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Current Hematologic Malignancy Reports

, Volume 13, Issue 4, pp 308–317 | Cite as

Pathogenesis of Enteropathy-Associated T Cell Lymphoma

  • Udit Chander
  • Rebecca J. Leeman-Neill
  • Govind Bhagat
T-Cell and Other Lymphoproliferative Malignancies (J Zain, Section Editor)
Part of the following topical collections:
  1. Topical Collection on T-Cell and Other Lymphoproliferative Malignancies

Abstract

Purpose of Review

To provide an update on the pathogenesis of enteropathy-associated T cell lymphoma (EATL) and its relationship with refractory celiac disease (RCD), in light of current knowledge of immune, genetic, and environmental factors that promote neoplastic transformation of intraepithelial lymphocytes (IELs).

Recent Findings

EATL frequently evolves from RCD type II (RCD II) but can occur “de novo” in individuals with celiac disease. Recurrent activating mutations in members of the JAK/STAT pathway have been recently described in EATL and RCD II, which suggests deregulation of cytokine signaling to be an early event in lymphomagenesis. Intraepithelial T cells are presumed to be the cell of origin of EATL (and RCD II). Recent in vitro molecular and phenotypic analyses and in vivo murine studies, however, suggest an origin of RCD II from innate IELs (NK/T cell precursors), which could also be the cell of origin of RCD II-derived EATL.

Summary

The immune microenvironment of the small intestinal mucosa in celiac disease fosters the development of EATL, often in a multistep pathway.

Keywords

EATL T cell lymphoma Celiac disease Refractory celiac disease Intestine Genetics 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance

  1. 1.
    CE SSH, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, et al. WHO classification of tumours and haematopoietic and lymphoid tissues. Revised 4th Edition ed. Lyon, France: IARC; 2017.Google Scholar
  2. 2.
    Gough KR, Read AE, Naish JM. Intestinal reticulosis as a complication of idiopathic steatorrhoea. Gut. 1962;3:232–9.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Isaacson P, Wright DH. Intestinal lymphoma associated with malabsorption. Lancet. 1978;1(8055):67–70.PubMedCrossRefGoogle Scholar
  4. 4.
    Isaacson PG, O’Connor NT, Spencer J, Bevan DH, Connolly CE, Kirkham N, et al. Malignant histiocytosis of the intestine: a T-cell lymphoma. Lancet. 1985;2(8457):688–91.PubMedCrossRefGoogle Scholar
  5. 5.
    Swerdlow SHCE, Harris NL, et al., editors. World Health Organization classification of tumors of haematopoietic and lymphoid tissues. Lyon, France: IARC; 2008.Google Scholar
  6. 6.
    • Tack GJ, van Wanrooij RL, Langerak AW, Tjon JM, von Blomberg BM, Heideman DA, et al. Origin and immunophenotype of aberrant IEL in RCDII patients. Mol Immunol. 2012;50(4):262–70. Phenotypic and genotypic (TCR gene rearrangement) analysis of refractory celiac disease type II (RCD II) intraepithelial lymphocytes, which suggested an origin of RCD II from T/NK-cell precursors. PubMedCrossRefGoogle Scholar
  7. 7.
    • Schmitz F, Tjon JM, Lai Y, Thompson A, Kooy-Winkelaar Y, Lemmers RJ, et al. Identification of a potential physiological precursor of aberrant cells in refractory coeliac disease type II. Gut. 2013;62(4):509–19. Phenotypic and gene expression analysis of innate intraepithelial lymphocytes and RCD II cell lines suggested a novel cell of origin of RCD II. PubMedCrossRefGoogle Scholar
  8. 8.
    • Schmitz F, Tjon JM, van Bergen J, Koning F. Dendritic cells promote expansion and survival of aberrant TCR-negative intraepithelial lymphocyte lines from refractory celiac disease type II patients. Mol Immunol. 2014;58(1):10–6. Identification of selective stimulation of RCD II intraepithelial lymphocytes by dendritic cells in the absence of IL-15. PubMedCrossRefGoogle Scholar
  9. 9.
    • Schmitz F, Kooy-Winkelaar Y, Wiekmeijer AS, Brugman MH, Mearin ML, Mulder C, et al. The composition and differentiation potential of the duodenal intraepithelial innate lymphocyte compartment is altered in coeliac disease. Gut. 2016;65(8):1269–78. Comparative phenotypic and transcriptional analysis of RCD II intraepithelial lymphocytes and T cells revealed lack of differentiation potential of RCD II. PubMedCrossRefGoogle Scholar
  10. 10.
    • Ettersperger J, Montcuquet N, Malamut G, Guegan N, Lopez-Lastra S, Gayraud S, et al. Interleukin-15-dependent T-cell-like innate intraepithelial lymphocytes develop in the intestine and transform into lymphomas in celiac disease. Immunity. 2016;45(3):610–25. In vivo and in vitro functional characterization of innate lymphocyte development to identify the cell of origin of RCD II and description of frequent JAK I and STAT3 mutations in RCD II. PubMedCrossRefGoogle Scholar
  11. 11.
    • Kooy-Winkelaar YM, Bouwer D, Janssen GM, Thompson A, Brugman MH, Schmitz F, et al. CD4 T-cell cytokines synergize to induce proliferation of malignant and nonmalignant innate intraepithelial lymphocytes. Proc Natl Acad Sci U S A. 2017;114(6):E980–E9. Evidence that gliadin responsive CD4+ T cells in the lamina propria can communicate with and stimulate the proliferation and survival of innate intraepithelial lymphocytes in RCD II. PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    • Roberti A, Dobay MP, Bisig B, Vallois D, Boechat C, Lanitis E, et al. Type II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations. Nat Commun. 2016;7:12602. Whole exome sequencing of MEITL (formerly EATL II) revealed frequent inactivating mutations and deletions of SETD2 that were absent in EATL (formerly EATL I), the latter showing frequent JAK1 and STAT3 mutations. PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    • Nicolae A, Xi L, Pham TH, Pham TA, Navarro W, Meeker HG, et al. Mutations in the JAK/STAT and RAS signaling pathways are common in intestinal T-cell lymphomas. Leukemia. 2016;30(11):2245–7. Targeted next-generation sequencing of EATL, MEITL, and PTCL, NOS, identified overlapping spectrum of mutations in these entities. PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    •• Moffitt AB, Ondrejka SL, McKinney M, Rempel RE, Goodlad JR, Teh CH, et al. Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2. J Exp Med. 2017;214(5):1371–86. Whole exome sequencing of EATL and MEITL revealed overlapping spectrum of mutations, with both entities showing frequent recurrent mutations in SETD2 and members of the JAK-STAT signaling pathway. In vivo functional analysis of SETD2 loss using a mouse model revealed a role of SETD2 in T cell lineage specification. PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Chott A, Haedicke W, Mosberger I, Fodinger M, Winkler K, Mannhalter C, et al. Most CD56+ intestinal lymphomas are CD8+CD5-T-cell lymphomas of monomorphic small to medium size histology. Am J Pathol. 1998;153(5):1483–90.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Delabie J, Holte H, Vose JM, Ullrich F, Jaffe ES, Savage KJ, et al. Enteropathy-associated T-cell lymphoma: clinical and histological findings from the international peripheral T-cell lymphoma project. Blood. 2011;118(1):148–55.PubMedCrossRefGoogle Scholar
  17. 17.
    A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The non-Hodgkin’s lymphoma classification project. Blood. 1997;89(11):3909–18.Google Scholar
  18. 18.
    • Malamut G, Chandesris O, Verkarre V, Meresse B, Callens C, Macintyre E, et al. Enteropathy associated T cell lymphoma in celiac disease: a large retrospective study. Dig Liver Dis. 2013;45(5):377–84. Retrospective analysis highlighting different clinicopathogentic characteristics of RCD II-derived and de novo EATL. PubMedCrossRefGoogle Scholar
  19. 19.
    Sieniawski M, Angamuthu N, Boyd K, Chasty R, Davies J, Forsyth P, et al. Evaluation of enteropathy-associated T-cell lymphoma comparing standard therapies with a novel regimen including autologous stem cell transplantation. Blood. 2010;115(18):3664–70.PubMedCrossRefGoogle Scholar
  20. 20.
    Verbeek WH, Van De Water JM, Al-Toma A, Oudejans JJ, Mulder CJ, Coupe VM. Incidence of enteropathy-associated T-cell lymphoma: a nation-wide study of a population-based registry in The Netherlands. Scand J Gastroenterol. 2008;43(11):1322–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Gale J, Simmonds PD, Mead GM, Sweetenham JW, Wright DH. Enteropathy-type intestinal T-cell lymphoma: clinical features and treatment of 31 patients in a single center. J Clin Oncol. 2000;18(4):795–803.PubMedCrossRefGoogle Scholar
  22. 22.
    O'Farrelly C, Feighery C, O'Briain DS, Stevens F, Connolly CE, McCarthy C, et al. Humoral response to wheat protein in patients with coeliac disease and enteropathy associated T cell lymphoma. Br Med J (Clin Res Ed). 1986;293(6552):908–10.PubMedCentralCrossRefGoogle Scholar
  23. 23.
    Swinson CM, Slavin G, Coles EC, Booth CC. Coeliac disease and malignancy. Lancet. 1983;1(8316):111–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Green PH, Cellier C. Celiac disease. N Engl J Med. 2007;357(17):1731–43.PubMedCrossRefGoogle Scholar
  25. 25.
    Leffler DA, Green PH, Fasano A. Extraintestinal manifestations of coeliac disease. Nat Rev Gastroenterol Hepatol. 2015;12(10):561–71.PubMedCrossRefGoogle Scholar
  26. 26.
    Howell WM, Leung ST, Jones DB, Nakshabendi I, Hall MA, Lanchbury JS, et al. HLA-DRB, -DQA, and -DQB polymorphism in celiac disease and enteropathy-associated T-cell lymphoma. Common features and additional risk factors for malignancy. Hum Immunol. 1995;43(1):29–37.PubMedCrossRefGoogle Scholar
  27. 27.
    Corrao G, Corazza GR, Bagnardi V, Brusco G, Ciacci C, Cottone M, et al. Mortality in patients with coeliac disease and their relatives: a cohort study. Lancet. 2001;358(9279):356–61.PubMedCrossRefGoogle Scholar
  28. 28.
    Holmes GK, Prior P, Lane MR, Pope D, Allan RN. Malignancy in coeliac disease—effect of a gluten free diet. Gut. 1989;30(3):333–8.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Silano M, Volta U, Vincenzi AD, Dessi M, Vincenzi MD, Collaborating Centers of the Italian Registry of the Complications of Coeliac D. Effect of a gluten-free diet on the risk of enteropathy-associated T-cell lymphoma in celiac disease. Dig Dis Sci. 2008;53(4):972–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Green PH, Fleischauer AT, Bhagat G, Goyal R, Jabri B, Neugut AI. Risk of malignancy in patients with celiac disease. Am J Med. 2003;115(3):191–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Catassi C, Bearzi I, Holmes GK. Association of celiac disease and intestinal lymphomas and other cancers. Gastroenterology. 2005;128(4 Suppl 1):S79–86.PubMedCrossRefGoogle Scholar
  32. 32.
    Sharaiha RZ, Lebwohl B, Reimers L, Bhagat G, Green PH, Neugut AI. Increasing incidence of enteropathy-associated T-cell lymphoma in the United States, 1973–2008. Cancer. 2012;118(15):3786–92.PubMedCrossRefGoogle Scholar
  33. 33.
    Askling J, Linet M, Gridley G, Halstensen TS, Ekstrom K, Ekbom A. Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis. Gastroenterology. 2002;123(5):1428–35.PubMedCrossRefGoogle Scholar
  34. 34.
    Catassi C, Fabiani E, Corrao G, Barbato M, De Renzo A, Carella AM, et al. Risk of non-Hodgkin lymphoma in celiac disease. JAMA. 2002;287(11):1413–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Leonard JN, Tucker WF, Fry JS, Coulter CA, Boylston AW, McMinn RM, et al. Increased incidence of malignancy in dermatitis herpetiformis. Br Med J (Clin Res Ed). 1983;286(6358):16–8.CrossRefGoogle Scholar
  36. 36.
    Sigurgeirsson B, Agnarsson BA, Lindelof B. Risk of lymphoma in patients with dermatitis herpetiformis. BMJ. 1994;308(6920):13–5.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Cottone M, Termini A, Oliva L, Magliocco A, Marrone C, Orlando A, et al. Mortality and causes of death in celiac disease in a Mediterranean area. Dig Dis Sci. 1999;44(12):2538–41.PubMedCrossRefGoogle Scholar
  38. 38.
    Gao Y, Kristinsson SY, Goldin LR, Bjorkholm M, Caporaso NE, Landgren O. Increased risk for non-Hodgkin lymphoma in individuals with celiac disease and a potential familial association. Gastroenterology. 2009;136(1):91–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Ilus T, Kaukinen K, Virta LJ, Huhtala H, Maki M, Kurppa K, et al. Refractory coeliac disease in a country with a high prevalence of clinically-diagnosed coeliac disease. Aliment Pharmacol Ther. 2014;39(4):418–25.PubMedCrossRefGoogle Scholar
  40. 40.
    Ilyas M, Niedobitek G, Agathanggelou A, Barry RE, Read AE, Tierney R, et al. Non-Hodgkin’s lymphoma, coeliac disease, and Epstein-Barr virus: a study of 13 cases of enteropathy-associated T- and B-cell lymphoma. J Pathol. 1995;177(2):115–22.PubMedCrossRefGoogle Scholar
  41. 41.
    Daum S, Ullrich R, Heise W, Dederke B, Foss HD, Stein H, et al. Intestinal non-Hodgkin’s lymphoma: a multicenter prospective clinical study from the German Study Group on Intestinal non-Hodgkin’s Lymphoma. J Clin Oncol. 2003;21(14):2740–6.PubMedCrossRefGoogle Scholar
  42. 42.
    Fasano A, Catassi C. Current approaches to diagnosis and treatment of celiac disease: an evolving spectrum. Gastroenterology. 2001;120(3):636–51.PubMedCrossRefGoogle Scholar
  43. 43.
    Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PH, et al. The Oslo definitions for coeliac disease and related terms. Gut. 2013;62(1):43–52.PubMedCrossRefGoogle Scholar
  44. 44.
    Trier JS. Celiac sprue. N Engl J Med. 1991;325(24):1709–19.PubMedCrossRefGoogle Scholar
  45. 45.
    Jewell DP. Ulcerative enteritis. Br Med J (Clin Res Ed). 1983;287(6407):1740–1.CrossRefGoogle Scholar
  46. 46.
    West J. Celiac disease and its complications: a time traveller’s perspective. Gastroenterology. 2009;136(1):32–4.PubMedCrossRefGoogle Scholar
  47. 47.
    Wright DH, Jones DB, Clark H, Mead GM, Hodges E, Howell WM. Is adult-onset coeliac disease due to a low-grade lymphoma of intraepithelial T lymphocytes? Lancet. 1991;337(8754):1373–4.PubMedCrossRefGoogle Scholar
  48. 48.
    Alfsen GC, Beiske K, Bell H, Marton PF. Low-grade intestinal lymphoma of intraepithelial T lymphocytes with concomitant enteropathy-associated T cell lymphoma: case report suggesting a possible histogenetic relationship. Hum Pathol. 1989;20(9):909–13.PubMedCrossRefGoogle Scholar
  49. 49.
    Isaacson P, Wright DH. Malignant histiocytosis of the intestine. Its relationship to malabsorption and ulcerative jejunitis. Hum Pathol. 1978;9(6):661–77.PubMedCrossRefGoogle Scholar
  50. 50.
    Cellier C, Delabesse E, Helmer C, Patey N, Matuchansky C, Jabri B, et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. French Coeliac Disease Study Group Lancet. 2000;356(9225):203–8.Google Scholar
  51. 51.
    Murray A, Cuevas EC, Jones DB, Wright DH. Study of the immunohistochemistry and T cell clonality of enteropathy-associated T cell lymphoma. Am J Pathol. 1995;146(2):509–19.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Ashton-Key M, Diss TC, Pan L, Du MQ, Isaacson PG. Molecular analysis of T-cell clonality in ulcerative jejunitis and enteropathy-associated T-cell lymphoma. Am J Pathol. 1997;151(2):493–8.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Bagdi E, Diss TC, Munson P, Isaacson PG. Mucosal intra-epithelial lymphocytes in enteropathy-associated T-cell lymphoma, ulcerative jejunitis, and refractory celiac disease constitute a neoplastic population. Blood. 1999;94(1):260–4.PubMedGoogle Scholar
  54. 54.
    Carbonnel F, Grollet-Bioul L, Brouet JC, Teilhac MF, Cosnes J, Angonin R, et al. Are complicated forms of celiac disease cryptic T-cell lymphomas? Blood. 1998;92(10):3879–86.PubMedGoogle Scholar
  55. 55.
    Daum S, Weiss D, Hummel M, Ullrich R, Heise W, Stein H, et al. Frequency of clonal intraepithelial T lymphocyte proliferations in enteropathy-type intestinal T cell lymphoma, coeliac disease, and refractory sprue. Gut. 2001;49(6):804–12.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Cellier C, Patey N, Mauvieux L, Jabri B, Delabesse E, Cervoni JP, et al. Abnormal intestinal intraepithelial lymphocytes in refractory sprue. Gastroenterology. 1998;114(3):471–81.PubMedCrossRefGoogle Scholar
  57. 57.
    Malamut G, Afchain P, Verkarre V, Lecomte T, Amiot A, Damotte D, et al. Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II. Gastroenterology. 2009;136(1):81–90.PubMedCrossRefGoogle Scholar
  58. 58.
    Al-Toma A, Verbeek WH, Hadithi M, von Blomberg BM, Mulder CJ. Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: retrospective evaluation of single-centre experience. Gut. 2007;56(10):1373–8.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Rubio-Tapia A, Kelly DG, Lahr BD, Dogan A, Wu TT, Murray JA. Clinical staging and survival in refractory celiac disease: a single center experience. Gastroenterology. 2009;136(1):99–107. quiz 352-3 PubMedCrossRefGoogle Scholar
  60. 60.
    Roshan B, Leffler DA, Jamma S, Dennis M, Sheth S, Falchuk K, et al. The incidence and clinical spectrum of refractory celiac disease in a north American referral center. Am J Gastroenterol. 2011;106(5):923–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Daum S, Cellier C, Mulder CJ. Refractory coeliac disease. Best Pract Res Clin Gastroenterol. 2005;19(3):413–24.PubMedCrossRefGoogle Scholar
  62. 62.
    Verkarre V, Asnafi V, Lecomte T, Patey Mariaud-de Serre N, Leborgne M, Grosdidier E, et al. Refractory coeliac sprue is a diffuse gastrointestinal disease. Gut. 2003;52(2):205–11.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Verbeek WH, Goerres MS, von Blomberg BM, Oudejans JJ, Scholten PE, Hadithi M, et al. Flow cytometric determination of aberrant intra-epithelial lymphocytes predicts T-cell lymphoma development more accurately than T-cell clonality analysis in Refractory Celiac Disease. Clin Immunol. 2008;126(1):48–56.PubMedCrossRefGoogle Scholar
  64. 64.
    Leffler DA, Dennis M, Hyett B, Kelly E, Schuppan D, Kelly CP. Etiologies and predictors of diagnosis in nonresponsive celiac disease. Clin Gastroenterol Hepatol. 2007;5(4):445–50.PubMedCrossRefGoogle Scholar
  65. 65.
    O’Mahony S, Howdle PD, Losowsky MS. Review article: management of patients with non-responsive coeliac disease. Aliment Pharmacol Ther. 1996;10(5):671–80.PubMedCrossRefGoogle Scholar
  66. 66.
    Arguelles-Grande C, Brar P, Green PH, Bhagat G. Immunohistochemical and T-cell receptor gene rearrangement analyses as predictors of morbidity and mortality in refractory celiac disease. J Clin Gastroenterol. 2013;47(7):593–601.PubMedCrossRefGoogle Scholar
  67. 67.
    Daum S, Ipczynski R, Schumann M, Wahnschaffe U, Zeitz M, Ullrich R. High rates of complications and substantial mortality in both types of refractory sprue. Eur J Gastroenterol Hepatol. 2009;21(1):66–70.PubMedCrossRefGoogle Scholar
  68. 68.
    Vader W, Stepniak D, Kooy Y, Mearin L, Thompson A, van Rood JJ, et al. 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. 2003;100(21):12390–5.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Al-Toma A, Goerres MS, Meijer JW, Pena AS, Crusius JB, Mulder CJ. Human leukocyte antigen-DQ2 homozygosity and the development of refractory celiac disease and enteropathy-associated T-cell lymphoma. Clin Gastroenterol Hepatol. 2006;4(3):315–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Dubois PC, Trynka G, Franke L, Hunt KA, Romanos J, Curtotti A, et al. Multiple common variants for celiac disease influencing immune gene expression. Nat Genet. 2010;42(4):295–302.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Trynka G, Hunt KA, Bockett NA, Romanos J, Mistry V, Szperl A, et al. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat Genet. 2011;43(12):1193–201.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Kumar V, Wijmenga C, Withoff S. From genome-wide association studies to disease mechanisms: celiac disease as a model for autoimmune diseases. Semin Immunopathol. 2012;34(4):567–80.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Castellanos-Rubio A, Fernandez-Jimenez N, Kratchmarov R, Luo X, Bhagat G, Green PH, et al. A long noncoding RNA associated with susceptibility to celiac disease. Science. 2016;352(6281):91–5.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Hrdlickova B, Mulder CJ, Malamut G, Meresse B, Platteel M, Kamatani Y, et al. A locus at 7p14.3 predisposes to refractory celiac disease progression from celiac disease. Eur J Gastroenterol Hepatol. 2018.  https://doi.org/10.1097/MEG.0000000000001168.
  75. 75.
    Meresse B, Malamut G, Cerf-Bensussan N. Celiac disease: an immunological jigsaw. Immunity. 2012;36(6):907–19.PubMedCrossRefGoogle Scholar
  76. 76.
    Malamut G, Cellier C. Refractory coeliac disease. Curr Opin Oncol. 2013;25(5):445–51.PubMedCrossRefGoogle Scholar
  77. 77.
    Jarry A, Cerf-Bensussan N, Brousse N, Selz F, Guy-Grand D. Subsets of CD3+ (T cell receptor alpha/beta or gamma/delta) and CD3- lymphocytes isolated from normal human gut epithelium display phenotypical features different from their counterparts in peripheral blood. Eur J Immunol. 1990;20(5):1097–103.PubMedCrossRefGoogle Scholar
  78. 78.
    Calleja S, Vivas S, Santiuste M, Arias L, Hernando M, Nistal E, et al. Dynamics of non-conventional intraepithelial lymphocytes—NK, NKT, and gammadelta T—in celiac disease: relationship with age, diet, and histopathology. Dig Dis Sci. 2011;56(7):2042–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Eiras P, Leon F, Camarero C, Lombardia M, Roldan E, Bootello A, et al. Intestinal intraepithelial lymphocytes contain a CD3- CD7+ subset expressing natural killer markers and a singular pattern of adhesion molecules. Scand J Immunol. 2000;52(1):1–6.PubMedCrossRefGoogle Scholar
  80. 80.
    Leon F, Roldan E, Sanchez L, Camarero C, Bootello A, Roy G. Human small-intestinal epithelium contains functional natural killer lymphocytes. Gastroenterology. 2003;125(2):345–56.PubMedCrossRefGoogle Scholar
  81. 81.
    van Wijk F, Cheroutre H. Intestinal T cells: facing the mucosal immune dilemma with synergy and diversity. Semin Immunol. 2009;21(3):130–8.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Eberl G, Colonna M, Di Santo JP, AN MK. Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology. Science. 2015;348(6237):aaa6566.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Spencer J, Cerf-Bensussan N, Jarry A, Brousse N, Guy-Grand D, Krajewski AS, et al. 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. 1988;132(1):1–5.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Lambolez F, Mayans S, Cheroutre H. Lymphocytes: intraepithelial. eLS. Hoboken: John Wiley & Sons, Ltd; 2001.Google Scholar
  85. 85.
    Tjon JM, Verbeek WH, Kooy-Winkelaar YM, Nguyen BH, van der Slik AR, Thompson A, et al. 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. 2008;112(13):5103–10.PubMedCrossRefGoogle Scholar
  86. 86.
    Jaffe ESAD, Campo E, Harris NL, Quintanilla-Fend L. Hematopathology. 2nd Edition ed. Philadelphia. USA: Elsevier; 2016.Google Scholar
  87. 87.
    Attygalle AD, Cabecadas J, Gaulard P, Jaffe ES, de Jong D, Ko YH, et al. Peripheral T-cell and NK-cell lymphomas and their mimics; taking a step forward—report on the lymphoma workshop of the XVIth meeting of the European Association for Haematopathology and the Society for Hematopathology. Histopathology. 2014;64(2):171–99.PubMedCrossRefGoogle Scholar
  88. 88.
    Chan JK, Chan AC, Cheuk W, Wan SK, Lee WK, Lui YH, et al. Type II enteropathy-associated T-cell lymphoma: a distinct aggressive lymphoma with frequent gammadelta T-cell receptor expression. Am J Surg Pathol. 2011;35(10):1557–69.PubMedCrossRefGoogle Scholar
  89. 89.
    van Wanrooij RL, de Jong D, Langerak AW, Ylstra B, van Essen HF, Heideman DA, et al. Novel variant of EATL evolving from mucosal γδ-T-cells in a patient with type I RCD. BMJ Open Gastroenterol. 2015;2(1):e000026.  https://doi.org/10.1136/bmjgast-2014-000026.
  90. 90.
    Abadie V, Sollid LM, Barreiro LB, Jabri B. Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Annu Rev Immunol. 2011;29:493–525.PubMedCrossRefGoogle Scholar
  91. 91.
    Hollon JR, Cureton PA, Martin ML, Puppa EL, Fasano A. Trace gluten contamination may play a role in mucosal and clinical recovery in a subgroup of diet-adherent non-responsive celiac disease patients. BMC Gastroenterol. 2013;13:40.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Malamut G, Meresse B, Cellier C, Cerf-Bensussan N. Refractory celiac disease: from bench to bedside. Semin Immunopathol. 2012;34(4):601–13.PubMedCrossRefGoogle Scholar
  93. 93.
    Hue S, Mention JJ, Monteiro RC, Zhang S, Cellier C, Schmitz J, et al. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity. 2004;21(3):367–77.PubMedCrossRefGoogle Scholar
  94. 94.
    Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhagat G, Krausz TN, et al. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity. 2004;21(3):357–66.PubMedCrossRefGoogle Scholar
  95. 95.
    Meresse B, Curran SA, Ciszewski C, Orbelyan G, Setty M, Bhagat G, et al. Reprogramming of CTLs into natural killer-like cells in celiac disease. J Exp Med. 2006;203(5):1343–55.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Benahmed M, Meresse B, Arnulf B, Barbe U, Mention JJ, Verkarre V, et al. Inhibition of TGF-beta signaling by IL-15: a new role for IL-15 in the loss of immune homeostasis in celiac disease. Gastroenterology. 2007;132(3):994–1008.PubMedCrossRefGoogle Scholar
  97. 97.
    Ben Ahmed M, Belhadj Hmida N, Moes N, Buyse S, Abdeladhim M, Louzir H, et al. IL-15 renders conventional lymphocytes resistant to suppressive functions of regulatory T cells through activation of the phosphatidylinositol 3-kinase pathway. J Immunol. 2009;182(11):6763–70.PubMedCrossRefGoogle Scholar
  98. 98.
    Mention JJ, Ben Ahmed M, Begue B, Barbe U, Verkarre V, Asnafi V, et al. Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology. 2003;125(3):730–45.PubMedCrossRefGoogle Scholar
  99. 99.
    Malamut G, El Machhour R, Montcuquet N, Martin-Lanneree S, Dusanter-Fourt I, Verkarre V, et al. 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. 2010;120(6):2131–43.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Tjon JM, Kooy-Winkelaar YM, Tack GJ, Mommaas AM, Schreurs MW, Schilham MW, et al. DNAM-1 mediates epithelial cell-specific cytotoxicity of aberrant intraepithelial lymphocyte lines from refractory celiac disease type II patients. J Immunol. 2011;186(11):6304–12.PubMedCrossRefGoogle Scholar
  101. 101.
    Rothenberg EV, Ungerback J, Champhekar A. Forging T-lymphocyte identity: intersecting networks of transcriptional control. Adv Immunol. 2016;129:109–74.PubMedCrossRefGoogle Scholar
  102. 102.
    Verkarre V, Romana SP, Cellier C, Asnafi V, Mention JJ, Barbe U, et al. Recurrent partial trisomy 1q22-q44 in clonal intraepithelial lymphocytes in refractory celiac sprue. Gastroenterology. 2003;125(1):40–6.PubMedCrossRefGoogle Scholar
  103. 103.
    Baumgartner AK, Zettl A, Chott A, Ott G, Muller-Hermelink HK, Starostik P. High frequency of genetic aberrations in enteropathy-type T-cell lymphoma. Lab Investig. 2003;83(10):1509–16.PubMedCrossRefGoogle Scholar
  104. 104.
    • Deleeuw RJ, Zettl A, Klinker E, Haralambieva E, Trottier M, Chari R, et al. Whole-genome analysis and HLA genotyping of enteropathy-type T-cell lymphoma reveals 2 distinct lymphoma subtypes. Gastroenterology. 2007;132(5):1902–11. Array-based genomic analysis and HLA genotyping showed differences and similarities of genomic changes in EATL (formerly EATL I) and MEITL (formerly EATL II). PubMedCrossRefGoogle Scholar
  105. 105.
    Zettl A, Ott G, Makulik A, Katzenberger T, Starostik P, Eichler T, et al. Chromosomal gains at 9q characterize enteropathy-type T-cell lymphoma. Am J Pathol. 2002;161(5):1635–45.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Obermann EC, Diss TC, Hamoudi RA, Munson P, Wilkins BS, Camozzi ML, et al. Loss of heterozygosity at chromosome 9p21 is a frequent finding in enteropathy-type T-cell lymphoma. J Pathol. 2004;202(2):252–62.PubMedCrossRefGoogle Scholar
  107. 107.
    Chen J, Zhang Y, Petrus MN, Xiao W, Nicolae A, Raffeld M, et al. Cytokine receptor signaling is required for the survival of ALK- anaplastic large cell lymphoma, even in the presence of JAK1/STAT3 mutations. Proc Natl Acad Sci U S A. 2017;114(15):3975–80.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Mazzarella G, Stefanile R, Camarca A, Giliberti P, Cosentini E, Marano C, et al. Gliadin activates HLA class I-restricted CD8+ T cells in celiac disease intestinal mucosa and induces the enterocyte apoptosis. Gastroenterology. 2008;134(4):1017–27.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Han A, Newell EW, Glanville J, Fernandez-Becker N, Khosla C, Chien YH, et al. Dietary gluten triggers concomitant activation of CD4+ and CD8+ alphabeta T cells and gammadelta T cells in celiac disease. Proc Natl Acad Sci U S A. 2013;110(32):13073–8.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Fina D, Sarra M, Caruso R, Del Vecchio Blanco G, Pallone F, MacDonald TT, et al. Interleukin 21 contributes to the mucosal T helper cell type 1 response in coeliac disease. Gut. 2008;57(7):887–92.PubMedCrossRefGoogle Scholar
  111. 111.
    Bodd M, Raki M, Tollefsen S, Fallang LE, Bergseng E, Lundin KE, et al. HLA-DQ2-restricted gluten-reactive T cells produce IL-21 but not IL-17 or IL-22. Mucosal Immunol. 2010;3(6):594–601.PubMedCrossRefGoogle Scholar
  112. 112.
    Colpitts SL, Stoklasek TA, Plumlee CR, Obar JJ, Guo C, Lefrancois L. Cutting edge: the role of IFN-alpha receptor and MyD88 signaling in induction of IL-15 expression in vivo. J Immunol. 2012;188(6):2483–7.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Bouziat R, Hinterleitner R, Brown JJ, Stencel-Baerenwald JE, Ikizler M, Mayassi T, et al. Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science. 2017;356(6333):44–50.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Kim SM, Mayassi T, Jabri B. Innate immunity: actuating the gears of celiac disease pathogenesis. Best Pract Res Clin Gastroenterol. 2015;29(3):425–35.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Cejkova P, Zettl A, Baumgartner AK, Chott A, Ott G, Muller-Hermelink HK, et al. Amplification of NOTCH1 and ABL1 gene loci is a frequent aberration in enteropathy-type T-cell lymphoma. Virchows Arch. 2005;446(4):416–20.PubMedCrossRefGoogle Scholar
  116. 116.
    Nairismagi ML, Tan J, Lim JQ, Nagarajan S, Ng CC, Rajasegaran V, et al. JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma. Leukemia. 2016;30(6):1311–9.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Udit Chander
    • 1
  • Rebecca J. Leeman-Neill
    • 1
  • Govind Bhagat
    • 1
  1. 1.Department of Pathology and Cell BiologyColumbia University Medical CenterNew YorkUSA

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