and serologic responses gluten-free diet should oats be reintroduced. While patients withand in some cases histologic improvement may take up to 2 years, CD who consumed ≤50–70g of oats per day for 6–12 months didhence the poor utility of repeating biopsies in patients on a gluten- not differ from patients on an oat-restricted, gluten-free diet, infree diet.[116] practice obtaining pure oat produce is difficult because oat prod-

ucts are frequently cross-contaminated in the mills with smallDietary compliance to a gluten-free diet in children and particu-larly in adolescents is quite difficult. Moreover, the concept of amounts of wheat grains.[119,120]


384 Kwon & Farrell

Because of the complexity of the gluten-free diet, it is under- efficacy of infliximab, a chimeric antibody to tumor necrosisfactor-α, in refractory CD.[128]standable that the main reason that patients with CD do not

respond to a gluten-free diet is because either the diagnosis isincorrect or there is inadvertent gluten ingestion rather than poor 5. Future Directionscompliance. It is always worthwhile to have the small intestinalbiopsies of non-responsive patients reviewed by a second exper- Overall, there are a significant number of patients who do notienced gastrointestinal pathologist. In children, other causes of respond to a gluten-free diet. The complexities of a gluten-freevillous atrophy that may be included in the differential diagnosis diet, the number of patients with truly refractory disease, and theof CD include cow’s milk and soy-protein intolerance, gas- growing awareness of the high prevalence of CD in the generaltroenteritis, chronic giardiasis, eosinophilic gastropathy, and population highlight the necessity for advancements in the treat-

ment of CD. Directions for these advancements include modifica-autoimmune enteropathy. Once the diagnosis of CD has beentions of gluten processing, targeting of HLA-associated molecularconfirmed, patients should see a nutritionist experienced in CD tointeractions, and cytokine regulation.identify inadvertent sources of ongoing gluten exposure. The

Our increasing knowledge of gluten processing has introducedremainder of patients who are still symptomatic despite a strictpotential strategies for the treatment of CD. The identification ofgluten-free diet often have other food intolerances such as coexist-epitopes on α-gliadin that function in T-cell activation has led toent lactase deficiency, or associated diarrheal conditions includingthe hypothesis that the elimination or modification of specificbacterial overgrowth, microscopic colitis, hyperthyroidism, orgliadin epitopes via the genetic modification of wheat proteinspancreatic insufficiency rather than refractory CD or intestinalmay lead to safer, less immunogenic, wheat-containing commer-lymphoma.cial products. However, genetically modifying food is controver-Refractory CD is a rare diagnosis of exclusion defined assial and while this process is theoretically enticing, it may prove

symptomatic severe enteropathy not responding to at least 6more complicated than previously thought. It has been hypothe-

months of a strict gluten-free diet and not accounted for by othersized that gluten may contain up to 50 T-cell, antigen-specific

causes of villous atrophy or by overt intestinal lymphoma. Inepitopes that contribute to the pathogenesis of CD.[65] Further-

general it is rarely diagnosed in pediatric patients. In adults, it hasmore, the concept of ‘epitope spreading’ relies on the acquisition

long been appreciated that patients with refractory CD are at highof new disease-determining epitopes distinct from the primary

risk of developing complications such as enteropathy-associateddisease-inducing epitope.[129]

T-cell lymphoma, ulcerative jejunoileitis, and collagenous CD.Alternative strategies include the development of gliadin ana-

The link between refractory CD and these complications haslogs that are capable of interfering with HLA binding and subse-

recently been clarified with the demonstration that almost 75% ofquent T-cell activation or the alternative delivery of dominant

patients with refractory CD have an aberrant clonal, intraepithelialgliadin epitopes to develop tolerance to glutens.[130] The timing

T-cell population, a condition called cryptic intestinal T-cell lym-and delivery of the gliadin epitopes will require a more complete

phoma.[121] These cells have destructive properties related to theirunderstanding of the epitope cascade in CD pathogenesis. Strate-

cytotoxic phenotype, which lead to mucosal ulceration, lymphgies that have been proposed for epitope delivery include in-

node cavitation, and sometimes cellular and clinical progression to tranasal delivery of whole gluten or specific epitopes, DNA vac-lymphoma. cine technology with plasmids to specific gluten epitopes, antigen-

The use of immunosuppressant medications for refractory CD, presenting cell genetic engineering to present gluten peptides, andpatients in ‘celiac crisis’ and as an adjunct to the initiation of a the use of FAS ligand to target FAS-positive T cells for thegluten-free diet is occasionally required.[122] However, this appli- induction of apoptosis and to block the CD28/B7 co-stimulatorycation is often reserved for adult patients and there is minimal pathway.[130] While this latter strategy has many potential benefits,knowledge regarding the efficacy of immunosuppressant medica- it does have the risk of enhancing immunization and CD pathogen-tions in the treatment of pediatric patients with CD. CD can be esis rather than promoting tolerance.treated with corticosteroids but patients often relapse after discon- The essential role of gluten processing in the pathogenesis oftinuation of the corticosteroid.[123] Azathioprine and mer- CD provides additional therapeutic strategies. Both lumenal andcaptopurine have been used in refractory CD as corticosteroid- intra-epithelial gluten processing appear to be important and de-sparing agents.[124,125] While its long-term efficacy is still un- fective gluten processing has been demonstrated in active CD.known, cyclosporine (ciclosporin) has been used in refractory Shan et al.[69] recently suggested the use of bacterial-derivedCD.[126,127] There has been one case report demonstrating the endoproteases to cleave gliadin peptides resulting in a decreased



delivery of gliadin peptides for epithelial processing. While it treatment. Currently, the most accepted treatment is the strictappears that epithelial processing is the more integral component adherence to a gluten-free diet. However, not only is a life-longin CD pathogenesis, decreasing epithelial gluten delivery clearly compliance to a gluten-free diet difficult to maintain, but also, notmay provide some therapeutic benefit. Furthermore, delivery of all patients respond to this strategy. Current alternative therapiesencapsulated endoproteases is a relatively straightforward and utilize available immunosuppressant medications, which have sig-testable strategy that may obviate the need for a gluten-free diet in nificant adverse effects and potential complications.the future. Future alternative therapies are obviously necessary for those

Our increasing knowledge of specific cytokines involved in CD patients unable to tolerate a gluten-free diet or with truly refractorypathogenesis provides further potential therapeutic options. Alter- disease. Most of these therapies will likely rely on genetic altera-native methods of delivery or regulation of IL-10 and IL-15 have tion of gluten proteins, immunization techniques, or genetic thera-been proposed.[131] IL-10 expression has been proposed as a target pies focused on either the development of immune tolerance or thefor potential modulation based on similarities between the immune localized regulation of inflammatory and anti-inflammatoryresponses in CD and Crohn disease. IL-10 inhibits IFNγ-produc- cytokine expression. In the future, the benefits of each of theseing T cells by preventing macrophage and dendritic cells from potential therapeutic approaches must be weighed with their inher-synthesizing IL-12.[132] In CD, IL-10 release is upregulated upon ent risks and ethical implications. As we increase our understand-T-cell activation.[133] Mice deficient in IL-10 spontaneously devel- ing of CD pathogenesis, the optimal therapeutic alternatives willop enterocolitis mediated by CD4+ T cells, which is similar to the likely become more readily apparent.pathogenesis of inflammation seen in CD.[134] Intralumenal IL-10delivery has been accomplished via delivery of genetically modi- Acknowledgmentsfied bacteria expressing the IL-10 gene.[135] Recently,CD45RBhigh T cells with a retrovirally transfected IL-10 were No sources of funding were used to assist in the preparation of this review.

The authors have no conflicts of interest that are directly relevant to theshown to prevent colitis in severe combined immunodeficientcontent of this review.mice.[136] It is possible that a further increase in IL-10 expression

in CD will result in a blunted immunologic response to gluten.As stated in section 2.3, IL-15 appears to play an integral role in References

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