Celiac Disease: Lessons for and from Chemical Biology - ACS

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Celiac Disease: Lessons for and from Chemical Biology Chaitan Khosla ACS Chem. Biol., Just Accepted Manuscript • DOI: 10.1021/acschembio.6b01155 • Publication Date (Web): 06 Feb 2017 Downloaded from http://pubs.acs.org on February 9, 2017

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Celiac Disease: Lessons for and from Chemical Biology Chaitan Khosla Stanford ChEM-H & Departments of Chemistry and Chemical Engineering Stanford University, Stanford CA 94305 [email protected] Abstract: Celiac disease is a lifelong immune disorder of the small intestine where inflammation is triggered by dietary gluten. There is an urgent need for the development of non-dietary therapies for this widespread but overlooked disease. More fundamentally, a molecular understanding of gluten-induced pathogenesis in celiac disease has the potential to provide new insights into mucosal immunology. Over the past two decades, three pathogenically critical molecules – gluten, TG2, and HLA-DQ2 – have served as focal points for collaborative efforts between biologists, chemists, engineers, and clinicians with an interest in celiac disease. This perspective summarizes a few examples of such multidisciplinary research directions with an emphasis on groundbreaking clinical studies that have profoundly informed the trajectory of subsequent molecular investigations. Examples of future challenges in fundamental and translational celiac disease research are also discussed. Introduction: Celiac disease is an inheritable immune disorder of the small intestine that affects 0.5-1% of most populations.1 In this lifelong condition, inflammation is triggered in genetically susceptible individuals by the ingestion of products containing gluten derived from wheat, rye or barley. As a consequence, a variety of gastrointestinal and extra-gastrointestinal symptoms are observed, such abdominal pain, malabsorption, anemia, failure to grow, osteoporosis and occasionally lymphoma. The only available treatment consists of complete and lifelong elimination of gluten from the patient’s diet. However, in most countries including the United States, gluten is a ubiquitous and unlabeled ingredient in food products, and is therefore extremely difficult to completely avoid. As a result, persistent symptoms and enteropathy are commonplace among celiac disease patients that attempt adherence to a gluten-free diet.2 There is thus an urgent need for new non-dietary therapies that improve patient health while ameliorating the rather severe dietary constraints. From a fundamental perspective, research into the pathogenesis of celiac disease offers a unique opportunity to elucidate basic mechanisms governing the health of mucosal lining of the small intestine.3 Gluten induces a characteristic HLA-DQ2 mediated T cell response in the small intestinal mucosa, leading to crypt hyperplasia and villous atrophy (Figure 1). In addition, patients ingesting gluten also have circulating disease-specific autoantibodies derived from B cells that recognize the enzyme transglutaminase 2 (TG2). Strikingly, both the intestinal lesions and the autoantibodies are reversibly dependent on oral gluten exposure. A molecular understanding of gluten-induced pathogenesis will therefore likely provide new insights into how the intestinal epithelium and its underlying immune system interact with each other with implications beyond celiac disease. Molecular advances with translational implications: Over the past two decades, three pathogenically critical molecules – gluten, TG2, and HLA-DQ2 (Figure 2) – have served as focal points for intensive collaborative efforts between biologists, chemists, engineers, and clinicians with an interest in celiac disease. Two examples of such multidisciplinary research directions are summarized below. Dietary gluten is comprised of a number of homologous proteins called gliadins and glutenins in wheat, hordeins in barley, and secalins in rye. Each of these proteins harbors multiple disease-specific T-cell epitopes.4 A common feature of these epitopes is the relative

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abundance of Pro and Gln residues. Although gastric and pancreatic proteases, such as pepsin, trypsin, chymotrypsin and elastase, are touted as poster-children of the awesome catalytic prowess of enzymes, the high Pro content of gluten-derived proteins renders large stretches of their sequences resistant to cleavage by these otherwise potent proteases.5 (It also contributes to the well-known adhesivity of gluten.) As a consequence, the concentration of certain antigenic peptides builds up (possibly in the range of 0.1 mM) in the upper intestinal lumen following ingestion of a typical meal harboring ~10 g gluten.6 This inherent proteolytic resistance of gluten sets the stage for a deranged HLA-DQ2 mediated inflammatory T cell response in individuals with the appropriate genetic background. Decoding this fundamental characteristic of what is ordinarily the most abundant protein in the human diet not only represented a significant advance at the chemistry-immunology interface but also paved the way for the discovery, scaleup, and ongoing clinical development of latiglutenase, an experimental oral enzyme therapy comprised of a fixed dose mixture of two proteases.2,7,8 More recently, a monoclonal antibody capable of sensitively and specifically detecting a protease-resistant and highly immunogenic gluten peptide has been commercialized, and subsequently used to develop assays for detecting inadvertent gluten consumption,9,10 thereby highlighting a potentially practical means for improved dietary compliance by celiac disease patients. Transglutaminase 2 (TG2) is a ubiquitous but non-essential protein in mammals.11 Its relationship to celiac disease pathogenesis (Figure 2) became apparent nearly two decades ago as a result of two more or less contemporaneous observations. First, TG2 was identified as the principal antigen recognized by disease-specific autoantibodies in the serum of patients with active celiac disease.12 Second, it was observed that, in order for the T cell epitopes from gluten to be recognized as high affinity ligands by HLA-DQ2, they must undergo post-translational modifications at selected Gln residues via TG2-catalyzed deamidation.13,14 While the mechanistic relationship between these two insights remains to be established, together they spawned the hypothesis that pre-systemic inhibition of TG2 in the small intestine may represent a viable non-dietary modality for celiac disease therapy. A number of investigators have independently engineered lead inhibitors against this cysteine protease-like enzyme.15 However, identification of appropriate cellular and animal models for pharmacological evaluation of these inhibitors turned out to be considerably more challenging than anticipated. An unexpected finding that enabled progress in this regard was the observation that an allosteric disulfide bond maintains extracellular TG2 in a catalytically inactive state in the intestine.16,17 This in turn led to a search for molecular factors capable of inducing TG2 activity.18 A growing number of inflammatory signals have been identified that induce extracellular TG2 activity in the small intestine,19,20,21 although their relevance to celiac disease remains to be definitively established. Notwithstanding this uncertainty, they offer pharmacologically essential models for structureactivity analysis of medicinally relevant TG2 inhibitors. Between the bench and the bedside: As in all translational research pursuits, the role of clinician-scientists has been critical to virtually every endeavor that has aspired to meaningfully connect discoveries at the molecular level to the clinical management of celiac disease. The relationship between the chemist and the clinician, which typically traces its roots to the college classroom, is deep but not especially strong. Re-establishing those connections in the context of unsolved mysteries in medicine is not only gratifying but also essential. A number of groundbreaking clinical studies on celiac disease patients have profoundly informed the trajectory of investigations into the molecular basis of this disorder. Going back to the 1950s, Frazer and colleagues made the seminal observation that a partially hydrolyzed and fractionated form of wheat gluten, known as Frazer’s Fraction III, was sufficient to induce active disease in well controlled patients on a gluten-free diet.22 This seemingly simple study transformed the primary environmental trigger of celiac disease from an insoluble and


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intractable mess into a soluble, chemically definable material, while also unambiguously establishing that the pathogenicity of gluten proteins did not result from their tertiary structures. Decades later, the bedside-to-bench research of Sollid and collaborators established that celiac disease was associated with HLA-DQ2.23 At that time there were very few established HLAassociated diseases, so this in itself was a significant achievement, but it was only the beginning. The same group of investigators went on to isolate and characterize disease-specific T cells from the intestinal mucosa of celiac patients,24 and to demonstrate that gluten modification by TG2 was critical for high-affinity epitope recognition.13 In contemporaneous clinical studies spanning several decades, Maki and colleagues investigated the natural history of celiac disease in adults,25 along with an analysis of the benefits of gluten exclusion in these patients regardless of symptoms.26 Their findings paved the way for the emergence of a powerful protocol for a short, biopsy-based clinical trial of experimental therapeutics targeted at this disease.8 The importance of simple proof-of-concept protocols for randomized controlled clinical trials in diseases for which no drug therapy exists cannot be over-emphasized. The logic is painfully obvious; if a drug candidate with uncertain efficacy is to be clinically tested via an unvalidated protocol, the risk of failure is considerably higher. In contrast to lengthy pivotal trials that must demonstrate the ability of an experimental therapeutic to improve clinically relevant disease outcomes, early clinical studies on experimental therapies targeting new modes of action are typically designed to obtain preliminary evidence in support of both the mode of action and the drug candidate. The availability of a quantitative biomarker for rapid assessment of drug efficacy in relatively small numbers of patients is therefore of vital importance, especially in diseases that represent new frontiers for drug development. The lack of objective, quantitative, and minimally invasive biomarkers for measuring relatively minor changes in the small intestinal health of celiac disease patients motivated us to launch an effort nearly a decade ago to change status quo. In humans, the widely used cholesterol-lowering drug simvastatin is primarily metabolized by cytochrome P450 3A4 (CYP3A4) in the small intestinal epithelium.27 Within this monolayer of cells (Figure 1), CYP3A4 expression is highest near the villous tips, decreasing markedly near the crypts. When villous atrophy develops in patients with celiac disease, the expression and activity of intestinal CYP3A4 is reduced.28 We therefore hypothesized that the maximum serum concentration (Cmax) of simvastatin following a single oral dose of this drug could potentially be used as a noninvasive marker of intestinal health. To test the hypothesis, celiac disease patients and healthy volunteers were studied.29 The mean Cmax in untreated patients was significantly higher than that in healthy subjects. Moreover, all patients who had an abnormally high Cmax at the first follow-up visit showed a marked reduction after one additional year on a gluten-free diet. Markers such as simvastatin Cmax may therefore be a useful alternative to multiple invasive biopsies in future proof-of-concept clinical trials of experimental therapeutics for celiac disease. Future directions: Amongst human autoimmune conditions with a strong HLA association, celiac disease is perhaps the only disorder where the principal environmental trigger has been identified and chemically characterized. As such, it remains an attractive topic for collaborative research in chemical biology. Below I highlight a few examples of outstanding challenges with considerable translational potential. Although the T cell epitopes in gluten have been extensively characterized,4 the mechanism by which they gain access to sub-epithelial antigen presenting cells is not understood. (Indeed, as outlined in Figure 2, it is not even clear whether the encounter between antigenic gluten peptides and T cells occurs on the luminal side or the serosal side of the intestinal epithelium.) A variety of possibilities, ranging from passive paracellular transport across inter-epithelial tight junctions to receptor-mediated uptake by enterocytes or specialized cells in the intestinal epithelium, deserve consideration. Preliminary studies lend support to both types of models.30,31



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Regardless of the actual mechanism, its elucidation will almost certainly shine light on an unprecedented process for the transport of intact peptides from the gut lumen to the subepithelial vasculature. Not only would such a process have broader physiological implications beyond celiac disease, but it could also be harnessed for oral drug delivery of substances that fall completely outside the scope of Lipinski’s rules.32 Whereas the roles of gluten and HLA-DQ2 (or infrequently HLA-DQ8) as the most important environmental and genetic causes, respectively, of celiac disease are well understood, it is also abundantly clear that other genetic33 and environmental34 factors play significant roles in disease onset. At the genetic level, more than 40 non-HLA disease associated loci have been identified thus far, yet none of them have led to a patho-mechanistic picture that is anywhere as clear as that surrounding HLA-DQ2. The situation is complicated by the fact that the vast majority of disease related alleles are in non-coding regions of the human genome. Nonetheless, any of these genetic clues could present an entirely new window into the onset, severity, or clinical heterogeneity of celiac disease. With respect to environmental factors beyond dietary gluten, the list of potential culprits is seemingly endless. Generally speaking, prenatal or perinatal exposures along with microbial or viral infections are among the most plausible contributors. Their discovery, along with an understanding of their interplay with gluten and inheritable factors, holds the promise of yet another fascinating chapter in our understanding of celiac disease. Perhaps the most significant translational advances in the foreseeable future will likely be the development of prototypical animal models for celiac disease. Not only does the absence of a suitable animal model present a major obstacle in structure-activity relationship (SAR) analysis of new drug candidates, but it also limits the ability to preclinically validate novel targets for drug discovery. Rational engineering of such an animal model is by no means a trivial task, as it must capture at least three essential features of the disease – its dependence on dietary gluten in an appropriate HLA background, the reversible occurrence of villous atrophy in response to introducing gluten into the diet of the animal, and the reversible appearance of antiTG2 autoantibodies in response to dietary gluten. Recent progress in translating our understanding of disease pathogenesis into a mouse model of celiac disease is encouraging in this regard.35 In conclusion, notwithstanding the fact that celiac disease remains an example of a lifelong chronic disorder for which no drug therapies are available, it has been a vivid example of the power of collaborative research at the chemistry-biology interface. One can only hope that, over the next decade, the celiac patient will start to reap the benefits of the scientific advances that have emerged as a result of this collaborative spirit. Acknowledgments This article is dedicated to the author’s coworkers and collaborators. Research on celiac disease in the author’s laboratory has been supported by a grant from the NIH (R01 DK063158). References 1) Rubio-Tapia, A, Murray, JA (2010) Celiac disease. Curr. Opin. Gastroenterol. 26, 116–122. 2) Murray JA, Kelly CP, Green PHR, Marcantonio A, Wu T-T, Mäki M, Adelman, DC, on behalf of the CeliAction Study® Group of Investigators (2016) No difference between latiglutenase and placebo in reducing villous atrophy or improving symptoms in patients with symptomatic celiac disease. Gastroenterology doi: 10.1053/j.gastro.2016.11.004. 3) Jabri, B, Sollid, LM (2009) Tissue-mediated control of immunopathology in coeliac disease. Nat. Rev. Immunol. 9, 858–870.


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4) Sollid, LM, Wang S-W, Anderson, RP, Gianfrani, C, Koning, F (2012) Nomenclature and listing of celiac disease relevant gluten T-cell epitopes restricted by HLA-DQ molecules. Immunogenetics 64, 455-460. 5) Shan, L, Molberg, Ø, Parrot, I, Hausch, F, Filiz, F, Gray, GM, Sollid, LM, Khosla, C (2002) Structural basis for gluten intolerance in celiac sprue. Science 297, 2275–2279. 6) Piper JL, Gray GM, Khosla C (2004) Effect of prolyl endopeptidase on digestive-resistant gliadin peptides in vivo. J. Pharmacol. Exp. Therap. 311, 213-219. 7) Bethune, MT, Khosla, C (2012) Oral enzyme therapy for celiac sprue. Methods Enzymol. (Eds: K.D. Wittrup and G.L. Verdine) 502, 241-271. 8) Lahdeaho ML, Kaukinen K, Laurila K, Vuotikka, P, Koivurova, O-P, Karja-Lahdensuu, T, Marcantonio, A, Adelman, DC, Maki, M (2014) Glutenase ALV003 attenuates gluten induced mucosal injury in patients with celiac disease. Gastroenterology 146, 1649-1658. 9) Soler, MM, Estevez, MC, Moreno, ML, Cebolla, A, Lechuga, LM (2016) Label-free SPR detection of gluten peptides in urine for non-invasive celiac disease follow-up. Biosens. Bioelectron. 79, 158-164. 10) Comino, I, Fernandez-Banares, F, Esteve, M, Ortigosa, L, Castillejo, G, Fambuena, B, Ribes-Koninckx, C, Sierra, C, Rodriguez-Herrera, A, Salazar, JC, Caunedo, A, MaruganMiguelsanz, JM, Garrote, JA, Vivas, S, lo Iacono, O, Nunez, A, Vaquero, L, Vegas, AM, Crespo, L, Fernandez-Salazar, L, Arranz, E, Jimenez-Garcia, VA, Montes-Cano, MA, Espin, B, Galera, A, Valverde, J, Giron, FJ, Bolonio, M, Milan A, Cerezo, FM Guajardo, C, Alberto, JR, Rosinach, M, Segura, V, Leon, F, Marinich, J, Munoz-Suano, A, Romero-Gomez, M, Cebolla, A, Sousa, C (2016) Fecal gluten peptides reveal limitations of serological tests and food questionnaires for monitoring gluten-free diet in celiac disease patients. Am. J. Gastroenterol. 111, 1456-1465. 11) Klöck, C, Khosla, C (2012) Regulation of the mammalian transglutaminase family of enzymes. Prot. Sci. 21, 1781-1791. 12) Dieterich, W, Ehnis, T, Bauer, M, Donner, P, Volta, U, Riecken, EO, Schuppan, D (1997) Identification of tissue transglutaminase as the autoantigen of celiac disease. Nature Med. 3, 797-801. 13) Molberg, Ø, McAdam, SN, Körner, R, Quarsten, H, Kristiansen, C, Madsen, L, Fugger, L, Scott, H, Noren, O, Roepstorff, P, Lundin, KEA, Sjöström, H, Sollid, LM. (1998) Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nature Med. 4, 713-717. 14) van de Wal, Y, Kooy, YM, van Veelen, PA, Peña, SA, Mearin, LM, Molberg, Ø, Lundin, KEA, Sollid, LM, Mutis, T, Benckhuijsen, WE, Drijfhout, JW, Koning, F. (1998) Small intestinal T cells of celiac disease patients recognize a natural pepsin fragment of gliadin. Proc Natl Acad Sci USA. 95, 10050-10054. 15) Keillor, JW, Apperley, KY (2016) Transglutaminase inhibitors: a patent review. Expert Opin. Ther. Pat. 26, 49-63. 16) Pinkas, DM, Strop, P, Brunger, AT, Khosla, C (2007). Transglutaminase 2 undergoes a large conformational change upon activation. PLoS Biol. 5, 2788–2796. 17) Stamnaes, J, Pinkas, DM, Fleckenstein, B, Khosla, C, Sollid, LM (2010) Redox regulation of transglutaminase 2 activity. J. Biol. Chem. 285, 25402-25409. 18) Jin, X, Stamnaes, J, Klöck, C, DiRaimondo, TR, Sollid, LM, Khosla, C. (2011) Activation of extracellular transglutaminase 2 by thioredoxin. J. Biol. Chem. 286, 37866-37873. 19) Siegel, M, Strnad, P, Watts, RE, Choi, K, Jabri, B, Omary, MB, Khosla, C (2008) Extracellular transglutaminase 2 is catalytically inactive but is transiently activated upon tissue injury. PLoS One 3, e1861 20) Plugis, NM, Palanski, BA, Weng, CH, Albertelli, M, Khosla, C (2017) Thioredoxin-1 selectively activates transglutaminase 2 in the extracellular matrix of the small intestine: Implications for celiac disease. J. Biol. Chem. In press.



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21) Bouziat, R, Hinterleitner, R, Brown, JJ, Stencel-Baerenwald, JE, Ikizler, M, Mayaasi, T, Meisel, M, Kim, SM, Discepolo, V, Pruijssers, AJ, Ernest, JD, Iskarpatyoti, JA, Costes, LMM, Lawrence, I, Palanski, BA, Varma, M, Zurenski, MA, Khomandiak, S, McAllister, N, Aravamudhan, P, Boehme, KW, Hu, F, Samsom, JN, Reinecker, HC, Kupfer, SS, Guandalini, S, Semrad, C, Abadie, V, Khosla, C, Barreiro, LB, Xavier, RJ, Ng, N, Dermody, TS, Jabri, B (2017) Reovirus infection breaks tolerance to dietary antigens and promotes development of celiac disease. Science In press. 22) Frazer, AC, Fletcher, RF, Ross, CAC, Shaw, B, Sammons, HG, Schneider, R (1959) Gluten-induced enteropathy: The effect of partially digested gluten. Lancet 252-255. 23) Sollid, LM, Markussen, G, Ek, J, Gjerde, H, Vartdal, F, Thorsby, E (1989) Evidence for a primary association of celiac disease to a particular HLA-DQ alpha/beta heterodimer. J. Exp. Med. 169, 345-350. 24) Lundin, KE, Scott, H, Hansen, T, Paulsen, G, Halstensen, TS, Fausa, O, Thorsby, E, Sollid, LM (1993) Gliadin-specific, HLA-DQ(alpha1*0501, beta1*0201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients. J. Exp. Med. 178, 187-196. 25) Maki, M, Holm, K (1990) Incidence and prevalence of celiac disease in Tampere. Acta Paediatr. Scand. 79, 980-982. 26) Kurppa, K, Paavola, A, Collin, P, Sievanen, H, Laurila, K, Huhtala, H, Saavalainen, P, Maki, M, Kaukinen, K (2014) Benefits of a gluten-free diet for asymptomatic patients with serologic markers of celiac disease. Gastroenterology 147, 610-617. 27) Lilja, JJ, Kivisto, KT, Neuvonen, PJ (1998) Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther. 64, 477–83. 28) Lang, CC, Brown, RM, Kinirons, MT, Deathridge, MA, Guengerich, FP, Kelleher, D, O’Briain, S, Ghishan, FK, Wood, AJJ. (1996) Decreased intestinal CYP3A in celiac disease: reversal after successful gluten-free diet: a potential source of interindividual variability in firstpass drug metabolism. Clin Pharmacol Ther. 59, 41–46. 29) Moron, B, Verma, AK, Das, P, Taavela, J, Dafik, L, DiRaimondo, TR, Albertelli, MA, Kraemer, T, Maki, M, Khosla, C, Rogler, G, Makharia, GK (2013) CYP3A4-catalyzed simvastatin metabolism as a non-invasive marker of small intestinal health in celiac disease. Am. J. Gastroenterol. 108, 1344-1351. 30) DiRaimondo, TR, Klöck, C, Khosla, C (2012) Interferon-γ activates transglutaminase 2 via phosphatidylinositol-3-kinase dependent pathway: Implications for celiac sprue therapy. J. Pharmacol. Exp. Ther. 341, 104-114. 31) Menard, S, Lebreton, C, Schumann, M, Matysiak-Budnik, T, Dugave, C, Bouhnik, Y, Malamut, G, Cellier, C, Allez, M, Crenn, P, Schulzke, JD, Cerf-Bensussan, N, Heyman, M (2012) Paracellular versus transcellular intestinal permeability to gliadin peptides in active celiac disease. Am. J. Pathol. 180, 608-615. 32) Lipinski, CA, Lombardo, F, Dominy, BW, Feeney, PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 46, 3-26. 33) Withoff, S, Li, Y, Jonkers, I, Wijmenga, C (2016) Understanding celiac disease by genomics. Trends Genet. 32, 295-308. 34) Lebwohl, B, Murray, JA, Verdu, EF, Crowe, SE, Dennis, M, Fasano, A, Green, PHR, Guandalini, S, Khosla, C (2016) Gluten introduction, breastfeeding, and celiac disease: Back to the drawing board. Am. J. Gastroenterol. 111, 12-14. 35) DePaolo, RW, Abadie, V, Tang, F, Fehlner-Peach, H, Hall, JA, Wang, W, Marietta, EV, Kasarda, DD, Waldmann, TA, Murray, JA, Semrad, C, Kupfer, SS, Belkaid, Y, Guandalini, S, Jabri, B (2011) Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471, 220-225.


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Figure 1: Small intestinal damage in celiac disease: The upper panel shows light microscopic image of a small intestinal biopsy specimen taken from a normal individual, and stained with hematoxylin and eosin (H&E). It reveals typical mucosal morphology including finger-like villi (0.5-1 mm long, 20-40 per mm2) separated by smaller crypts. The villous structure of the small intestine vastly increases the surface area of the epithelium available for digestion and absorption. The lower panel shows a small bowel biopsy specimen from a newly diagnosed celiac disease patient where exposure to dietary gluten has induced villous atrophy and crypt hyperplasia. It results in a greatly reduced intestinal surface area. (Courtesy M. Maki)



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Figure 2: Molecular pathogenesis of celiac disease: Proteolytically resistant, Pro- and Gln-rich peptides derived from gluten accumulate in the gut lumen. By themselves, these peptides are weak antigens. However, their affinity for HLA-DQ2 (or occasionally HLA-DQ8) is markedly enhanced by TG2-catalyzed Gln Glu conversion of selected residues. The resulting peptideDQ2 complexes activate inflammatory Th1 cells, which presumably provide help to B cells capable of producing anti-TG2 antibodies. This gluten-induced immune response leads to villous atrophy and crypt hyperplasia in the small intestine of celiac disease patients.


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