Regulation and characterization of antimicrobial peptides in man and mice
Year: 2007
Type: dissertation
Abstract: The gene-encoded antimicrobial peptides have emerged as an important \ncomponent of innate immunity. In mammals, antimicrobial peptides are \neither directly secreted from cells or found in cell granules, which can \nbe released after stimuli. This thesis aims at investigating \nantimicrobial peptides stored in granules in neutrophils and in Paneth \ncells of the small intestine. \n \n \n \nThe condition severe congenital neutropenia (SCN) illustrates the pivotal \nrequirement for neutrophils as primary defence cells since affected \nindividuals die in infancy. In this thesis I show that all patients with \nSCN, independent of inheritance pattern, genetic mutations or G-CSF \nresponsiveness, display a deficiency of the antimicrobial peptide LL-37 \nand its pro-form in plasma and in neutrophils, even after G-CSF \ntreatment. This deficiency points at a common mechanistic denominator for \nall patients with SCN. The LL-37 phenotype may be used as a diagnostic \nmethod to discriminate the lifelong, and without treatment, life \nthreatening disease SCN from the more benign forms of chronic \nneutropenia. Granulocytic precursors from patients with SCN were here \ndemonstrated to produce pro-LL-37 after in vitro stimulation with the \nhormonal form of vitamin D3 . The induction of pro-LL-37 in plasma did \nnot take place in vivo following oral treatment of one patient with a low \ndose vitamin D3. \n \n \n \nNeutrophils and Paneth cells are strikingly similar in their repertoire \nof granule derived antimicrobial peptides. Paneth cells reside at the \nbase of the crypt of the small intestine of most mammals, where they \nsecrete high concentrations of antimicrobial substances that sterilize \nthe crypt and shape the profile of the resident microflora. Here I show \nthat the mouse Paneth cell arsenal is broadened by the presence of \ncryptdin related sequence (CRS) peptides. The antimicrobial spectrum is \nincreased further by their ability to form both homo- and hetero dimers, \nwhich have distinct but overlapping antimicrobial spectra. In addition, \ndifferent repertoires of CRS peptides in different mouse strains, suggest \na highly efficient positive selection pressure. Two groups of transcripts \ncoding for CRS peptides could be separated based on expression profile in \nthe small intestine. One group was expressed at a consistently high level \nalong the small intestine, while the other group increased strongly \nthrough the length of the small intestine. A similar increase, although \nnot as prominent, has also been demonstrated by others for the enteric \nantimicrobial peptide human defensin 5, which is involved in the \npathomechanism of Crohn´s ileitis. Elucidating the regulatory pattern in \nmice may thus be useful in unravelling the regulation of human enteric \nantimicrobial peptides.
Source: Figshare
Author: Jenny Karlsson
Language: English
Subfield: Microbiology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1533747463