Abstract
Autoimmune enteropathy (AIE) is a rare condition characterized by intractable diarrhea and immune-mediated injury of the intestinal mucosa. As the clinical and histopathologic manifestations of this disease are highly variable, its diagnosis is challenging for both clinicians and pathologists. In fact, the term autoimmune enteropathies is likely more appropriate since the clinicopathologic manifestations are observed in association with a heterogeneous group of disorders. The pathophysiology of AIE has not been fully elucidated. It appears to result from dysregulation of intestinal immunity and particularly in children, often presents in association with immunodeficiency. The overarching histopathologic changes seen in AIE include mucosal inflammation and epithelial injury, although this can manifest in the form of different patterns. Recognition of the clinical settings and of the various histologic patterns can aid the pathologist in establishing the correct diagnosis.
Similar content being viewed by others
References
Unsworth DJ, Walker-Smith JA (1985) Autoimmunity in diarrhoeal disease. J Pediatr Gastroenterol Nutr 4(3):375–380
Akram S, Murray JA, Pardi DS, Alexander GL, Schaffner JA, Russo PA, Abraham SC (2007) Adult autoimmune enteropathy: Mayo Clinic Rochester experience. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 5(11):1282–1290; quiz 1245. https://doi.org/10.1016/j.cgh.2007.05.013
Catassi C, Fabiani E, Spagnuolo MI, Barera G, Guarino A (1999) Severe and protracted diarrhea: results of the 3-year SIGEP multicenter survey. Working Group of the Italian Society of Pediatric Gastroenterology and Hepatology (SIGEP). J Pediatr Gastroenterol Nutr 29(1):63–68
Goulet OJ, Brousse N, Canioni D, Walker-Smith JA, Schmitz J, Phillips AD (1998) Syndrome of intractable diarrhoea with persistent villous atrophy in early childhood: a clinicopathological survey of 47 cases. J Pediatr Gastroenterol Nutr 26(2):151–161
Patey-Mariaud de Serre N, Canioni D, Ganousse S, Rieux-Laucat F, Goulet O, Ruemmele F, Brousse N (2009) Digestive histopathological presentation of IPEX syndrome. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 22(1):95–102. https://doi.org/10.1038/modpathol.2008.161
Singhi AD, Goyal A, Davison JM, Regueiro MD, Roche RL, Ranganathan S (2014) Pediatric autoimmune enteropathy: an entity frequently associated with immunodeficiency disorders. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 27(4):543–553. https://doi.org/10.1038/modpathol.2013.150
Bacchetta R, Barzaghi F, Roncarolo MG (2016) From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation. Ann N Y Acad Sci. https://doi.org/10.1111/nyas.13011
Bennett CL, Ochs HD (2001) IPEX is a unique X-linked syndrome characterized by immune dysfunction, polyendocrinopathy, enteropathy, and a variety of autoimmune phenomena. Curr Opin Pediatr 13(6):533–538
Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, Schickel JN, Tran DQ, Stoddard J, Zhang Y, Frucht DM, Dumitriu B, Scheinberg P, Folio LR, Frein CA, Price S, Koh C, Heller T, Seroogy CM, Huttenlocher A, Rao VK, HC S, Kleiner D, Notarangelo LD, Rampertaap Y, Olivier KN, McElwee J, Hughes J, Pittaluga S, Oliveira JB, Meffre E, Fleisher TA, Holland SM, Lenardo MJ, Tangye SG, Uzel G (2014) Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 345(6204):1623–1627. https://doi.org/10.1126/science.1255904
Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A, Bulashevska A, Petersen BS, Schaffer AA, Gruning BA, Unger S, Frede N, Baumann U, Witte T, Schmidt RE, Dueckers G, Niehues T, Seneviratne S, Kanariou M, Speckmann C, Ehl S, Rensing-Ehl A, Warnatz K, Rakhmanov M, Thimme R, Hasselblatt P, Emmerich F, Cathomen T, Backofen R, Fisch P, Seidl M, May A, Schmitt-Graeff A, Ikemizu S, Salzer U, Franke A, Sakaguchi S, Walker LS, Sansom DM, Grimbacher B (2014) Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med 20(12):1410–1416. https://doi.org/10.1038/nm.3746
Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Niemela JE, Lyons JJ, Engelhardt KR, Zhang Y, Topcagic N, Roberson ED, Matthews H, Verbsky JW, Dasu T, Vargas-Hernandez A, Varghese N, McClain KL, Karam LB, Nahmod K, Makedonas G, Mace EM, Sorte HS, Perminow G, Rao VK, O’Connell MP, Price S, Su HC, Butrick M, McElwee J, Hughes JD, Willet J, Swan D, Xu Y, Santibanez-Koref M, Slowik V, Dinwiddie DL, Ciaccio CE, Saunders CJ, Septer S, Kingsmore SF, White AJ, Cant AJ, Hambleton S, Cooper MA (2015) Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood 125(4):591–599. https://doi.org/10.1182/blood-2014-09-602763
Uzel G, Sampaio EP, Lawrence MG, Hsu AP, Hackett M, Dorsey MJ, Noel RJ, Verbsky JW, Freeman AF, Janssen E, Bonilla FA, Pechacek J, Chandrasekaran P, Browne SK, Agharahimi A, Gharib AM, Mannurita SC, Yim JJ, Gambineri E, Torgerson T, Tran DQ, Milner JD, Holland SM (2013) Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. J Allergy Clin Immunol 131(6):1611–1623. https://doi.org/10.1016/j.jaci.2012.11.054
Lohr NJ, Molleston JP, Strauss KA, Torres-Martinez W, Sherman EA, Squires RH, Rider NL, Chikwava KR, Cummings OW, Morton DH, Puffenberger EG (2010) Human ITCH E3 ubiquitin ligase deficiency causes syndromic multisystem autoimmune disease. Am J Hum Genet 86(3):447–453. https://doi.org/10.1016/j.ajhg.2010.01.028
Verbsky JW, Chatila TA (2013) Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases. Curr Opin Pediatr 25(6):708–714. https://doi.org/10.1097/MOP.0000000000000029
Walter JE, Farmer JR, Foldvari Z, Torgerson TR, Cooper MA (2016) Mechanism-based strategies for the management of autoimmunity and immune dysregulation in primary immunodeficiencies. J Allergy Clin Immunol Pract 4(6):1089–1100. https://doi.org/10.1016/j.jaip.2016.08.004
Kisand K, Peterson P (2015) Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol 35(5):463–478. https://doi.org/10.1007/s10875-015-0176-y
Agarwal S, Cunningham-Rundles C (2009) Autoimmunity in common variable immunodeficiency. Curr Allergy Asthma Rep 9(5):347–352
Genre J, Errante PR, Kokron CM, Toledo-Barros M, Camara NO, Rizzo LV (2009) Reduced frequency of CD4(+)CD25(HIGH)FOXP3(+) cells and diminished FOXP3 expression in patients with common variable immunodeficiency: a link to autoimmunity? Clin Immunol 132(2):215–221. https://doi.org/10.1016/j.clim.2009.03.519
Leon F, Olivencia P, Rodriguez-Pena R, Sanchez L, Redondo C, Alvarez I, Moreira V, Roy G (2004) Clinical and immunological features of adult-onset generalized autoimmune gut disorder. Am J Gastroenterol 99(8):1563–1571. https://doi.org/10.1111/j.1572-0241.2004.40039.x
Corazza GR, Biagi F, Volta U, Andreani ML, De Franceschi L, Gasbarrini G (1997) Autoimmune enteropathy and villous atrophy in adults. Lancet 350(9071):106–109. https://doi.org/10.1016/S0140-6736(97)01042-8
Geyer M, Fairchild J, Moore D, Moore L, Henning P, Tham E (2014) Recalcitrant hypocalcaemia in autoimmune enteropathy. Pediatrics 134(6):e1720–e1726. https://doi.org/10.1542/peds.2013-3308
Volta U, De Angelis GL, Granito A, Petrolini N, Fiorini E, Guidi M, Muratori P, Bianchi FB (2006) Autoimmune enteropathy and rheumatoid arthritis: a new association in the field of autoimmunity. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 38(12):926–929. https://doi.org/10.1016/j.dld.2006.02.003
Mais DD, Mulhall BP, Adolphson KR, Yamamoto K (1999) Thymoma-associated autoimmune enteropathy. A report of two cases. Am J Clin Pathol 112(6):810–815
Volta U, Mumolo MG, Caio G, Boschetti E, Latorre R, Giancola F, Paterini P, De Giorgio R (2016) Autoimmune enteropathy: not all flat mucosa mean coeliac disease. Gastroenterology and hepatology from bed to bench 9(2):140–145
Elwing JE, Clouse RE (2005) Adult-onset autoimmune enteropathy in the setting of thymoma successfully treated with infliximab. Dig Dis Sci 50(5):928–932
Masia R, Peyton S, Lauwers GY, Brown I (2014) Gastrointestinal biopsy findings of autoimmune enteropathy: a review of 25 cases. Am J Surg Pathol 38(10):1319–1329. https://doi.org/10.1097/PAS.0000000000000317
Montalto M, D’Onofrio F, Santoro L, Gallo A, Gasbarrini A, Gasbarrini G (2009) Autoimmune enteropathy in children and adults. Scand J Gastroenterol 44(9):1029–1036. https://doi.org/10.1080/00365520902783691
Wurm P, Spindelboeck W, Krause R, Plank J, Fuchs G, Bashir M, Petritsch W, Halwachs B, Langner C, Hogenauer C, Gorkiewicz G (2017) Antibiotic-associated apoptotic enterocolitis in the absence of a defined pathogen: the role of intestinal microbiota depletion. Crit Care Med 45(6):e600–e606. https://doi.org/10.1097/CCM.0000000000002310
Abdel-Rahman O, ElHalawani H, Fouad M (2015) Risk of gastrointestinal complications in cancer patients treated with immune checkpoint inhibitors: a meta-analysis. Immunotherapy 7(11):1213–1227. https://doi.org/10.2217/imt.15.87
Mirakian R, Hill S, Richardson A, Milla PJ, Walker-Smith JA, Bottazzo GF (1988) HLA product expression and lymphocyte subpopulations in jejunum biopsies of children with idiopathic protracted diarrhoea and enterocyte autoantibodies. J Autoimmun 1(3):263–277
Dahan S, Roth-Walter F, Arnaboldi P, Agarwal S, Mayer L (2007) Epithelia: lymphocyte interactions in the gut. Immunol Rev 215:243–253. https://doi.org/10.1111/j.1600-065X.2006.00484.x
Reynoso ED, Elpek KG, Francisco L, Bronson R, Bellemare-Pelletier A, Sharpe AH, Freeman GJ, Turley SJ (2009) Intestinal tolerance is converted to autoimmune enteritis upon PD-1 ligand blockade. J Immunol 182(4):2102–2112. https://doi.org/10.4049/jimmunol.0802769
Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, Restifo NP, Haworth LR, Seipp CA, Freezer LJ, Morton KE, Mavroukakis SA, Duray PH, Steinberg SM, Allison JP, Davis TA, Rosenberg SA (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A 100(14):8372–8377. https://doi.org/10.1073/pnas.1533209100
Oble DA, Mino-Kenudson M, Goldsmith J, Hodi FS, Seliem RM, Dranoff G, Mihm M, Hasserjian R, Lauwers GY (2008) Alpha-CTLA-4 mAb-associated panenteritis: a histologic and immunohistochemical analysis. Am J Surg Pathol 32(8):1130–1137. https://doi.org/10.1097/PAS.0b013e31817150e3
Kambayashi T, Laufer TM (2014) Atypical MHC class II-expressing antigen-presenting cells: can anything replace a dendritic cell? Nat Rev Immunol 14(11):719–730. https://doi.org/10.1038/nri3754
Fiocchi C, Roche JK, Michener WM (1989) High prevalence of antibodies to intestinal epithelial antigens in patients with inflammatory bowel disease and their relatives. Ann Intern Med 110(10):786–794
Martin-Villa JM, Camblor S, Costa R, Arnaiz-Villena A (1993) Gut epithelial cell autoantibodies in AIDS pathogenesis. Lancet 342(8867):380
Skogh T, Heuman R, Tagesson C (1982) Anti-brush border antibodies (ABBA) in Crohn’s disease. J Clin Lab Immunol 9(3):147–150
Biagi F, Bianchi PI, Trotta L, Corazza GR (2009) Anti-goblet cell antibodies for the diagnosis of autoimmune enteropathy? Am J Gastroenterol 104(12):3112. https://doi.org/10.1038/ajg.2009.511
Walker-Smith JA, Unsworth DJ, Hutchins P, Phillips AD, Holborow EJ (1982) Autoantibodies against gut epithelium in child with small-intestinal enteropathy. Lancet 1(8271):566–567
Moran CJ, Kolman OK, Russell GJ, Brown IS, Mino-Kenudson M (2012) Neutrophilic infiltration in gluten-sensitive enteropathy is neither uncommon nor insignificant: assessment of duodenal biopsies from 267 pediatric and adult patients. Am J Surg Pathol 36(9):1339–1345. https://doi.org/10.1097/PAS.0b013e318254f413
Tegtmeyer D, Seidl M, Gerner P, Baumann U, Klemann C (2017) IBD due to PID: inflammatory bowel disease caused by primary immunodeficiencies-clinical presentations, review of literature, and proposal of a rational diagnostic algorithm. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. https://doi.org/10.1111/pai.12734
Fontaine JL, Navarro J (1975) Small intestinal biopsy in cows milk protein allergy in infancy. Arch Dis Child 50(5):357–362
Maluenda C, Phillips AD, Briddon A, Walker-Smith JA (1984) Quantitative analysis of small intestinal mucosa in cow’s milk-sensitive enteropathy. J Pediatr Gastroenterol Nutr 3(3):349–356
Gonzalez RS, Salaria SN, Bohannon CD, Huber AR, Feely MM, Shi C (2017) PD-1 inhibitor gastroenterocolitis: case series and appraisal of ‘immunomodulatory gastroenterocolitis. Histopathology 70(4):558–567. https://doi.org/10.1111/his.13118
Coutzac C, Adam J, Soularue E, Collins M, Racine A, Mussini C, Boselli L, Kamsukom N, Mateus C, Charrier M, Cassard L, Planchard D, Ribrag V, Fizazi K, Loriot Y, Lepage P, Scoazec J-Y, Robert C, Carbonnel F, Chaput N (2017) Colon immune-related adverse events: anti-CTLA-4 and anti-PD-1 blockade induce distinct immunopathologic entities. J Crohn’s Colitis 11. https://doi.org/10.1093/ecco-jcc/jjx081
Bamias G, Delladetsima I, Perdiki M, Siakavellas SI, Goukos D, Papatheodoridis GV, Daikos GL, Gogas H (2017) Immunological characteristics of colitis associated with anti-CTLA-4 antibody therapy. Cancer Investig:1–13. https://doi.org/10.1080/07357907.2017.1324032
Collins M, Michot JM, Danlos FX, Champiat S, Mussini C, Soularue E, Mateus C, Loirat D, Buisson A, Rosa I, Lambotte O, Laghouati S, Voisin AL, Soria JC, Marabelle A, Robert C, Carbonnel F (2017) P315 gastrointestinal immune related adverse events associated with programmed-Death 1 blockade. Journal of Crohn’s and Colitis 11 (suppl_1):S237-S237. doi:https://doi.org/10.1093/ecco-jcc/jjx002.440
Weidner AS, Panarelli NC, Geyer JT, Bhavsar EB, Furman RR, Leonard JP, Jessurun J, Yantiss RK (2015) Idelalisib-associated colitis: histologic findings in 14 patients. Am J Surg Pathol 39(12):1661–1667. https://doi.org/10.1097/PAS.0000000000000522
Louie CY, DiMaio MA, Matsukuma KE, Coutre SE, Berry GJ, Longacre TA (2015) Idelalisib-associated enterocolitis: clinicopathologic features and distinction from other enterocolitides. Am J Surg Pathol 39(12):1653–1660. https://doi.org/10.1097/PAS.0000000000000525
Rubio-Tapia A, Herman ML, Ludvigsson JF, Kelly DG, Mangan TF, TT W, Murray JA (2012) Severe spruelike enteropathy associated with olmesartan. Mayo Clin Proc 87(8):732–738. https://doi.org/10.1016/j.mayocp.2012.06.003
Scialom S, Malamut G, Meresse B, Guegan N, Brousse N, Verkarre V, Derrieux C, Macintyre E, Seksik P, Savoye G, Cadiot G, Vuitton L, Marthey L, Carbonnel F, Cerf-Bensussan N, Cellier C (2015) Gastrointestinal disorder associated with olmesartan mimics autoimmune enteropathy. PLoS One 10(6):e0125024. https://doi.org/10.1371/journal.pone.0125024
Marthey L, Cadiot G, Seksik P, Pouderoux P, Lacroute J, Skinazi F, Mesnard B, Chayvialle JA, Savoye G, Druez A, Parlier D, Abitbol V, Gompel M, Eoche M, Poncin E, Bobichon R, Colardelle P, Wils P, Salloum H, Peschard S, Zerbib F, Meresse B, Cerf-Bensussan N, Malamut G, Carbonnel F (2014) Olmesartan-associated enteropathy: results of a national survey. Aliment Pharmacol Ther 40(9):1103–1109. https://doi.org/10.1111/apt.12937
Esteve M, Temino R, Carrasco A, Batista L, Del Val A, Ble M, Santaolaria S, Molina-Infante J, Soriano G, Agudo S, Zabana Y, Andujar X, Aceituno M, Ribes J, Madridejos R, Fernandez-Banares F (2016) Potential coeliac disease markers and autoimmunity in olmesartan induced enteropathy: a population-based study. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 48(2):154–161. https://doi.org/10.1016/j.dld.2015.09.014
Lagana SM, Braunstein ED, Arguelles-Grande C, Bhagat G, Green PH, Lebwohl B (2015) Sprue-like histology in patients with abdominal pain taking olmesartan compared with other angiotensin receptor blockers. J Clin Pathol 68(1):29–32. https://doi.org/10.1136/jclinpath-2014-202615
Marietta EV, Nadeau AM, Cartee AK, Singh I, Rishi A, Choung RS, TT W, Rubio-Tapia A, Murray JA (2015) Immunopathogenesis of olmesartan-associated enteropathy. Aliment Pharmacol Ther 42(11–12):1303–1314. https://doi.org/10.1111/apt.13413
Gentile NM, Murray JA, Pardi DS (2012) Autoimmune enteropathy: a review and update of clinical management. Current gastroenterology reports 14(5):380–385. https://doi.org/10.1007/s11894-012-0276-2
Ruemmele FM, Brousse N, Goulet O (2004) Autoimmune enteropathy: molecular concepts. Curr Opin Gastroenterol 20(6):587–591
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Umetsu, S.E., Brown, I., Langner, C. et al. Autoimmune enteropathies. Virchows Arch 472, 55–66 (2018). https://doi.org/10.1007/s00428-017-2243-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00428-017-2243-7