Abstract
Lysozyme is as an innate enzyme with potent antibacterial properties found in Paneth cells in normal duodenal crypts. Since celiac disease concurs with an abnormal duodenal microbiota we explored the expression of lysozyme in this disease. Fifty-three duodenal biopsies were stained with anti-lysozyme: 15 had normal duodenal mucosa (NDM), 7 chronic active duodenitis (CAD), 3 borderline (BL), 17 subtotal villous atrophy (SVA) and 11 total villous atrophy (TVA). NDM showed lysozyme-positive Paneth cells arranged in “Indian file” in 93.3%. In contrast, lysozyme-positive mucus metaplasia in crypts (LPMMC) replacing Paneth cells was found in 71.5% in CAD, in 96.4% in SVA/TVA, and in 2 cases with B. In 19.3% cases with BL/SVA/TVA, LPMMC replaced all Paneth cells in all crypts in entire sections. In crypts and villi, lysozyme-positive goblet cells (LPGC) were found in 92.8%. Changes were more frequent in the duodenal bulb than in pars descendens. In normal duodenal mucosa, absorptive enterocytes and goblet cells migrate from stem cells upwards, while Paneth cells migrate downwards, towards the base of the crypts. In celiac disease stem cells seem to have been re-programmed, as the normal production of Paneth cells in the crypts was replaced by lysozyme-producing mucus cells. LPMMC and LPGC in celiac disease might mirror an antimicrobial adaptation of stem cells to signals generated by pathogenic duodenal bacteria. The molecular mechanism(s) behind the abrogation of Paneth cells in duodenal crypts and its substitution by LPMMC in celiac disease remains to be elucidated.
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References
Gramlich T, Petras R (2007) Small intestine/duodenum. In: Mills SE (ed) Histology for pathologists, 3rd edn. Lippincott Williams & Wilkins, Philadelphia, pp 613–616
He XC, Zhang J, Tong WG, Tawfik O, Ross J, Scoville DH, Tian Q, Zeng X, He X, Wiedemann LM, Mishina Y, Li (2004) BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nat Genet 36:1117–1121
de Santa BP, van den Brink GR, Roberts DJ (2003) Development and differentiation of the intestinal epithelium. Cell Mol Life Sci 60:1322–1332, Review
Rubio CA, Nesi G (2003) A simple method to demonstrate normal and metaplastic Paneth cells in tissue sections. In Vivo 17:67–71
Ayabe T, Ashida T, Kohgo Y, Kono T (2004) The role of Paneth cells and their antimicrobial peptides in innate host defense. Trends Microbiol 12:394–398
Sundbom M, Elphick DA, Mahida YR, Cunliffe RN, Midtvedt T, Engstrand L, Rubio CA, Axelsson LG (2007) Alteration in human defensin-5 expression following gastric bypass surgery. J Clin Pathol 60:1029–1034
Di Sabatino A, Miceli E, Dhaliwal W, Biancheri P, Salerno R, Cantoro L, Vanoli A, De Vincenzi M, Blanco Cdel V, MacDonald TT, Corazza GR (2008) Distribution, proliferation, and function of Paneth cells in uncomplicated and complicated adult celiac disease. Am J Clin Pathol 130:34–42
Dewar DH, Ciclitira PJ (2005) Clinical features and diagnosis of celiac disease. Gastroenterology 128(Suppl 1):S19–24, Review
Högberg L, Stenhammar L (2009) Celiac disease: diagnosis criteria in young children. Nat Rev Gastroenterol Hepatol 6:447–448
Ivarsson A, Högberg L, Stenhammar L, Swedish Childhood Coeliac Disease Working Group (2010) The Swedish Childhood Coeliac Disease Working Group after 20 years: history and future. Acta Paediatr 99:1429–1431
Myléus A, Ivarsson A, Webb C, Danielsson L, Hernell O, Högberg L, Karlsson E, Lagerqvist C, Norström F, Rosén A, Sandström O, Stenhammar L, Stenlund H, Wall S, Carlsson A (2009) Celiac disease revealed in 3% of Swedish 12-year-olds born during an epidemic. J Pediatr Gastroenterol Nutr 49:170–176
Sánchez E, Donat E, Ribes-Koninckx C, Calabuig M, Sanz Y (2010) Intestinal Bacteroides species associated with coeliac disease. J Clin Pathol 63:1105–1111
Schippa S, Iebba V, Barbato M, Di Nardo G, Totino V, Checchi MP, Longhi C, Maiella G, Cucchiara S, Conte MP (2010) A distinctive ‘microbial signature’ in celiac pediatric patients. BMC Microbiol 10:175–179
Forsberg G, Fahlgren A, Hörstedt P, Hammarström S, Hernell O, Hammarström ML (2004) Presence of bacteria and innate immunity of intestinal epithelium in childhood celiac disease. Am J Gastroenterol 99:894–904
Ou G, Hedberg M, Hörstedt P, Baranov V, Forsberg G, Drobni M, Sandström O, Wai SN, Johansson I, Hammarström ML, Hernell O, Hammarström S (2009) Proximal small intestinal microbiota and identification of rod-shaped bacteria associated with childhood celiac disease. Am J Gastroenterol 104:3058–3067
Fleming A (1922) On a remarkable bacteriolytic element found in tissues and secretions. Proc Roy Soc Sec B 93:306–317
Yoshimura K, Toibana A, Nakahama K (1988) Human lysozyme: sequencing of a cDNA, and expression and secretion by Saccharomyces cerevisiae. Biochem Biophys Res Commun 150:794–801
Peters C, Kruse U, Pollwein R, Grzeschik K, Sippel (1989) The human lysozyme gene. Sequence organization and chromosomal localization. Eur J Bioch 182:507–512
Wehkamp J, Chu H, Shen B, Feathers RW, Kays RJ, Lee SK, Bevins CL (2006) Paneth cell antimicrobial peptides: topographical distribution and quantification in human gastrointestinal tissues. FEBS Lett 580:5344–5350
Saito H, Kasajima T, Masuda A, Imai Y, Ishikawa M (1988) Lysozyme localization in human gastric and duodenal epithelium. An immune-cytochemical study. Cell Tissue Res 251:307–313
Rubio CA, Befrits R (2009) Increased lysozyme expression in gastric biopsies with intestinal metaplasia and pseudopyloric metaplasia. Int J Clin Exp Med 2:248–253
Rubio CA, Lörinc (2011) Lysozyme is upregulated in Barrett’s mucosa. Histopathology (in press)
Tang Q, Wang L, Tao K, Ge C, Jing Li Y, Peng JC, Geng M (2006) Expression of polymeric immunoglobulin receptor mRNA and protein in human Paneth cells: Paneth cells participate in acquired immunity. Am J Gastroenterol 101:1625–1632
Rubio CA (2011) Lysozyme expression in microscopic colitis. J Clin Pathol (in press)
Rubio CA (2003) Colorectal adenomas produce lysozyme. Anticancer Res 23:5165–5171
Helmerhorst E, Zamakhchari M, Schuppan D, Oppenheim F (2010) Discovery of a novel and rich source of gluten-degrading microbial enzymes in the oral cavity. PLoS One 5:13264–13267
Hayat M, Cairns A, Dixon MF, O’Mahony S (2002) Quantitation of intraepithelial lymphocytes in human duodenum: what is normal? J Clin Pathol 55:393–394
Scoville DH, Sato T, He XC, Li L (2008) Current view: intestinal stem cells and signaling. Gastroenterology 134:849–864, Review
Rubio CA (2011) Putative stem cells in mucosas of the esophago-gastrointestinal tract. Chapter 10. In: Singh SR (ed) Stem cell, regenerative medicine and cancer. Nova Science Haupauge, NY, pp 281–310
Kosinski C, Stange DE, Xu C, Chan AS, Ho C, Yuen ST, Mifflin RC, Powell DW, Clevers H, Leung SY, Chen X (2010) Indian hedgehog regulates intestinal stem cell fate through epithelial–mesenchymal interactions during development. Gastroenterology 139:893–903
Barker N, van de Wetering M, Clevers H (2008) The intestinal stem cell. Genes Dev 22:1856–1864
Nakamura T, Tsuchiya K, Watanabe T (2007) Crosstalk between Wnt and Notch signaling in intestinal epithelial cell fate decision. J Gastroenterol 42:705–710
Klaus A, Birchmeier W (2008) Wnt signalling and its impact on development and cancer. Nat Rev Cancer 8:387–398
Shroyer NF, Helmrath MA, Wang VY, Antalffy B, Henning SJ, Zoghbi HY (2007) Intestine-specific ablation of Mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis. Gastroenterology 132:2478–2488
VanDussen KL, Samuelson LC (2010) Mouse atonal homolog 1 directs intestinal progenitors to secretory cell rather than absorptive cell fate. Dev Biol 346:215–223
Varnat F, Heggeler BB, Grisel P, Boucard N, Corthésy-Theulaz I, Wahli W, Desvergne B (2006) PPAR beta/delta regulates Paneth cell differentiation via controlling the hedgehog signaling pathway. Gastroenterology 131:538–553
Tanigawa Y, Yakura R, Komiya T (2007) The bHLH transcription factor Tcf12 (ME1) mRNA is abundantly expressed in Paneth cells of mouse intestine. Gene Expr Patterns 7:709–713
Babbin BA, Jesaitis AJ, Ivanov AI, Kelly D, Laukoetter M, Nava P, Parkos CA, Nusrat A (2007) Formyl peptide receptor-1 activation enhances intestinal epithelial cell restitution through phosphatidylinositol 3-kinase-dependent activation of Rac1 and Cdc42. J Immunol 179:8112–8121
Peignon G, Durand A, Cacheux W, Ayrault O, Terris B, Laurent-Puig P, Shroyer NF, Van Seuningen I, Honjo T, Perret C, Romagnolo B (2011) Complex interplay between β-catenin signalling and Notch effectors in intestinal tumorigenesis. Gut 60:166–176
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Rubio, C.A. Lysozyme-rich mucus metaplasia in duodenal crypts supersedes Paneth cells in celiac disease. Virchows Arch 459, 339–346 (2011). https://doi.org/10.1007/s00428-011-1129-3
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DOI: https://doi.org/10.1007/s00428-011-1129-3