Pathogenesis of coeliac disease
DETLEF SCHUPPAN Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Introduction intestine. These first were described in 1954 [8] and refined further by Marsh [9]. With the Classical coeliac disease is an inflammatory advent of serum diagnostic tests such as im- disorder of the small intestine that is characte- munoglobulin A (IgA) antibodies to gliadin and rised by global malabsorption of macronu- especially to an autoantigen present in reticu- trients, minerals and vitamins. It is charac- lin and endomysium (see later), coeliac disease terised histologically by a predominant T-cell could be differentiated more easily from other infiltration in the epithelium and the lamina malabsorptive disorders [10]. More important- propria that may lead to complete destruction ly, population studies using the antibody tests of the small intestinal villi and to significant as screening tools and confirmatory small in- reduction of the gastrointestinal tract absorp- testinal biopsies revealed a hitherto unexpec- tive surface [1-4]. Coeliac disease was common- tedly high prevalence of coeliac disease in the ly fatal in the recent past as attested by the 12% Western world, Northern Africa, and the Near mortality among affected children reported and the Middle East, ranging from ~1:80-1:150 in a retrospective study done in 1939 [5]. The [11-13] (see C. Catassi, E. Fabiani and A. Fasano aetiology of this disorder remained unex- in this issue, pp. 83-94). In these studies, the plained until the Dutch paediatrician Willem vast majority (>80%) of affected individuals Dicke recognised an association between the identified by screening presented with clini- consumption of wheat products and relapsing cally “silent” or atypical forms of the disease. If diarrhoea. He confirmed his suspicions du ring and to what extent asymptomatic or oligosymp- food shortages in the Second World War when tomatic affected individuals identified through the symptoms of his patients improved as screening subsequently develop overt coeliac bread was replaced by noncereal containing foods. After the war, Dicke, Weijers and van de Kamer performed controlled experiments Gluten proteins can be separated into by exposing affected children to defined diets the ethanol-insoluble glutenins and the and determining faecal weight and faecal fat as measures of malabsorption. These metabolic alcohol-soluble gliadins. Both gliadins studies demonstrated clearly that wheat, bar- and glutenins display a high content ley and rye triggered gastrointestinal signs and symptoms that defined coeliac disease and that of the amino acids glutamine (32-56%) these were reversed after their exclusion from and proline (15-30%), and due to their diets [6]. They also identified the toxic agents as present mainly in the alcohol-soluble gliadin cysteine content glutenins can fraction of wheat gluten [7]. form complex homopolymers and The characteristic coeliac microscopic le- sions are mucosal inflammation, crypt hyper- heteropolymers with gliadins. plasia and villous atrophy in the proximal small
Annales Nestlé 2004;62:95-106 95 Detlef Schuppan
disease, secondary autoimmune diseases or GLIADIN PEPTIDE 4 CELL RESPONSE even malignancy remains to be shown. This is especially of concern because these indivi- (,! $1 duals are likely to continue consuming gluten- HETERODIMER containing diets. ^ OF FIRST DEGREE #$ PATIENTS $1 RELATIVES AFFECTED $1 'ENERAL POPULATION ^ Gluten: the causative agent
Gluten comprises the storage proteins of wheat endosperm that are responsible for many of B A $2A $2 the desired baking properties. Gluten proteins can be separated into the ethanol-insoluble glu- B $2 tenins and the alcohol-soluble gliadins. Each wheat variant produces an estimated 40-50 glia- ENCODED IN CIS ENCODED IN TRANS GENE DOSE dins that are structurally similar proteins with ~250-500 amino acids, and a limited number of Figure 1: HLA-DQ2 (DQ8) and presentation of gluten high and low molecular weight glutenins, with peptides to T-cells. HLA-DQ2 (DQ8) is a heterodimer of an α1 and a β1 chain that is necessary to present ~650-800 and ~270-320 amino acids, respective- (modified) gluten peptides to gluten reactive T-cells. ly. Both gliadins and glutenins display a high In most populations, more than 90% of coeliac pa- content of the amino acids glutamine (32-56%) tients express DQ2, and the minority DQ8. The two and proline (15-30%), and due to their cysteine DQ2 chains can be encoded on a single allele (in cis) content glutenins can form complex homopoly- in association with DR3, or on the two alleles in as- mers and heteropolymers with gliadins [14, 15]. sociation with DR5 and DR7 (in trans). In case of the Storage proteins similar to gliadins (generally trans configuration, only 1 out of the 4 possible hete- termed prolamines) are found in rye (secalins) rodimers that can form contains the correct chains. and barley (hordeins). Avenins of oats and es- In case of homozygosity, the cis configuration can lead to 4 out of 4 heterodimers with the correct chain pecially the zeins of rice are more distantly re- composition. Homozygosity for DQ2 in cis underlies lated to these other cereal proteins (Table I). On the observed gene dose effect described in fig. 2.
Table I: Cereal proteins that cause intestinal inflam- mation in patients with coeliac disease. the basis of their electrophoretic properties and Cereal Prolamine Composition “Toxicity” primary structures the gliadins are subdivided Wheat α-gliadin 36% Q, 17-23% P +++ into the classes of α, γ and ω. These are further Barley hordeins 36% Q, 17-23% P ++ classified into several distinct proteins, such as Rye secalins 36% Q, 17-23% P ++ α1-11, γ1-6, and ω1-5. Although the proinflam- Oats avenins high Q, low P (+) matory effects of all gliadin fractions were Maize zeins low Q, high A, V – shown in vitro [16] and after intraduodenal or Millet ? low Q, high A, V – Rice ? low Q, high A, V – rectal challenge in vivo [17], most experimen- tal and human studies focused on α-gliadins, The “toxic” prolamines (gliadins, secalins and hor- and more specifically on proinflammatory pep- deins) that drive the destructive intestinal T-cell tides in its amino terminal region [18, 19]. response in coeliac disease are rich in glutamine (Q) and proline (P). The proteins from grains that do not cause intestinal inflammation contain less Q and P, and a higher proportion of alanine (A) and valine (V). The genetic component In addition to the prolamines, the structurally diffe- rent glutenins from wheat and likely related proteins The risk to coeliac disease is genetically de- from barley and rye harbour immunogenic epitopes termined. Moreover, this genetic component is relevant to this condition. more relevant than that of most other inherited
96 Annales Nestlé 2004;62:95-106 Pathogenesis of coeliac disease
diseases. Transmission is autosomal dominant In addition, the DR3 linked genes MICA-A4 and with incomplete penetrance, resulting in a di- -A5.1, MICB-CA24 and MIB-350 were found to sease prevalence of ~15% in first-degree rela- confer a higher risk for coeliac disease in two tives [20-22], and reaching a concordance rate European cohorts [30, 31]. of 75 % in monozygotic twins [23]. Coeliac di- Coeliac disease is associated with other, sease is associated uniquely with the HLA class classical autoimmune diseases, such as type 1 II antigens DQ2 and DQ8 located on chromo- diabetes, autoimmune thyroiditis, connective some 6p21 [21, 22]. This association is so tight tissue diseases, idiopathic cardiomyopathy that between 85 to 95% of coeliac patients carry and autoimmune hepatitis. The prevalence of HLA-DQ2 and virtually all remaining patients coexisting celiac disease and a single other au- express HLA-DQ8 [24]. DQ2 is a heterodimer toimmune disease ranges from ~3-15% [32-42]. encoded by the alleles DQA1*05 (α) and DQB1*02 A large cross-sectional study suggested that (β). These are associated with the DR3-DQ2 the duration of gluten exposure correlated with haplotype (when encoded on the same allele the co-occurrence of these autoimmune disea- in cis) or with the DR5/DR7-DQ2 haplotype ses. The reported prevalence of co-occurrence (when encoded on both alleles in trans) [21, 22] ranged from 5.1% to 23.6% with ages at diagno- (Fig. 1). DQ8 is a heterodimer encoded by sis <2 years and >10 years, respectively [32]. DQA1*0301 and DQB1*0302. DQ2 or DQ8 is ne- However, a subsequent study demonstrated cessary for the development of the disease, that susceptibility to secondary autoimmunity accounting for roughly 40% of the genetic pre- was related mainly to the ages of the coeliac pa- disposition. However, since these antigens are tients [33]. It is therefore most likely that older expressed in 25-30% and 5-15%, respectively, ages and shared genetic predispositions, such of healthy controls in susceptible populations, as DR4, HLA-DQ8 and genes on chromosomes large international studies have been initiated 2q33 and 15q26 associated with type 1 diabetes to search for additional genetic determinants. [36-38], or HLA-DQ2/DQ8 and CTLA-4 polymor- These studies suggested several genetic loci phisms associated with autoimmune thyroidi- linked to coeliac disease, with and without tis [36, 42] underlie the association, as opposed identification of target genes and with hetero- to causative roles for coeliac disease and the geneity among the investigated populations. duration and intensity of gluten ingestion. Importantly, their impact appears to be much lower than that of either DQ2 or DQ8. The most convincing data relate to chromosome 5q31-33, Tissue transglutaminase: encoding a cluster of cytokine genes [25-27]. the coeliac disease autoantigen Minor associations were found for chromosome 2q33 where immune regulatory genes such as Patients with untreated coeliac disease have CTLA-4, ICOS-1 and CD28 are encoded [28, 29]. circulating IgA class autoantibodies against endomysium (the connective tissue around smooth muscle) or reticulin (fibronectin and collagen containing extracellular fibrils). Due to their high positive and negative predictive Coeliac disease is associated uniquely value, ranging between 90 and 100%, these with the HLA class II antigens DQ2 autoantibodies are valuable tools for disease diagnosis and population screening [10]. The and DQ8 located on chromosome 6p21. discovery that this autoantigen is an enzyme, This association is so tight that between namely tissue transglutaminase (tTG) was unexpected [43]. tTG or transglutaminase 2 85 to 95% of coeliac patients carry is expressed by almost all cell types and usu- HLA-DQ2 and virtually all remaining ally is retained intracellularly in an inactive form. Cells under mechanical or inflammatory patients express HLA-DQ8. stress release tTG into the extracellular space. This explains its association with the extracel-
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lular matrix [44, 45]. tTG belongs to a family tTG expression [44-47]. On the other hand, tTG of at least eight calcium-dependent transami- tethers the inactive proform of the pluripotent dating enzymes that catalyze the covalent and cytokine TGF-β (latent TGF-β) to the cellular irreversible crosslinking of a protein with a surface which allows its proteolytic activation glutamine residue (glutamine donor) to a se- to mature TGF-β by plasmin [51]. This could be cond protein with a lysine residue (glutamine relevant to coeliac disease pathophysiology be- acceptor), resulting in the formation of an ε- cause TGF-β can induce the differentiation of (γ-glutamyl)-lysine isopeptide bond [44-46]. human intestinal epithelial cells that are less tTG displays a high specificity for only certain differentiated in active coeliac disease [52]. protein-bound glutamine residues as glutamine donor substrates, whereas the lysine-contai- ning glutamine acceptor substrates are nume- Tissue transglutaminase rous. The reaction is calcium-dependent and and coeliac disease: a missing link tTG is only active in the presence of high cal- cium concentrations, as are found in extracel- After it became clear that the disease-associa- lular spaces, where it contributes to the extra- ted HLA molecules are HLA-DQ2 and, to a lesser cellular matrix’s stabilisation [47]. Intracellular extent, HLA-DQ8, the existence of gluten spe- tTG activation and subsequent crosslinking also cific T-cells remained hypothetical until 1993 occurs when cellular integrity is destroyed and when such T-cells were isolated from patients intracellular calcium rises in apoptosis. The lat- and found to be absent in healthy controls [22]. ter function may prevent leakage of potentially HLA-DQ molecules harbour a peptide binding harmful molecules from virus-infected or dying groove that accommodates peptides of 9 amino cells. Notably, tTG and tTG-derived crosslin- acids length that must contain negatively king appears to play a role in a variety of neu- charged amino acids at so called anchor posi- rodegenerative disorders, such as Alzheimer’s tions [54-56]. However, such acidic peptides do and Huntington’s disease [48, 49]. Under cer- not occur in the gluten molecules. This mystery tain conditions, e.g., when primary lysines are was solved when it was found that tTG, the tar- unavailable as glutamine acceptors or at low get autoantigen, can crosslink gluten peptides pH, tTG merely deamidates target glutamine that are preferred glutamine donor substrates in the substrate protein, transforming neutral and deamidate certain glutamines in these pep- glutamine to a negatively charged glutamic acid tides, which introduces the negative charges residue [50]. required for binding to HLA-DQ molecules. tTG is upregulated in wound healing, angio- Thus, ingested gluten molecules, degraded to genesis and apoptosis. Transforming growth peptides by gastrointestinal enzymes and mo- factor-β (TGF-β), tumor necrosis factor-α (TNF- dified by tTG, bind to HLA-DQ2 or HLA-DQ8 and α), interleukin-6, retinoids and corticosteroids trigger an inflammatory T-cell response. stimulate, whereas bone morphogenetic pro- Further work revealed the identity of a series teins-2 and -4 and histamine downregulate of (deamidated) gluten peptides that can trigger such T-cell responses, both in vitro and ex vivo using cultures of biopsies from coeliac patients [57-64]. However, most T-cell clones derived Patients with untreated coeliac disease from paediatric patients and some T-cell clones from adult patients responded primarily to non- have circulating IgA class autoantibodies deamidated gliadins and glutenins, indicating against endomysium or reticulin. that the early immune response is directed to several unmodified gluten peptides, whereas The discovery that this autoantigen long-standing disease favours a few immunodo- is an enzyme, namely tissue minant and preferentially deamidated peptides [63]. transglutaminase (tTG) was unexpected. The peptide PQPQLPY (proline-glutamine- proline-glutamine-leucine-proline-tyrosine)
98 Annales Nestlé 2004;62:95-106 Pathogenesis of coeliac disease
from α-gliadin that can be deamidated to DQ2/8 gene dose and extent of gluten PQPELPY (E, exchange of a glutamine for a exposure determine disease manifestation glutamic acid residue) was identified as an immunodominant epitope [60]. Interestingly, Although the major determinants of coeliac a 33-mer peptide from α2-gliadin that con- disease, i.e. immunogenic gluten peptides, tains three partly overlapping stretches of this HLA-DQ2/DQ8 and tTG, and their interplay have epitope and is fairly resistant to digestion by been defined, their quantities, i.e. exposure, intestinal proteases [65, 68]. This stability is also contribute to the manifestation of coeliac attributable to a rigid, three-dimensional struc- disease in a given patient. Thus, an early and ture with a type II polyproline helix that makes massive gluten exposure favours coeliac di- the peptide inaccessible to endopeptidases. sease manifestation. This explains the 5-10 fold Neutralisation of the 33-mer peptide that can be higher prevalence of classical coeliac disease considered a gluten superantigen is therefore a in Swedish compared to Danish children, two key target for non-dietary approaches to treat otherwise genetically similar populations [74] coeliac disease. Clinical trials using bacterial (see A. Ivarsson and O. Hernell, in this issue, endopeptidase that degrades this and related pp. 107-118). Furthermore, patients can express peptides are underway. two copies or only a single copy of HLA-DQ2 Synthetic peptide libraries were used to (DQ8) that dramatically increases the likeli- define the primary sequence requirements for hood of effective antigen presentation and di- those glutamine residues that are substrates sease manifestation [75-78]. Lastly, tTG expres- for tTG. These studies showed that the rela- sion is upregulated by mechanical stress and by tive positions of proline to glutamine residues intestinal inflammation. [57, 79, 80] and it can are crucial. Thus, the sequences QXP and QXX be hypothesised that mechanical irritation and (X representing a hydrophobic amino acid) are proinflammatory non proliferating agents and targeted by tTG. On the otherhand, tTG is not microbes can trigger the disease in genetically active on the sequences QP or QXXP [61, 62, susceptible individuals whose coeliac disease 65, 68]. Based on these tTG recognition motifs, remained subliminal for years (Fig. 2). algorithms were designed and used to screen the available sequence data bases of cereal pro- teins for preferred tTG recognition sequences. The cytokine response in coeliac disease The authors detected ~50 T-cell epitopes in wheat gliadins, and similar epitopes in the Within the first two hours after a gliadin chal- phylogenetically related hordeins from bar- lenge, HLA molecules are upregulated on ley and secalins from rye [65, 68]. In addi- enterocytes and adjacent macrophages. This tion, some T-cell stimulatory sequences also response is followed by an increased expres- were found in the structurally unrelated wheat sion of intercellular adhesion molecule ICAM-1 glutenins, confirming prior observations with and T-cell activation [81]. Gluten ingestion in glutenin reactive T-cell clones [69]. The lack patients with untreated coeliac disease induces of optimal tTG recognition sequences and thus a non-proliferative activation of T-cell receptor ineffective deamidation by tTG in the avenins α/β positive CD4+ T-cells in the lamina propria of oats [65, 70], which have a high glutamine and a proliferative activation of T-cell receptor but a low proline content (Table I), lends scien- α/β- or γ/δ-positive CD8+ intraepithelial lym- tific support to clinical studies that showed phocytes (IEL) [82]. that pure oats are safe for coeliac patients [71, DQ2-restricted gliadin-specific T-cell clones 72]. A recent study from Norway, however, express mainly the Th1 type cytokine IFN-γ, described three patients who did not tolerate and an IFN-γ blocking antibody could prevent oats and presented with intestinal inflamma- histological damage to healthy mucosa in an tion following its consumption. Avenin reactive intestinal organ culture system exposed to T-cell clones were isolated from these patients supernatants of gliadin-specific T-cell clones [73], indicating that in rare occasions oats may from coeliac patients [83]. Immunohistochemi- result in coeliac disease. cal studies confirmed the increased expres-
Annales Nestlé 2004;62:95-106 99 Detlef Schuppan
α $1$1 $1$1 li [88]. Therefore, IFN- treatment of patients with subliminal coeliac disease, e.g. for chronic hepatitis C, may be risky [89]. Contrary to its role in Crohn’s disease, IL-12, a prominent in- ducer of the Th1 reaction, does not appear to be rele vant in coeliac disease, since IL-12 is virtu- $1$1X
6ILLOUS ATROPHY ally absent from biopsy specimens of coeliac -ICROBIAL INFECTION patients [86, 90]. This role may be fulfilled by 4HRESHOLD IL-18 that is expressed in intestinal biopsies of OF GLUTEN INTOLERANCE patients with coeliac disease but not of controls [91]. IL-15 further adds to the complex cytokine profile of the disease. IL-15 shares many biologi- cal properties with IL-2, such as signalling via .ORMAL VILLI the same β- and γ-chain of the IL-2 high affinity EARLY GLUTEN DOSE receptor. It functions as a chemoattractant for Figure 2: DQ2 gene dose and gluten load. DQ2 gene peripheral blood lymphocytes and stimulates dose and the extent of (early) gluten exposure deter- the growth of activated T-cells and cytotoxic mine the manifestation and severity of the disease. Al- effector cells [92]. IL-15 can induce enterocyte though a low gene dose of DQ2 (see Fig. 1) and a care- proliferation and at the same time increase en- ful dietary introduction of gluten can keep intestinal terocyte apoptosis in biopsies of patients with inflammation subliminal, a high gene dose (and thus active coeliac disease [93]. A study using intes- surface expression) of DQ2, coupled with early and tinal biopsies suggested that the α-gliadin pep- massive gluten ingestion, can spark off overt coeliac disease. Additional triggers are probably mechani- tide p31-43, which does not bind to HLA-DQ2 or cal irritation and inflammation by chemicals or mi- -DQ8, can trigger IL-15 release from macropha- crobes that lead to enhanced intestinal permeability. ges and dendritic cells by activation of the innate (unspecific, pathogen recognising) immune system. This may prime the adaptive (HLA-me- diated, T-cell specific) immune system in pre- sion of IL-2, IFN-γ and TNF-α positive cells in disposed individuals for effective reaction with the lamina propria of patients with active coe- the immunodominant gluten peptides [94, 95] liac disease compared to patients in remission (Fig. 3). or controls [84]. Although a central role for Cytokines appear to be the major driving IFN-γ secreted by lamina propria lymphocytes force of tissue remodelling that results in vil- and IEL is undisputed, studies using quantita- lous atrophy and crypt hyperplasia, characte- tive polymerase chain reaction (PCR) in mate- ristic for coeliac disease. Using human foetal rial from intestinal biopsies did not show an intestinal explant cultures, Pender et al. increase of TNF-α and IL-2 in classical coeliac demonstrated that IFN-γ activates intestinal disease [85, 86]. Most studies demonstrated increased expression of IL-10 in active coeliac disease, with a shift from lamina propria lym- phocytes to IEL [85]. IL-10 suppresses Th1-cells Neutralisation of the 33-mer peptide and is likely acting as a counter-regulatory that can be considered a gluten cytokine. IFN-α that is found in the intestinal mucosa of coeliac patients but not of controls superantigen is a key target for non- [87] did not induce histological changes and dietary approaches to treat coeliac only minor IFN-γ and TNF-α production in foe- tal gut explants, but caused crypt hyperplasia disease. Clinical trials using bacterial and an an exaggerated Th1 response in com- endopeptidase that degrades this bination with a stimulatory anti-CD3 antibody, thus potentially facilitating coeliac disease and related peptides are underway. immunopathology in concert with other stimu-
100 Annales Nestlé 2004;62:95-106 Pathogenesis of coeliac disease
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Figure 3: Mechanisms of mucosal injury in coeliac disease. Dietary gluten peptides that reach lamina propria lead to enhanced intestinal expression of tTG. Cross-linking and particularly deamidation of gluten peptides by tTG create potent immunostimulatory epitopes that are presented via HLA-DQ2 or -DQ8 on antigen presen- ting cells, i.e. mature dendritic cells, macrophages or B-lymphocytes. Subsequently, CD4+ T-cells are activated, secreting mainly Th1-cytokines that via activation of macrophages cause the release and activation of matrix metalloproteinases (MMPs) by mesenchymal cells, that finally result in mucosal destruction. macro phages that in turn secrete TNF-α. TNF-α autoantibodies to tTG and since these autoan- potently stimulates the expression of matrix tibodies slowly disappear after institution of metalloproteases (MMPs) by intestinal myofi- a gluten free diet, coeliac disease is not con- broblasts, with MMP-1 and especially MMP-3 sidered a classical autoimmune disease. A mediating extracellular matrix degradation likely explanation for these autoantibodies is and remodelling [96]. In active coeliac disease, the incorporation of gliadins into complexes myofibroblast MMP-1 and MMP-3 mRNA are in- with tTG. In these complexes, tTG serves as creased in the subepithelial region, returning glutamine acceptor protein in a process of au- to normal after adherence to a gluten-free diet tocatalysis [43, 98]. Due to the close vicinity [97]. of gliadin and tTG in these complexes, gliadin- specific T-cells could help to stimulate the au- toantibody production by residual tTG-specific Autoantibodies to tTG B-cells that have escaped thymic selection [99]. Anti-tTG autoantibodies may not be innocent Since gluten ingestion drives the production bystanders but cause pathology themselves. of IgA- (and in the case of IgA deficiency IgG-) Indeed, in vitro gliadin challenge of small in-
Annales Nestlé 2004;62:95-106 101 Detlef Schuppan
testinal biopsies from treated coeliac patients structure resolution of the complex between induce production of IgA anti-tTG [100]. These DQ2 and the immunodominant α-gliadin pep- autoantibodies can block tTG activity and thus tide [104]; and 4) modulation of the intestinal inhibit the activation of latent TGF-β that is cytokine milieu, e.g. by immunomodulatory dependent on tTG [51]. The inhibition of TGF- cytokines or by cytokine antagonists [101] β activation by the anti-tTG antibodies could (Fig. 3). Apart from benefiting patients with contribute to observed intestinal epithelium coeliac disease, such novel therapies may final- dedifferentiation and dysfunction in coeliac ly provide a template for the treatment of other disease. Nonetheless, the inhibitory capacity of autoimmune diseases. the autoantibodies that are directed mainly to the amino- and carboxyterminal regions of tTG remains controversial. Acknowledgements
The author was supported by Deutsche For- Novel therapies and conclusions schungsgemeinschaft (Grant Schu 646/11-3), by the project QLK1-CT-1999-00037 of the European Due to tremendous recent advances, coeliac Union and the German Coeliac Association. dise ase could be considered the best under- stood HLA-linked disorder. The disease: i) is driven by a defined external (nutritional) trig- References ger, namely gluten proteins from wheat, rye and barley; ii) develops on the background of a 1. Trier JS. Celiac sprue. N Engl J Med 1991;325:1709- strong genetic association with HLA-DQ2/DQ8; 19. and iii) involves tTG as an autoantigen that 2. Schuppan D. Current concepts of celiac disease plays a key role in its pathogenesis, namely an- pathogenesis. Gastroenterology 2000;119:234-42. tigenic potentiation of gluten peptides. In ad- 3. Ciclitira PJ, King AL, Fraser JS. AGA technical re- dition, the amount of gluten ingested, the gene view on celiac sprue. American Gastroenterologi- cal Association. Gastroenterology 2001;120:1526- dose of HLA-DQ2 (DQ8) and the local expression 40. of tTG appear to be important determinants 4. Farrell RJ, Kelly CP. Celiac sprue. N Engl J Med of coeliac disease manifestation and severity. 2002;346:180-8. A sizable number of immunodominant gluten 5. Hardwick, C. Prognosis in coeliac disease. Arch peptides have been identified, part of them re- Dis Child 1939;14:279-89. sisting degradation by intestinal peptidases 6. Dicke WK, Weijers HA, van de Kamer JH. Coeliac and thus reaching the intestinal mucosa where disease. II. The presence in wheat of a factor hav- T-cells are recruited. Th1 cytokines released ing a deleterious effect in cases of coeliac disease. from these activated gluten-specific T-cells or Acta Paediatr 1953;42:34-42. from IEL cause the typical mucosal damage. 7. Van de Kamer JH, Weyers HA, Dicke WK. Coeliac An effective therapy of coeliac disease is ad- disease IV. An investigation into the injurious con- herence to a strictly gluten-free diet, a burden stituents of wheat in connection with their action for most patients. Therefore, alternative treat- on patients with coeliac disease. Acta Paediatr ments are being explored [101]. These include: 1953;42: 223-31. 1) degradation of immunodominant gliadin pep- 8. Paulley JW. Observation on the aetiology of idio- tides that resist intestinal proteases by use of pathic steatorrhoea; jejunal and lymph-node biop- exogenous bacterial prolyl endopeptidases [64, sies. Br Med J 1954;4900:1318-21. 9. Marsh MN. Gluten, major histocompatibility com- TG 67]; 2) inhibition of intestinal t activity by plex, and the small intestine: a molecular and im- specific inhibitors [102]; 3) inhibition of specif- munobiologic approach to the spectrum of gluten ic T-cell stimulation by peptides that only bind sensitivity (“celiac sprue”). Gastroenterology to HLA-DQ2 or -DQ8 DQ but not to the gluten pep- 1992; 102:330-54. tide-specific T-cell receptors [103], the targeted 10. Wong RC, Steele RH, Reeves GE, et al. Antibody design of such “inhibitors” being now feasible and genetic testing in coeliac disease. Pathology because of the successful crystallographic fine 2003;35:285-304.
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