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Originally published online as doi:10.2353/ajpath.2008.070755 on February 7, 2008

Published online before print February 7, 2008
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(American Journal of Pathology. 2008;172:702-713.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070755

Impaired Luminal Processing of Human Defensin-5 in Crohn’s Disease

Persistence in a Complex with Chymotrypsinogen and Trypsin

David Elphick*{dagger}, Susan Liddell{ddagger} and Yashwant R. Mahida*{dagger}

From the Institute of Infection, Immunity, and Inflammation,*the Division of Gastroenterology,{dagger}and the School of Biosciences,{ddagger}University of Nottingham, Nottingham, United Kingdom

Human defensin (HD)-5 is an antimicrobial peptide expressed in small intestinal Paneth cells, and alterations in HD-5 expression may be important in Crohn’s disease (CD) pathogenesis. Levels of HD-5 in Paneth cells and ileostomy fluid from control and CD patients were studied by quantitative immunodot analysis, immunohistochemistry, acid urea-polyacrylamide gel electrophoresis and sodium dodecyl sulfate-polyacrylamide gel electrophoresis Western blotting, reverse phase-high performance liquid chromatography, N-terminal amino acid sequencing, and ES-QToF mass spectrometry. In both control and CD patients, HD-5 in Paneth cell extracts was present almost exclusively in the precursor form. HD-5 levels in ileostomy fluid were lower in CD patients (n = 51) than in controls (n = 20): median (range), 7.9 (5.5 to 35.0) µg/ml versus 10.5 (6.0 to 30.4) µg/ml; P = 0.05; this difference was most marked in CD patients with homozygous/compound heterozygous mutations in NOD2 (P = 0.03). In control ileostomy fluid, HD-5 was present in the mature form only. In contrast, CD patient ileostomy fluid contained both precursor and mature forms of HD-5, with the majority present in a complex with trypsin, chymotrypsinogen/chymotrypsin, and {alpha}1-anti-trypsin. Pro-HD-5 was not associated with trypsin or chymotrypsinogen in Paneth cell extracts. In conclusion, pro-HD-5 in the intestinal lumen is processed by trypsin in a complex in which chymotrypsinogen is also cleaved for activation. The persistence of this complex in CD may be attributable to increased luminal levels of proteinase inhibitors such as {alpha}1-anti-trypsin.




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