Abstract
Refractory celiac disease is defined by the persistence of symptoms of malnutrition and intestinal villous atrophy for more than 6–12 months despite strict gluten-free diet in celiac patients. Diagnosis of this rare condition is made after excluding other causes of chronic small intestinal inflammation and villous atrophy and inadvertent intake of gluten. Over the past 15 years, multidisciplinary approaches have been developed to assess the mechanism of resistance to the diet, and two distinct entities have been delineated. Type II refractory celiac disease (RCD) can be defined as a low-grade intraepithelial lymphoma. RCD II is characterised by a massive accumulation of abnormal IEL that display an aberrant hybrid NK/T cell phenotype, contain clonal T cell rearrangement(s) and can mediate a cytolytic attack of the gut epithelium. This condition has a severe prognosis, largely due to the frequent transformation of RCDII IEL into overt aggressive enteropathy-type-associated T cell lymphoma. In contrast, in type I RCD, intestinal lymphocytes have a normal phenotype, and this generally milder condition remains often difficult to differentiate from uncomplicated CD except for the resistance to gluten-free diet (GFD). Several mechanisms may underlie resistance to gluten. Herein, we review the distinctive characteristics of RCD I and RCD II, the mechanisms underlying the onset of resistance to GFD, the risk of developing high grade lymphoma and possible clues to improve their treatment.
Similar content being viewed by others
References
Meresse B, Malamut G, Cerf-Bensussan N (2012) Celiac disease: an immunological jigsaw. Immunity 36(6):907–915
Vahedi K, Mascart F, Mary JY, Laberenne JE, Bouhnik Y, Morin MC, Ocmant A, Velly C, Colombel JF, Matuchansky C (2003) Reliability of antitransglutaminase antibodies as predictors of gluten-free diet compliance in adult celiac disease. Am J Gastroenterol 98(5):1079–1087
Akram S, Murray JA, Pardi DS, Alexander GL, Schaffner JA, Russo PA, Abraham SC (2007) Adult autoimmune enteropathy (2007) Mayo clinic rochester experience. Clin Gastroenterol Hepatol 5(11):1282–1290
Malamut G, Verkarre V, Suarez F, Viallard JF, Lascaux AS, Cosnes J, Bouhnik Y, Lambotte O, Bechade D, Ziol M, Lavergne A, Hermine O, Cerf-Bensussan N, Cellier C (2010) The enteropathy associated with common variable immunodeficiency: the delineated frontiers with celiac disease. Am J Gastroenterol 105(10):2262–2275
Carbonnel F, d’Almagne H, Lavergne A, Matuchansky C, Brouet JC, Sigaux F, Beaugerie L, Nemeth J, Coffin B, Cosnes J, Gendre JP, Rambaud JC (1999) The clinicopathological features of extensive small intestinal CD4 T cell infiltration. Gut 45(5):662–667
Khokhar N, Gill ML (2004) Tropical sprue: revisited. J Pak Med Assoc 54(3):133–134
Malamut G, Afchain P, Verkarre V, Lecomte T, Amiot A, Damotte D, Bouhnik Y, Colombel JF, Delchier JC, Allez M, Cosnes J, Lavergne-Slove A, Meresse B, Trinquart L, Macintyre E, Radford-Weiss I, Hermine O, Brousse N, Cerf-Bensussan N, Cellier C (2009) Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II. Gastroenterology 136(1):81–90
Rubio-Tapia A, Kelly DG, Lahr BD, Dogan A, Wu TT, Murray JA (2009) Clinical staging and survival in refractory celiac disease: a single center experience. Gastroenterology 136(1):99–107
Green PH, Cellier C (2007) Celiac disease. N Engl J Med 357(17):1731–1743
Cellier C, Patey N, Mauvieux L, Jabri B, Delabesse E, Cervoni JP, Burtin ML, Guy-Grand D, Bouhnik Y, Modigliani R, Barbier JP, Macintyre E, Brousse N, Cerf-Bensussan N (1998) Abnormal intestinal intraepithelial lymphocytes in refractory sprue. Gastroenterology 114(3):471–481
Cellier C, Delabesse E, Helmer C, Patey N, Matuchansky C, Jabri B, Macintyre E, Cerf-Bensussan N, Brousse N, French Coeliac Disease Study Group (2000) Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. Lancet 356(9225):203–208
Cerf-Bensussan N, Jarry A, Brousse N, Lisowska-Grospierre B, Guy-Grand D, Griscelli C (1987) A monoclonal antibody (HML-1) defining a novel membrane molecule present on human intestinal lymphocytes. Eur J Immunol 17(9):1279–1285
Cepek KL, Shaw SK, Parker CM, Russell GJ, Morrow JS, Rimm DL, Brenner MB (1994) Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the alpha E beta 7 integrin. Nature 372:190–193
Hue S, Mention JJ, Monteiro RC, Zhang S, Cellier C, Schmitz J, Verkarre V, Fodil N, Bahram S, Cerf-Bensussan N, Caillat-Zucman S (2004) A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 21(3):367–377
Verkarre V, Asnafi V, Lecomte T, Patey Mariaud-de Serre N, Leborgne M, Grosdidier E, Le Bihan C, Macintyre E, Cellier C, Cerf-Bensussan N, Brousse N (2003) Refractory coeliac sprue is a diffuse gastrointestinal disease. Gut 52(2):205–211
Perfetti V, Brunetti L, Biagi F, Ciccocioppo R, Bianchi PI, Corazza GR (2012) TCR beta clonality improves diagnostic yield of TCRgamma clonality in refractory celiac disease. J Clin Gastroenterol. doi:10.1097/MCG.0b013e31823eff20
Isaacson P, Wright DH (1978) Malignant histiocytosis of the intestine. Its relationship to malabsorption and ulcerative jejunitis. Hum Pathol 9(6):661–677
Mubarak A, Oudshoorn JH, Kneepkens CM, Butler JC, Schreurs MW, Mulder CJ, Houwen RH (2011) A child with refractory coeliac disease. J Pediatr Gastroenterol Nutr 53(2):216–218
West J (2009) Celiac disease and its complications: a time traveller's perspective. Gastroenterology 136(1):32–34
Roshan B, Leffler DA, Jamma S, Dennis M, Sheth S, Falchuk K, Najarian R, Goldsmith J, Tariq S, Schuppan D, Kelly CP (2011) The incidence and clinical spectrum of refractory celiac disease in a north american referral center. Am J Gastroenterol 106(5):923–928
Daum S, Ipczynski R, Schumann M, Wahnschaffe U, Zeitz M, Ullrich R (2009) High rates of complications and substantial mortality in both types of refractory sprue. Eur J Gastroenterol Hepatol 21(1):66–70
Al-Toma A, Verbeek WH, Hadithi M, von Blomberg BM, Mulder CJ (2007) Survival in refractory coeliac disease and enteropathy associated T cell lymphoma: retrospective evaluation of single centre experience. Gut 56(10):1373–1378
Cottone M, Termini A, Oliva L, Magliocco A, Marrone C, Orlando A, Pinzone F, Di Mitri R, Rosselli M, Rizzo A, Pagliaro L (1999) Mortality and causes of death in celiac disease in a Mediterranean area. Dig Dis Sci 44(12):2538–2541
Corrao G, Corazza GR, Bagnardi V, Brusco G, Ciacci C, Cottone M, Sategna Guidetti C, Usai P, Cesari P, Pelli MA, Loperfido S, Volta U, Calabro A, Certo M (2001) Mortality in patients with coeliac disease and their relatives: a cohort study. Lancet 358(9279):356–361
Askling J, Linet M, Gridley G, Halstensen TS, Ekstrom K, Ekbom A (2002) Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis. Gastroenterology 123(5):1428–1435
Verbeek WH, Van De Water JM, Al-Toma A, Oudejans JJ, Mulder CJ, Coupe VM (2008) Incidence of enteropathy-associated T-cell lymphoma: a nation-wide study of a population-based registry in the Netherlands. Scand J Gastroenterol 43(11):1322–1328
Sharaiha RZ, Lebwohl B, Reimers L, Bhagat G, Green PH, Neugut AI (2012) Increasing incidence of enteropathy-associated T-cell lymphoma in the United States, 1973–2008. Cancer. doi:10.1002/cncr.26700
Telega G, Bennet TR, Werlin S (2008) Emerging new clinical patterns in the presentation of celiac disease. Arch Pediatr Adolesc Med 162(2):164–168
Green PH (2009) Mortality in celiac disease, intestinal inflammation, and gluten sensitivity. Jama 302(11):1225–1226
Deleeuw RJ, Zettl A, Klinker E, Haralambieva E, Trottier M, Chari R, Ge Y, Gascoyne RD, Chott A, Muller-Hermelink HK, Lam WL (2007) Whole-genome analysis and HLA genotyping of enteropathy-type T-cell lymphoma reveals 2 distinct lymphoma subtypes. Gastroenterology 132(5):1902–1911
Tio M, Cox MR, Eslick GD, Meta-analysis (2012) Coeliac disease and the risk of all-cause mortality, any malignancy and lymphoid malignancy. Aliment Pharmacol Ther 35(5):540–551
Spencer J, Cerf-Bensussan N, Jarry A, Brousse N, Guy-Grand D, Krajewski AS, Isaacson PG (1988) Enteropathy-associated T cell lymphoma (malignant histiocytosis of the intestine) is recognized by a monoclonal antibody (HML-1) that defines a membrane molecule on human mucosal lymphocytes. Am J Pathol 132(1):1–5
Verkarre V, Romana SP, Cellier C, Asnafi V, Mention JJ, Barbe U, Nusbaum S, Hermine O, Macintyre E, Brousse N, Cerf-Bensussan N, Radford-Weiss I (2003) Recurrent partial trisomy 1q22-q44 in clonal intraepithelial lymphocytes in refractory celiac sprue. Gastroenterology 125(1):40–46
Malamut G, Verkarre V, Meresse B, Macintyre E, Brousse N, Cerf-Bensussan N, Cellier C (2008) High rate of abnormal intestinal intraepithelial lymphocytes is predictive of extra-digestive diffusion in refractory coeliac disease. (Abstract) Gut 57(suppl II):A 30
Egan LJ, Walsh SV, Stevens FM, Connolly CE, Egan EL, McCarthy CF (1995) Celiac-associated lymphoma. A single institution experience of 30 cases in the combination chemotherapy era. J Clin Gastroenterol 21(2):123–129
Gale J, Simmonds PD, Mead GM, Sweetenham JW, Wright DH (2000) Enteropathy-type intestinal t-cell lymphoma: clinical features and treatment of 31 patients in a single center. J Clin Oncol 18(4):795–803
Daum S, Ullrich R, Heise W, Dederke B, Foss HD, Stein H, Thiel E, Zeitz M, Riecken EO (2003) Intestinal non-Hodgkin's lymphoma: a multicenter prospective clinical study from the german study group on intestinal non-Hodgkin's lymphoma. J Clin Oncol 21(14):2740–2746
Malamut G, Chandesris O, Verkarre V, Macintyre E, Brousse N, Meresse B, Bouhnik Y, Allez M, Berger A, Jian R, Cerf-Bensussan N, Hermine O, Cellier C (2010) Tumour mass reduction surgery improves the prognosis of enteropathy associated T cell lymphoma. (Abstract) Gastroenterology 138 (6) (suppl 1)
Howell MD, Austin RK, Kelleher D, Nepom GT, Kagnoff MF (1986) An HLA-D region restriction fragment length polymorphism associated with celiac disease. J Exp Med 164(1):333–338
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(1):345–350
Fallang LE, Bergseng E, Hotta K, Berg-Larsen A, Kim CY, Sollid LM (2009) Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation. Nat Immunol 10(10):1096–1101
Sollid LM, Qiao SW, Anderson RP, Gianfrani C, Koning F (2012) Nomenclature and listing of celiac disease relevant gluten T-cell epitopes restricted by HLA-DQ molecules. Immunogenetics64 (6):455–460
Abadie V, Sollid LM, Barreiro LB, Jabri B (2011) Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Annu Rev Immunol 29:493–525
Vader W, Stepniak D, Kooy Y, Mearin L, Thompson A, van Rood JJ, Spaenij L, Koning F (2003) The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses. Proc Natl Acad Sci U S A 100(21):12390–12395
Al-Toma A, Goerres MS, Meijer JW, Pena AS, Crusius JB, Mulder CJ (2006) Human leukocyte antigen-DQ2 homozygosity and the development of refractory celiac disease and enteropathy-associated T-cell lymphoma. Clin Gastroenterol Hepatol 4(3):315–319
Smyth DJ, Plagnol V, Walker NM, Cooper JD, Downes K, Yang JH, Howson JM, Stevens H, McManus R, Wijmenga C, Heap GA, Dubois PC, Clayton DG, Hunt KA, van Heel DA, Todd JA (2008) Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med 359(26):2767–2777
Hunt KA, Zhernakova A, Turner G, Heap GA, Franke L, Bruinenberg M, Romanos J, Dinesen LC, Ryan AW, Panesar D, Gwilliam R, Takeuchi F, McLaren WM, Holmes GK, Howdle PD, Walters JR, Sanders DS, Playford RJ, Trynka G, Mulder CJ, Mearin ML, Verbeek WH, Trimble V, Stevens FM, O'Morain C, Kennedy NP, Kelleher D, Pennington DJ, Strachan DP, McArdle WL, Mein CA, Wapenaar MC, Deloukas P, McGinnis R, McManus R, Wijmenga C, van Heel DA (2008) Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet 40(4):395–402
Dubois PC, Trynka G, Franke L, Hunt KA, Romanos J, Curtotti A, Zhernakova A, Heap GA, Adany R, Aromaa A, Bardella MT, van den Berg LH, Bockett NA, de la Concha EG, Dema B, Fehrmann RS, Fernandez-Arquero M, Fiatal S, Grandone E, Green PM, Groen HJ, Gwilliam R, Houwen RH, Hunt SE, Kaukinen K, Kelleher D, Korponay-Szabo I, Kurppa K, MacMathuna P, Maki M, Mazzilli MC, McCann OT, Mearin ML, Mein CA, Mirza MM, Mistry V, Mora B, Morley KI, Mulder CJ, Murray JA, Nunez C, Oosterom E, Ophoff RA, Polanco I, Peltonen L, Platteel M, Rybak A, Salomaa V, Schweizer JJ, Sperandeo MP, Tack GJ, Turner G, Veldink JH, Verbeek WH, Weersma RK, Wolters VM, Urcelay E, Cukrowska B, Greco L, Neuhausen SL, McManus R, Barisani D, Deloukas P, Barrett JC, Saavalainen P, Wijmenga C, van Heel DA (2010) Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42(5):295–302
Trynka G, Hunt KA, Bockett NA, Romanos J, Mistry V, Szperl A, Bakker SF, Bardella MT, Bhaw-Rosun L, Castillejo G, de la Concha EG, de Almeida RC, Dias KR, van Diemen CC, Dubois PC, Duerr RH, Edkins S, Franke L, Fransen K, Gutierrez J, Heap GA, Hrdlickova B, Hunt S, Izurieta LP, Izzo V, Joosten LA, Langford C, Mazzilli MC, Mein CA, Midah V, Mitrovic M, Mora B, Morelli M, Nutland S, Nunez C, Onengut-Gumuscu S, Pearce K, Platteel M, Polanco I, Potter S, Ribes-Koninckx C, Ricano-Ponce I, Rich SS, Rybak A, Santiago JL, Senapati S, Sood A, Szajewska H, Troncone R, Varade J, Wallace C, Wolters VM, Zhernakova A, Thelma BK, Cukrowska B, Urcelay E, Bilbao JR, Mearin ML, Barisani D, Barrett JC, Plagnol V, Deloukas P, Wijmenga C, van Heel DA (2011) Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat Genet 43(12):1193–1201
Fina D, Sarra M, Caruso R, Del Vecchio BG, Pallone F, MacDonald TT, Monteleone G (2008) Interleukin 21 contributes to the mucosal T helper cell type 1 response in coeliac disease. Gut 57(7):887–892
Bodd M, Raki M, Tollefsen S, Fallang LE, Bergseng E, Lundin KE, Sollid LM (2010) HLA-DQ2 restricted gluten-reactive T cells produce IL-21 but not IL-17 or IL-22. Mucosal Immunol 3(6):594–601
Zeng R, Spolski R, Finkelstein SE, Oh S, Kovanen PE, Hinrichs CS, Pise-Masison CA, Radonovich MF, Brady JN, Restifo NP, Berzofsky JA, Leonard WJ (2005) Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J Exp Med 201(1):139–148
Devalliere J, Charreau B (2011) The adaptor LNK (SH2B3): an emerging regulator in vascular cells and a link between immune and inflammatory signaling. Biochem Pharmacol 82(10):1391–1402
Holmes GK, Prior P, Lane MR, Pope D, Allan RN (1989) Malignancy in coeliac disease—effect of a gluten free diet. Gut 30(3):333–338
Olen O, Askling J, Ludvigsson JF, Hildebrand H, Ekbom A, Smedby KE (2011) Coeliac disease characteristics, compliance to a gluten free diet and risk of lymphoma by subtype. Dig Liver Dis 43(11):862–868
Biagi F, Corazza GR (2010) Mortality in celiac disease. Nat Rev Gastroenterol Hepatol 7(3):158–162
Plot L, Amital H (2009) Infectious associations of celiac disease. Autoimmun Rev 8(4):316–319
Bourliere M, Oules V, Perrier H, Mengotti C (2001) Onset of coeliac disease and interferon treatment. Lancet 357(9258):803–804
Westhoff TH, Vergoulidou M, Loddenkemper C, Schwartz S, Hofmann J, Schneider T, Zidek W, van der Giet M (2009) Chronic norovirus infection in renal transplant recipients. Nephrol Dial Transplant 24(3):1051–1053
Foxman EF, Iwasaki A (2011) Genome-virome interactions: examining the role of common viral infections in complex disease. Nat Rev Microbiol 9(4):254–264
Gough DJ, Messina NL, Clarke CJ, Johnstone RW, Levy DE (2012) Constitutive type I interferon modulates homeostatic balance through tonic signaling. Immunity 36(2):166–174
Colpitts SL, Stoklasek TA, Plumlee CR, Obar JJ, Guo C, Lefrancois L (2012) Cutting edge: the role of IFN-alpha receptor and MYD88 signaling in induction of IL-15 expression in vivo. J Immunol 188:2483–2487
Dafik L, Albertelli M, Stamnaes J, Sollid LM, Khosla C (2012) Activation and inhibition of transglutaminase 2 in mice. PLoS One 7(2):e30642
Vella AT, Dow S, Potter TA, Kappler J, Marrack P (1998) Cytokine-induced survival of activated T cells in vitro and in vivo. Proc Natl Acad Sci U S A 95(7):3810–3815
Vakiani E, Arguelles-Grande C, Mansukhani MM, Lewis SK, Rotterdam H, Green PH, Bhagat G (2010) Collagenous sprue is not always associated with dismal outcomes: a clinicopathological study of 19 patients. Mod Pathol 23(1):12–26
Xiao Z, Dasari VM, Kirby DF, Bronner M, Plesec TP, Lashner BA (2009) Collagenous sprue: a case report and literature review. Gastroenterol Hepatol (N Y) 5(6):418–424
Daum S, Foss HD, Schuppan D, Riecken EO, Zeitz M, Ullrich R (2006) Synthesis of collagen I in collagenous sprue. Clin Gastroenterol Hepatol 4(10):1232–1236
Cosnes J, Cellier C, Viola S, Colombel JF, Michaud L, Sarles J, Hugot JP, Ginies JL, Dabadie A, Mouterde O, Allez M, Nion-Larmurier I (2008) Incidence of autoimmune diseases in celiac disease: protective effect of the gluten-free diet. Clin Gastroenterol Hepatol 6(7):753–758
Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhagat G, Krausz TN, Raulet DH, Lanier LL, Groh V, Spies T, Ebert EC, Green PH, Jabri B (2004) Coordinated induction by IL-15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 21(3):357–366
Ogasawara K, Hamerman JA, Ehrlich LR, Bour-Jordan H, Santamaria P, Bluestone JA, Lanier LL (2004) NKG2D blockade prevents autoimmune diabetes in nod mice. Immunity 20(6):757–767
Mention JJ, Ben Ahmed M, Begue B, Barbe U, Verkarre V, Asnafi V, Colombel JF, Cugnenc PH, Ruemmele FM, McIntyre E, Brousse N, Cellier C, Cerf-Bensussan N, Interleukin 15 (2003) A key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology 125(3):730–745
Di Sabatino A, Ciccocioppo R, Cupelli F, Cinque B, Millimaggi D, Clarkson MM, Paulli M, Cifone MG, Corazza GR (2006) Epithelium derived interleukin 15 regulates intraepithelial lymphocyte TH1 cytokine production, cytotoxicity, and survival in coeliac disease. Gut 55(4):469–477
Ben Ahmed M, Meresse B, Arnulf B, Barbe U, Mention J, Verkarre V, Allez M, Cellier C, Hermine O, Cerf-Bensussan N (2007) Inhibition of TGF-β signaling by IL-15: A new role for IL-15 in the loss of immune homeostasis in celiac disease. Gastroenterology 132(3):994–1008
Li MO, Sanjabi S, Flavell RA (2006) Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25(3):455–471
Marie JC, Liggitt D, Rudensky AY (2006) Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity 25(3):441–454
Wildin RS, Freitas A (2005) IPEX and FOXP3: clinical and research perspectives. J Autoimmun 25(Suppl):56–62
Ben Ahmed M, Belhadj Hmida N, Moes N, Buyse S, Abdeladhim M, Louzir H, Cerf-Bensussan N (2009) Il-15 renders conventional lymphocytes resistant to suppressive functions of regulatory T cells through activation of the phosphatidylinositol 3-kinase pathway. J Immunol 182(11):6763–6770
Hmida NB, Ahmed MB, Moussa A, Rejeb MB, Said Y, Kourda N, Meresse B, Abdeladhim M, Louzir H, Cerf-Bensussan N (2012) Impaired control of effector T cells by regulatory T cells: a clue to loss of oral tolerance and autoimmunity in celiac disease? Am J Gastroenterol 107(4):604–611
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(7337):220–224
Bergamaschi C, Rosati M, Jalah R, Valentin A, Kulkarni V, Alicea C, Zhang GM, Patel V, Felber BK, Pavlakis GN (2008) Intracellular interaction of interleukin-15 with its receptor alpha during production leads to mutual stabilization and increased bioactivity. J Biol Chem 283(7):4189–4199
Fehniger TA, Caligiuri MA (2001) Interleukin 15: biology and relevance to human disease. Blood 97(1):14–32
Malamut G, El Machhour R, Montcuquet N, Martin-Lanneree S, Dusanter-Fourt I, Verkarre V, Mention JJ, Rahmi G, Kiyono H, Butz EA, Brousse N, Cellier C, Cerf-Bensussan N, Meresse B (2010) Il-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. J Clin Invest 120(6):2131–2143
Ohta N, Hiroi T, Kweon MN, Kinoshita N, Jang MH, Mashimo T, Miyazaki J, Kiyono H (2002) Il-15-dependent activation-induced cell death-resistant TH1 type CD8 alpha beta + NK1.1+ T cells for the development of small intestinal inflammation. J Immunol 169(1):460–468
Fehniger TA, Suzuki K, Ponnappan A, VanDeusen JB, Cooper MA, Florea SM, Freud AG, Robinson ML, Durbin J, Caligiuri MA (2001) Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells. J Exp Med 193(2):219–231
Tjon JM, Verbeek WH, Kooy-Winkelaar YM, Nguyen BH, van der Slik AR, Thompson A, Heemskerk MH, Schreurs MW, Dekking LH, Mulder CJ, van Bergen J, Koning F (2008) Defective synthesis or association of t-cell receptor chains underlies loss of surface T-cell receptor-CD3 expression in enteropathy-associated T-cell lymphoma. Blood 112(13):5103–5110
Maiuri L, Ciacci C, Auricchio S, Brown V, Quaratino S, Londei M (2000) Interleukin 15 mediates epithelial changes in celiac disease. Gastroenterology 119(4):996–1006
Wang Y, Seidl T, Whittall T, Babaahmady K, Lehner T (2010) Stress-activated dendritic cells interact with CD4+ T cells to elicit homeostatic memory. Eur J Immunol 40 (6):1628–1638
Rubio-Tapia A, Murray JA (2010) Classification and management of refractory coeliac disease. Gut 59(4):547–557
Goerres MS, Meijer JW, Wahab PJ, Kerckhaert JA, Groenen PJ, Van Krieken JH, Mulder CJ (2003) Azathioprine and prednisone combination therapy in refractory coeliac disease. Aliment Pharmacol Ther 18(5):487–494
Dray X, Joly F, Lavergne-Slove A, Treton X, Bouhnik Y, Messing B (2006) A severe but reversible refractory sprue. Gut 55(8):1210–1211
Al-Toma A, Goerres MS, Meijer JW, von Blomberg BM, Wahab PJ, Kerckhaert JA, Mulder CJ (2006) Cladribine therapy in refractory celiac disease with aberrant t cells. Clin Gastroenterol Hepatol 4(11):1322–1327
Al-Toma A, Visser OJ, van Roessel HM, von Blomberg BM, Verbeek WH, Scholten PE, Ossenkoppele GJ, Huijgens PC, Mulder CJ (2006) Autologous hematopoietic stem cell transplantation in refractory celiac disease with aberrant T-cells. Blood 109(5):2243–2249
Tack GJ, Wondergem MJ, Al-Toma A, Verbeek WH, Schmittel A, Machado MV, Perri F, Ossenkoppele GJ, Huijgens PC, Schreurs MW, Mulder CJ, Visser OJ (2011) Auto-SCT in refractory celiac disease type II patients unresponsive to cladribine therapy. Bone Marrow Transplant 46(6):840–846
Fleischmann R, Cutolo M, Genovese MC, Lee EB, Kanik KS, Sadis S, Connell CA, Gruben D, Krishnaswami S, Wallenstein G, Wilkinson BE, Zwillich SH (2012) Phase IIb dose-ranging study of the oral Jak inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum 64(3):617–629
Acknowledgements
The authors acknowledge funding from INSERM, Ligue Contre le Cancer, Fondation Pour la Recherche Médicale, Agence Nationale pour la Recherche, Association pour la Recherche contre le Cancer, Association française des Patients Intolérants au Gluten, Fondation Princesse Grace. They thank all members of INSERM U989 for sharing work and helpful discussions. They also thank members of GERMC and CELAC for providing samples and sharing data from their patients as well as for helpful discussions.
Authors declare no conflict of interest
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is published as part of the Special Issue on Celiac Disease (34:5).
Rights and permissions
About this article
Cite this article
Malamut, G., Meresse, B., Cellier, C. et al. Refractory celiac disease: from bench to bedside. Semin Immunopathol 34, 601–613 (2012). https://doi.org/10.1007/s00281-012-0322-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00281-012-0322-z