Abstract
In about 70% of patients Crohn's disease (CD) affects the small intestine. This disease location is stable over time and associated with a genetic background different from isolated colonic disease. A characteristic feature of small intestinal host defense is the presence of Paneth cells at the bottom of the crypts of Lieberkühn. These cells produce different broad spectrum antimicrobial peptides (AMPs) most abundantly the α-defensins HD-5 and -6 (DEFA5 und DEFA6). In small intestinal Crohn's disease both these PC products are specifically reduced. As a functional consequence, ileal extracts from Crohn's disease patients are compromised in clearing bacteria and enteroadherent E. coli colonize the mucosa. Mechanisms for defective antimicrobial Paneth cell function are complex and include an association with a NOD2 loss of function mutation, a disturbance of the Wnt pathway transcription factor TCF7L2 (also known as TCF4), the autophagy factor ATG16L1, the endosomal stress protein XBP1, the toll-like receptor TLR9, the calcium mediated potassium channel KCNN4 as well as mutations or inactivation of HD5. Thus we conclude that small intestinal Crohn's disease is most likely a complex disease of the Paneth cell: Paneth's disease.
Copyright © 2010 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
MeSH terms
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Animals
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Autophagy-Related Proteins
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / immunology
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Carrier Proteins / genetics
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Carrier Proteins / immunology
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Crohn Disease / genetics
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Crohn Disease / immunology*
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Crohn Disease / physiopathology
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / immunology
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Gene Expression / immunology
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Humans
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Ileitis / genetics
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Ileitis / immunology*
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Ileitis / physiopathology
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Immunity, Innate / genetics
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Immunity, Innate / immunology
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Immunity, Mucosal / genetics
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Immunity, Mucosal / immunology
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Intermediate-Conductance Calcium-Activated Potassium Channels / genetics
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Intermediate-Conductance Calcium-Activated Potassium Channels / immunology
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Mice
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Mutation / immunology
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Nod2 Signaling Adaptor Protein / genetics
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Nod2 Signaling Adaptor Protein / immunology
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Paneth Cells / cytology
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Paneth Cells / immunology*
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Paneth Cells / pathology*
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Regulatory Factor X Transcription Factors
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Signal Transduction / genetics
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Signal Transduction / immunology
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Toll-Like Receptor 9 / genetics
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Toll-Like Receptor 9 / immunology
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Transcription Factor 4
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Transcription Factor 7-Like 2 Protein / genetics
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Transcription Factor 7-Like 2 Protein / immunology
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Transcription Factors / genetics
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Transcription Factors / immunology
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Wnt Proteins / genetics
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Wnt Proteins / immunology
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X-Box Binding Protein 1
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alpha-Defensins / deficiency
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alpha-Defensins / genetics
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alpha-Defensins / immunology
Substances
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ATG16L1 protein, human
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Autophagy-Related Proteins
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Carrier Proteins
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DEFA5 protein, human
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DNA-Binding Proteins
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Intermediate-Conductance Calcium-Activated Potassium Channels
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KCNN4 protein, human
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NOD2 protein, human
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Nod2 Signaling Adaptor Protein
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Regulatory Factor X Transcription Factors
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TCF4 protein, human
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TCF7L2 protein, human
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TLR9 protein, human
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Toll-Like Receptor 9
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Transcription Factor 4
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Transcription Factor 7-Like 2 Protein
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Transcription Factors
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Wnt Proteins
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X-Box Binding Protein 1
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XBP1 protein, human
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Xbp1 protein, mouse
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alpha-Defensins