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Autoimmune Enteropathy: An Updated Review with Special Focus on Stem Cell Transplant Therapy

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Abstract

Autoimmune enteropathy (AIE) is a complex disease affecting both children and adults. Although associated with significant morbidity and mortality, the pathophysiology of the disease and its treatment have not been well characterized. This study aims to review the medical literature available on this rare but clinically significant ailment, to help establish a better understanding of its pathophysiology and enumerate the available diagnostic and treatment modalities. A literature search was conducted on PubMed using key terms related to autoimmune enteropathy and intractable diarrhea, with no restrictions on the date of publication or language. We found a total of 98 reports of AIE published in the form of case reports and case series. The evidence reviewed suggests that AIE is a multifaceted disorder that requires a high index of suspicion in the appropriate clinical setting to be able to make an early diagnosis. Current evidence supports the use of supportive care to correct nutritional and metabolic deficiencies, and immunosuppressives and immunomodulators as directed therapies. Hematopoietic stem cell transplant is an aggressive, but successful curative modality for patients with AIE as part of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Cumulative clinical experience with management of AIE has allowed improved outcomes in transplanted and non-transplanted AIE patients even though morbidity and mortality with are still high in patients with this condition. More research is needed to further define the role of new therapies for AIE, and a central registry with participation of multiple institutions might help share and standardize care of patients with this rare but serious condition.

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Abbreviations

AIE:

Autoimmune enteropathy

APECED:

Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy

IL:

Interleukin

IFN:

Interferon

IPEX:

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

MHC:

Major histocompatibility complex

MSC:

Mesenchymal stem cell

TNF:

Tumor necrosis factor

TPN:

Total parenteral nutrition

References

  1. Avery GB, Villavicencio O, Lilly JR, Randolph JG. Intractable diarrhea in early infancy. Pediatrics. 1968;41:712–722.

    CAS  PubMed  Google Scholar 

  2. Lo CW, Walker WA. Chronic protracted diarrhea of infancy: a nutritional disease. Pediatrics. 1983;72:786–800.

    CAS  PubMed  Google Scholar 

  3. Sherman PM, Mitchell DJ, Cutz E. Neonatal enteropathies: defining the causes of protracted diarrhea of infancy. J Pediatr Gastroenterol Nutr. 2004;38:16–26.

    Article  PubMed  Google Scholar 

  4. Unsworth DJ, Walker-Smith JA. Autoimmunity in diarrhoeal disease. J Pediatr Gastroenterol Nutr. 1985;4:375–380.

    Article  CAS  PubMed  Google Scholar 

  5. Gentile NM, Murray JA, Pardi DS. Autoimmune enteropathy: a review and update of clinical management. Curr Gastroenterol Rep. 2012;14:380–385.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Akram S, Murray JA, Pardi DS, et al. Adult autoimmune enteropathy: Mayo Clinic Rochester experience. Clin Gastroenterol Hepatol. 2007;5:1282–1290. (quiz 1245).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Marthinsen LM, Scott H, Ejderhamn J. Autoimmune enteropathy in Swedish children, 1985–2002: a call for strict diagnostic criteria. Scand J Gastroenterol. 2008;43:1102–1107.

    Article  PubMed  Google Scholar 

  8. Catassi C, Fabiani E, Spagnuolo MI, Barera G, Guarino A. Severe and protracted diarrhea: results of the 3-year SIGEP multicenter survey. J Pediatr Gastroenterol Nutr. 1999;29:63–68.

    Article  CAS  PubMed  Google Scholar 

  9. Bousvaros A, Leichtner AM, Book L, et al. Treatment of pediatric autoimmune enteropathy with tacrolimus (FK506). Gastroenterology. 1996;111:237–243.

    Article  CAS  PubMed  Google Scholar 

  10. Mirakian R, Hill S, Richardson A, Milla PJ, Walker-Smith JA, Bottazzo GF. HLA product expression and lymphocyte subpopulations in jejunum biopsies of children with idiopathic protracted diarrhoea and enterocyte autoantibodies. J Autoimmun. 1988;1:263–277.

    Article  CAS  PubMed  Google Scholar 

  11. Mirakian R, Richardson A, Milla PJ, et al. Protracted diarrhoea of infancy: evidence in support of an autoimmune variant. BMJ. 1986;293:1132–1136.

    Article  CAS  PubMed  Google Scholar 

  12. Quirós-Tejeira RE, Ament ME, Vargas JH. Induction of remission in a child with autoimmune enteropathy using mycophenolate mofetil. J Pediatr Gastroenterol Nutr. 2003;36:482–485.

    Article  PubMed  Google Scholar 

  13. Guarino A, De Marco G. Failure INNfPI. Natural history of intestinal failure, investigated through a national network-based approach. J Pediatr Gastroenterol Nutr. 2003;37:136–141.

    Article  PubMed  Google Scholar 

  14. Ruemmele FM, Brousse N, Goulet O. Autoimmune enteropathy: molecular concepts. Curr Opin Gastroenterol. 2004;20:587–591.

    Article  PubMed  Google Scholar 

  15. Montalto M, D’Onofrio F, Santoro L, Gallo A, Gasbarrini A, Gasbarrini G. Autoimmune enteropathy in children and adults. Scand J Gastroenterol. 2009;44:1029–1036.

    Article  CAS  PubMed  Google Scholar 

  16. Catassi C, Mirakian R, Natalini G, et al. Unresponsive enteropathy associated with circulating enterocyte autoantibodies in a boy with common variable hypogammaglobulinemia and type I diabetes. J Pediatr Gastroenterol Nutr. 1988;7:608–673.

    Article  CAS  PubMed  Google Scholar 

  17. Valitutti F, Barbato M, Aloi M, et al. Autoimmune enteropathy in a 13-year-old celiac girl successfully treated with infliximab. J Clin Gastroenterol. 2014;48:264–266.

    Article  PubMed  Google Scholar 

  18. Savage M, Mirakian R, Harries J, Bottazzo G. Could protracted diarrhoea of infancy have an autoimmune pathogenesis? Lancet. 1982;319:966–967.

    Article  Google Scholar 

  19. Martini A, Scotta M, Notarangelo L, Maggiore G, Guarnaccia S, Giacomo Cd. Membranous glomerulopathy and chronic small-intestinal enteropathy associated with autoantibodies directed against renal tubular basement membrane and the cytoplasm of intestinal epithelial cells. Acta Paediatr. 1983;72:931–934.

    Article  CAS  Google Scholar 

  20. Corazza GR, Biagi F, Volta U, Andreani ML, De Franceschi L, Gasbarrini G. Autoimmune enteropathy and villous atrophy in adults. Lancet. 1997;350:106–109.

    Article  CAS  PubMed  Google Scholar 

  21. León F, Olivencia P, Rodríguez-Pena R, et al. Clinical and immunological features of adult-onset generalized autoimmune gut disorder. Am J Gastroenterol. 2004;99:1563–1571.

    Article  PubMed  Google Scholar 

  22. Hasan SS, Siddiqui NS, Arudra SKC, de Las Casas L, Akpunonu B, Nawras A. Diffuse autoimmune enteropathy and colopathy in an adult patient successfully treated with adalimumab and a review of the literature. Am J Ther. 2014;23:e963.

    Article  Google Scholar 

  23. Al Khalidi H, Kandel G, Streutker CJ. Enteropathy with loss of enteroendocrine and paneth cells in a patient with immune dysregulation: a case of adult autoimmune enteropathy. Hum Pathol. 2006;37:373–376.

    Article  PubMed  Google Scholar 

  24. Volta U, De Angelis G, Granito A, et al. Autoimmune enteropathy and rheumatoid arthritis: a new association in the field of autoimmunity. Dig Liver Dis. 2006;38:926–929.

    Article  CAS  PubMed  Google Scholar 

  25. Elwing JE, Clouse RE. Adult-onset autoimmune enteropathy in the setting of thymoma successfully treated with infliximab. Dig Dis Sci. 2005;50:928–932. https://doi.org/10.1007/s10620-005-2666-x

    Article  PubMed  Google Scholar 

  26. Bland P. MHC class II expression by the gut epithelium. Immunol Today. 1988;9:174–178.

    Article  CAS  PubMed  Google Scholar 

  27. Hill S, Milla P, Bottazzo G, Mirakian R. Autoimmune enteropathy and colitis: Is there a generalised autoimmune gut disorder? Gut. 1991;32:36–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cuenod B, Brousse N, Goulet O, et al. Classification of intractable diarrhea in infancy using clinical and immunohistological criteria. Gastroenterology. 1990;99:1037–1043.

    Article  CAS  PubMed  Google Scholar 

  29. Ciccocioppo S R, D’alo S, Sabatino A, et al. Mechanisms of villous atrophy in autoimmune enteropathy and coeliac disease. Clin Exper Immunol. 2002;128:88–93.

    Article  Google Scholar 

  30. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92:34–48.

    Article  CAS  PubMed  Google Scholar 

  31. McCarthy D, Katz S, Gazze L, Waldmann T, Nelson D, Strober W. Selective IgA deficiency associated with total villous atrophy of the small intestine and an organ-specific anti-epithelial cell antibody. J Immunol. 1978;120:932–938.

    CAS  PubMed  Google Scholar 

  32. Bennett CL, Brunkow ME, Ramsdell F, et al. A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA → AAUGAA) leads to the IPEX syndrome. Immunogenetics. 2001;53:435–439.

    Article  CAS  PubMed  Google Scholar 

  33. Khattri R, Cox T, Yasayko S-A, Ramsdell F. An essential role for Scurfin in CD4 + CD25 + T regulatory cells. Nat Immunol. 2003;4:337–342.

    Article  CAS  PubMed  Google Scholar 

  34. Wildin R, Smyk-Pearson S, Filipovich A. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet. 2002;39:537–545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Owen CJ, Jennings CE, Imrie H, et al. Mutational analysis of the FOXP3 gene and evidence for genetic heterogeneity in the immunodysregulation, polyendocrinopathy, enteropathy syndrome. J Clin Endocrinol Metab. 2003;88:6034–6039.

    Article  CAS  PubMed  Google Scholar 

  36. Heltzer ML, Choi JK, Ochs HD, Sullivan KE, Torgerson TR, Ernst LM. A potential screening tool for IPEX syndrome. Pediatr Dev Pathol. 2007;10:98–105.

    Article  CAS  PubMed  Google Scholar 

  37. Aaltonen J, Björses P. Cloning of the APECED gene provides new insight into human autoimmunity. Ann Med. 1999;31:111–116.

    Article  CAS  PubMed  Google Scholar 

  38. Lankisch TO, Strassburg CP, Debray D, Manns MP, Jacquemin E. Detection of autoimmune regulator gene mutations in children with type 2 autoimmune hepatitis and extrahepatic immune-mediated diseases. J Pediatr. 2005;146:839–842.

    Article  CAS  PubMed  Google Scholar 

  39. Savilahti E, Pelkonen P, Holmberg C, Perkkiö M, Unsworth J. Fatal unresponsive villous atrophy of the jejunum, connective tissue disease and diabetes in a girl with intestinal epithelial cell antibody. Acta Paediatr. 1985;74:472–476.

    Article  CAS  Google Scholar 

  40. Fiocchi C, Roche JK, Michener WM. High prevalence of antibodies to intestinal epithelial antigens in patients with inflammatory bowel disease and their relatives. Ann Intern Med. 1989;110:786–794.

    Article  CAS  PubMed  Google Scholar 

  41. Walker-Smith J, Unsworth D, Hutchins P, Phillips A, Holborow E. Autoantibodies against gut epithelium in child with small-intestinal enteropathy. Lancet. 1982;319:566–567.

    Article  Google Scholar 

  42. Virological S. Anti-goblet cell antibodies for the diagnosis of autoimmune enteropathy? Lancet. 1997;350:959–960.

    Google Scholar 

  43. Martin-Villa J, Camblor S, Costa R, Arnaiz-Villena A. Gut epithelial cell autoantibodies in AIDS pathogenesis. Lancet. 1993;342:380.

    Article  CAS  PubMed  Google Scholar 

  44. Biagi F, Bianchi PI, Trotta L, Corazza GR. Anti-goblet cell antibodies for the diagnosis of autoimmune enteropathy? Am J Gastroenterol. 2009;104:3112.

    Article  CAS  PubMed  Google Scholar 

  45. Kobayashi I, Imamura K, Kubota M, et al. Identification of an autoimmune enteropathy—related 75-kilodalton antigen. Gastroenterology. 1999;117:823–830.

    Article  CAS  PubMed  Google Scholar 

  46. Colletti RB, Guillot AP, Rosen S, et al. Autoimmune enteropathy and nephropathy with circulating anti-epithelial cell antibodies. J Pediatr. 1991;118:858–864.

    Article  CAS  PubMed  Google Scholar 

  47. Singhi AD, Goyal A, Davison JM, Regueiro MD, Roche RL, Ranganathan S. Pediatric autoimmune enteropathy: an entity frequently associated with immunodeficiency disorders. Mod Pathol. 2014;27:543–553.

    Article  CAS  PubMed  Google Scholar 

  48. de Serre NP-M, Canioni D, Ganousse S, et al. Digestive histopathological presentation of IPEX syndrome. Mod Pathol. 2009;22:95–102.

    Article  CAS  Google Scholar 

  49. Masia R, Peyton S, Lauwers GY, Brown I. Gastrointestinal biopsy findings of autoimmune enteropathy: a review of 25 cases. Am J Surg Pathol. 2014;38:1319–1329.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Scialom S, Malamut G, Meresse B, et al. Gastrointestinal disorder associated with olmesartan mimics autoimmune enteropathy. PLoS ONE. 2015;10:e0125024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Assarzadegan N, Montgomery E, Anders RA. Immune checkpoint inhibitor colitis: the flip side of the wonder drugs Virchows. Archiv Int J Pathol. 2018;472:125–133.

    Article  CAS  Google Scholar 

  52. Jonas MM, Bell MD, Eidson MS, Koutouby R, Hensley GT. Congenital diabetes mellitus and fatal secretory diarrhea in two infants. J Pediatr Gastroenterol Nutr. 1991;13:415–425.

    Article  CAS  PubMed  Google Scholar 

  53. Barzaghi F, Amaya Hernandez LC, Neven B, et al. Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: an international multicenter retrospective study. J Allergy Clin Immunol. 2018;141:e1035.

    Article  Google Scholar 

  54. von Hahn T, Stopik D, Koch M, Wiedenmann B, Dignass A. Management of severe refractory adult autoimmune enteropathy with infliximab and tacrolimus. Digestion. 2004;71:141–144.

    Article  CAS  Google Scholar 

  55. Vanderhoof JA, Young RJ. Autoimmune enteropathy in a child: response to infliximab therapy. J Pediatr Gastroenterol Nutr. 2002;34:312–316.

    Article  PubMed  Google Scholar 

  56. Gupta NK, Yilmaz O, Fisher M, Yajnik V. Abatacept: a new treatment option for refractory adult autoimmune enteropathy. J Clin Gastroenterol. 2014;48:55–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Murch SH, Fertleman CR, Rodrigues C, et al. Autoimmune enteropathy with distinct mucosal features in T-cell activation deficiency: the contribution of T cells to the mucosal lesion. J Pediatr Gastroenterol Nutr. 1999;28:393–399.

    Article  CAS  PubMed  Google Scholar 

  58. Horino S, Sasahara Y, Sato M, et al. Selective expansion of donor-derived regulatory T cells after allogeneic bone marrow transplantation in a patient with IPEX syndrome. Pediatr Transplant. 2014;18:E25–E30.

    Article  CAS  PubMed  Google Scholar 

  59. Maccario R, Podestà M, Moretta A, et al. Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4 + T-cell subsets expressing a regulatory/suppressive phenotype. Haematologica. 2005;90:516–525.

    CAS  PubMed  Google Scholar 

  60. Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107:367–372.

    Article  CAS  Google Scholar 

  61. Parekkadan B, Tilles AW, Yarmush ML. Bone marrow-derived mesenchymal stem cells ameliorate autoimmune enteropathy independently of regulatory T cells. Stem Cells. 2008;26:1913–1919.

    Article  PubMed  Google Scholar 

  62. Ciccocioppo R, Bernardo ME, Sgarella A, et al. Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut. 2011;60:788–798.

    Article  Google Scholar 

  63. Ciccocioppo R, Russo ML, Bernardo ME, et al. Mesenchymal stromal cell infusions as rescue therapy for corticosteroid-refractory adult autoimmune enteropathy. Mayo Clin Proc. 2012;87:909–914.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Gambarara M, Bracci F, Diamanti A, et al. Long-term parenteral nutrition in pediatric autoimmune enteropathies. Transpl Proc. 2005;37:2270–2271.

    Article  CAS  Google Scholar 

  65. Rolny P, Sigurjonsdottir H, Remotti H, et al. Role of immunosuppressive therapy in refractory sprue-like disease. Am J Gastroenterol. 1999;94:219–225.

    Article  CAS  PubMed  Google Scholar 

  66. Perheentupa J. APS-I/APECED: the clinical disease and therapy. Endocrinol Metab Clin N Am. 2002;31:295–320.

    Article  Google Scholar 

  67. Rao A, Kamani N, Filipovich A, et al. Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Blood. 2007;109:383–385.

    Article  CAS  PubMed  Google Scholar 

  68. Mazzolari E, Forino C, Fontana M, et al. A new case of IPEX receiving bone marrow transplantation. Bone Marrow Transplant. 2005;35:1033–1034.

    Article  CAS  PubMed  Google Scholar 

  69. Baud O, Goulet O, Canioni D, et al. Treatment of the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) by allogeneic bone marrow transplantation. N Engl J Med. 2001;344:1758–1762.

    Article  CAS  PubMed  Google Scholar 

  70. Zhan H, Sinclair J, Adams S, et al. Immune reconstitution and recovery of FOXP3 (forkhead box P3)-expressing T cells after transplantation for IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome. Pediatrics. 2008;121:e998–e1002.

    Article  PubMed  Google Scholar 

  71. Seidel MG, Fritsch G, Lion T, et al. Selective engraftment of donor CD4 + 25 high FOXP3-positive T cells in IPEX syndrome after nonmyeloablative hematopoietic stem cell transplantation. Blood. 2009;113:5689–5691.

    Article  CAS  PubMed  Google Scholar 

  72. Nademi Z, Slatter M, Gambineri E, et al. Single centre experience of haematopoietic SCT for patients with immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Bone Marrow Transplant. 2014;49:310–312.

    Article  CAS  PubMed  Google Scholar 

  73. Lucas KG, Ungar D, Comito M, Bayerl M, Groh B. Submyeloablative cord blood transplantation corrects clinical defects seen in IPEX syndrome. Bone Marrow Transplant. 2007;39:55–56.

    Article  CAS  PubMed  Google Scholar 

  74. Kucuk ZY, Bleesing JJ, Marsh R, Zhang K, Davies S, Filipovich AH. A challenging undertaking: Stem cell transplantation for immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. J Allergy Clin Immunol. 2016;137:953.e954–955.e954.

    Article  Google Scholar 

  75. Burroughs LM, Torgerson TR, Storb R, et al. Stable hematopoietic cell engraftment after low-intensity nonmyeloablative conditioning in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. J Allergy Clin Immunol. 2010;126:1000–1005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Dorsey MJ, Petrovic A, Morrow MR, Dishaw LJ, Sleasman JW. FOXP3 expression following bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Immunol Res. 2009;44:179–184.

    Article  CAS  PubMed  Google Scholar 

  77. Kasow KA, Morales-Tirado VM, Wichlan D, et al. Therapeutic in vivo selection of thymic-derived natural T regulatory cells following non-myeloablative hematopoietic stem cell transplant for IPEX. Clin Immunol (Orlando, Fla.). 2011;141:169–176.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. School of Medicine, University of Alabama, Montgomery Campus, 2055 E South Blvd Ste 202, Montgomery, AL, 36116, USA

    Zunirah Ahmed

  2. Division of Pediatric Gastroenterology, SUNY Upstate Medical University, 725 Irving Street, Suite 501, Syracuse, NY, 13210, USA

    Aamer Imdad

  3. Division of Pediatric Hematology-Oncology, Vanderbilt University Medical Center, 2100 Children’s Way, Nashville, TN, 37212, USA

    James A. Connelly

  4. Division of Pediatric Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, 2100 Children’s Way, Nashville, TN, 37212, USA

    Sari Acra

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  1. Zunirah Ahmed
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  2. Aamer Imdad
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  3. James A. Connelly
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  4. Sari Acra
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Dr Zunirah Ahmed and Aamer Imdad did the literature search and wrote the first draft. Dr. James A. Connelly and Dr. Sari Acra supervised and gave feedback at each stage of manuscript writing.

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Correspondence to Sari Acra.

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Ahmed, Z., Imdad, A., Connelly, J.A. et al. Autoimmune Enteropathy: An Updated Review with Special Focus on Stem Cell Transplant Therapy. Dig Dis Sci 64, 643–654 (2019). https://doi.org/10.1007/s10620-018-5364-1

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