Immundefekte als Ursache von chronisch-entzündlichen Erkrankungen des Darmes

Zusammenfassung

Chronisch-entzündliche Darmerkrankungen (CED), mit ihren beiden prominentesten Vertretern M. Crohn und Colitis ulcerosa, zeichnen sich durch eine multifaktorielle Ätiologie mit komplexer Regulation zwischen polygenetischer Grundlage und Umwelteinflüssen aus. In den letzten Jahren wurden zahlreiche, jedoch insgesamt seltene, monogenetische Erkrankungen identifiziert, die sich mit einem CED-Phänotyp manifestieren können. Das frühe Erkennen und Anpassen der Therapien dieser heterogenen, immunologischen Erkrankungen sind von hoher Relevanz für den weiteren Verlauf der Erkrankung. In diesem Review diskutieren wir charakteristische Befunde und Umstände, die an das Vorliegen einer monogenetischen Ursache für die intestinale Inflammation denken lassen: Hinweisend können ein früher Krankheitsbeginn, ein Versagen klassischer Therapien, elterliche Konsanguinität, eine auffallende Infektanfälligkeit oder CED-untypische Begleiterkrankungen, Pathologien oder Blutwerte sein. Wir beschreiben ausgewählte Erkrankungen anhand von Fallbeispielen und zeigen auf, wie diese Erkrankungen durch die Kombination von anamnestischen Angaben und klinischen, zellulären sowie genetischen Untersuchungen diagnostiziert werden können. Hierfür schlagen wir eine gestufte, diagnostische Strategie vor, um diesen außergewöhnlichen Erkrankungen als Differenzialdiagnose einer CED nachzugehen.

Summary

Inflammatory bowel diseases (IBD) including Crohn’s disease and ulcerative colitis have a multifactorial pathogenesis with a complex interaction between polygenetic predispositions and environmental factors. Recently, several but alltogether rare monogenetic diseases mimicking an IBD-phenotype have been identified. Early recognition of these conditions and adaption of therapies are highly important for the course of these diseases. In this review we discuss findings that may direct to monogenetic causes of intestinal inflammation such as early onset of disease, failure to respond to standard therapeutic regiments, parental consanguinity, increased susceptibility to infections, or related symptoms, pathology or blood results atypical for CED. We describe selected diseases and discuss in case studies how these conditions can be diagnosed by a combination of patient history, and cellular as well as genetic analyses. Finally, we propose a rational diagnostic pathway to elucidate the underlying cause of these differentials of IBD.

Schlüsselwörter

Immundefekt - chronisch-entzündliche Darmerkrankung (CED) - monogenetische Ursachen von CED

Keywords

Immundeficiency - Inflammatory Bowel Disease (IBD) - monogenetic causes of IBD

^* CK & DT trugen zu gleichen Teilen zum vorliegenden Manuskript bei.

• Literatur

• 1 Helander HF, Fändriks L. Surface area of the digestive tract – revisited. Scand J Gastroenterol 2014; 49: 681-689 doi:
• 2 McCabe RP. Gastrointestinal Manifestations of Non-AIDS Immunodeficiency. Curr Treat Options Gastroenterol 2002; 5: 17-25.
• 3 Spahn TW, Kucharzik T. Modulating the intestinal immune system: the role of lymphotoxin and GALT organs. Gut 2004; 53: 456-465.
• 4 Fiocchi C. Inflammatory bowel disease pathogenesis: Where are we?. J Gastroenterol Hepatol 2015; 30: 12-18 doi:
• 5 Jostins L, Ripke S, Weersma RK. et al. Hostmicrobe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012; 491: 119-24 doi:
• 6 Uhlig HH. Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease. Gut 2013; 62: 1795-1805 doi:
• 7 Landrum MJ, Lee JM, Riley GR. et al. ClinVar: Public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res 2014; 42 doi:
• 8 Kotlarz D, Beier R, Murugan D. et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: Implications for diagnosis and therapy. Gastroenterology 2012; 143: 347-355 doi:
• 9 Barzaghi F, Passerini L, Bacchetta R. Immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome: a paradigm of immunodeficiency with autoimmunity. Front Immunol 2012; 3: 211 doi:
• 10 Galeotti C, Meinzer U, Quartier P. et al. Efficacy of interleukin-1-targeting drugs in mevalonate kinase deficiency. Rheumatology (Oxford) 2012; 51: 1855-1859 doi:
• 11 Uhlig HH, Schwerd T, Koletzko S. et al. The Diagnostic Approach to Monogenic Very Early Onset Inflammatory Bowel Disease. Gastroenterology 2014; 147: 990-1007.e3 doi:
• 12 Levine A, Griffiths A, Markowitz J. et al. Pediatric modification of the Montreal classification for inflammatory bowel disease: The Paris classification. Inflamm Bowel Dis 2011; 17: 1314-1321 doi:
• 13 Muise AM, Snapper SB, Kugathasan S. The age of gene discovery in very early onset inflammatory bowel disease. Gastroenterology 2012; 143: 285-288 doi:
• 14 Eszter Müller K, Laszlo Lakatos P, Papp M, Veres G. Incidence and paris classification of pediatric inflammatory bowel disease. Gastroenterol Res Pract 2014; 2014: 904307 doi:
• 15 Winkelstein JA, Marino MC, Ochs H. et al. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore) 2003; 82: 373-384 doi:
• 16 Oksenhendler E, Gérard L, Fieschi C. et al. Infections in 252 patients with common variable immunodeficiency. Clin Infect Dis 2008; 46: 1547-1554 doi:
• 17 Kammermeier J, Drury S, James CT. et al. Targeted gene panel sequencing in children with very early onset inflammatory bowel disease – evaluation and prospective analysis. J Med Genet 2014; 51: 748-755 doi:
• 18 Cheng LE, Kanwar B, Tcheurekdjian H. et at. Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome. Clin Immunol 2009; 132: 124-131 doi:
• 19 Aradhya S, Woffendin H, Jakins T. et al. A recurrent deletion in the ubiquitously expressed NEMO (IKK-gamma) gene accounts for the vast majority of incontinentia pigmenti mutations. Hum Mol Genet 2001; 10: 2171-2179.
• 20 Fish JD, Duerst RE, Gelfand EW. et al. Challenges in the use of allogeneic hematopoietic SCT for ectodermal dysplasia with immune deficiency. Bone Marrow Transplant 2009; 43: 217-221 doi:
• 21 Fournier BM, Parkos CA. The role of neutrophils during intestinal inflammation. Mucosal Immunol 2012; 5: 354-366 doi:
• 22 Seger RA. Chronic granulomatous disease: recent advances in pathophysiology and treatment. Neth J Med 2010; 68: 334-340.
• 23 Matute JD, Arias AA, Wright NAM. et al. A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity. Blood 2009; 114: 3309-3315 doi:
• 24 Schappi MG, Smith VV, Goldblatt D. et al. Colitis in chronic granulomatous disease. Arch Dis Child 2001; 84: 147-151 doi:
• 25 Marks DJB, Miyagi K, Rahman FZ. et al. Inflammatory bowel disease in CGD reproduces the clinicopathological features of Crohn’s disease. Am J Gastroenterol 2009; 104: 117-124 doi:
• 26 Marciano BE, Rosenzweig SD, Kleiner DE. et al. Gastrointestinal involvement in chronic granulomatous disease. Pediatrics 2004; 114: 462-468 doi:
• 27 Van den Berg JM, van Koppen E, Ahlin A. et al. Chronic granulomatous disease: the European experience. PLoS One 2009; 4: e5234 doi:
• 28 Fike FB, Mortellaro V, Juang D. et al. Neutropenic colitis in children. J Surg Res 2011; 170: 73-76 doi:
• 29 Reyna-Figueroa J, Garcia-Beristain JC, Galindo-Delgado P. et al. Antibiotic Use Before Chemotherapy. J Pediatr Hematol Oncol 2015; 37: 121-127 doi:
• 30 Koh MB, Cheung DY, Noh CH. et al. Bleeding polypoid lesions in the colon as a presentation of neutropenic colitis in aplastic anemia. Gastrointest Endosc 2009; 69: 953-954 doi:
• 31 Gamboa-Domínguez A, Velázquez Ceceña JL, Reyes-Gutiérrez E. (2 cases of neutropenic enteropathy and bone marrow hypoplasia. An association not reported in Mexico). Rev Invest Clin 47: 303-309.
• 32 Gamboa-Domínguez A, Velázquez-Ceceña JL, Reyes-Gutiérrez E. (Neutropenic enteropathy associated with multiple myeloma). Rev Gastroenterol México 60: 94-97.
• 33 Bavaro MF. Neutropenic enterocolitis. Curr Gastroenterol Rep 2002; 4: 297-301.
• 34 Rohr J, Pannicke U, Döring M. et al. Chronic inflammatory bowel disease as key manifestation of atypical ARTEMIS deficiency. J Clin Immunol 2010; 30: 314-320 doi:
• 35 Felgentreff K, Perez-Becker R, Speckmann C. et al. Clinical and immunological manifestations of patients with atypical severe combined immunodeficiency. Clin Immunol 2011; 141: 73-82 doi:
• 36 Borggraefe I, Koletzko S, Arenz T, Fuehrer M, Hoffmann F, Dokal I. et al. Severe variant of x-linked dyskeratosis congenita (Hoyeraal-Hreidarsson Syndrome) causes significant enterocolitis in early infancy. J Pediatr Gastroenterol Nutr 2009; 49: 359-363 doi:
• 37 Catucci M, Castiello MC, Pala F, Bosticardo M, Villa A. Autoimmunity in Wiskott-Aldrich syndrome: An unsolved enigma. Front Immunol 2012; 3 doi:
• 38 Bader-Meunier B, Florkin B, Sibilia J. et al. Mevalonate kinase deficiency: a survey of 50 patients. Pediatrics 2011; 128: e152-159 doi:
• 39 Speckmann C, Ehl S. XIAP deficiency is a mendelian cause of late-onset IBD. Gut 2014; 63: 1031-1032 doi:
• 40 Pachlopnik Schmid J, Canioni D, Moshous D. et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood 2011; 117: 1522-1529 doi:
• 41 Glocker E-O, Kotlarz D, Boztug K. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 2009; 361: 2033-2045 doi:
• 42 Bennett CL, Christie J, Ramsdell F. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001; 27: 20-21 doi:
• 43 Rigaud S, Fondanèche M-C, Lambert N. et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 2006; 444: 110-114 doi:
• 44 Glocker EO, Kotlarz D, Klein C. et al. IL-10 and IL-10 receptor defects in humans. Ann N Y Acad Sci 2011; 1246: 102-107 doi:
• 45 Moratto D, Giliani S, Notarangelo LD. et al. The Wiskott-Aldrich syndrome: from genotype-phenotype correlation to treatment. Expert Rev Clin Immunol 2007; 3: 813-824 doi:
• 46 Mogensen TH. Primary Immunodeficiencies with Elevated IgE. Int Rev Immunol. 2015 doi:
• 47 Mora AJ, Wolfsohn DM. The Management of Gastrointestinal Disease in Hermansky-Pudlak Syndrome. J Clin Gastroenterol 2011; 45: 700-702 doi:
• 48 Malamut G, Verkarre V, Suarez F. et al. The enteropathy associated with common variable immunodeficiency: the delineated frontiers with celiac disease. Am J Gastroenterol 2010; 105: 2262-2275 doi:
• 49 Khodadad A, Aghamohammadi A, Parvaneh N. et al. Gastrointestinal manifestations in patients with common variable immunodeficiency. Dig Dis Sci 2007; 52: 2977-2983 doi:
• 50 Bode S, Vraetz T, Schulze I. et al. Zwei Knaben mit rezidivierenden Abszessen. Kinderarztl Prax 2012; 3: 158-160.