title: The peri-islet basement membrane, a barrier to infiltrating leukocytes in type 1 diabetes in mouse and human.
abstract: We provide the first comprehensive analysis of the extracellular matrix (ECM) composition of peri-islet capsules, composed of the peri-islet basement membrane (BM) and subjacent interstitial matrix (IM), in development of type 1 diabetes in NOD mice and in human type 1 diabetes. Our data demonstrate global loss of peri-islet BM and IM components only at sites of leukocyte infiltration into the islet. Stereological analyses reveal a correlation between incidence of insulitis and the number of islets showing loss of peri-islet BM versus islets with intact BMs, suggesting that leukocyte penetration of the peri-islet BM is a critical step. Protease- and protease inhibitor-specific microarray analyses (CLIP-CHIP) of laser-dissected leukocyte infiltrated and noninfiltrated pancreatic islets and confirmatory quantitative real time PCR and protein analyses identified cathepsin S, W, and C activity at sites of leukocyte penetration of the peri-islet BM in association with a macrophage subpopulation in NOD mice and human type 1 diabetic samples and, hence, potentially a novel therapeutic target specifically acting at the islet penetration stage. Interestingly, the peri-islet BM and underlying IM are reconstituted once inflammation subsides, indicating that the peri-islet BM-producing cells are not lost due to the inflammation, which has important ramifications to islet transplantation studies.
authors.affiliation: Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany. korpos@uni-muenster.de
authors.forename: Éva
authors.initials: É
authors.lastname: Korpos
authors.forename: Nadir
authors.initials: N
authors.lastname: Kadri
authors.forename: Reinhild
authors.initials: R
authors.lastname: Kappelhoff
authors.forename: Jeannine
authors.initials: J
authors.lastname: Wegner
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Overall
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Weber
authors.forename: Dan
authors.initials: D
authors.lastname: Holmberg
authors.forename: Susanna
authors.initials: S
authors.lastname: Cardell
authors.forename: Lydia
authors.initials: L
authors.lastname: Sorokin
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000276:immunology*; D020789:Cathepsin C / Q000032:analysis; D056664:Cathepsin W / Q000032:analysis; D002403:Cathepsins / Q000032:analysis; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005109:Extracellular Matrix / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D040081:Protein Array Analysis; D053491:Proteinase Inhibitory Proteins, Secretory / Q000032:analysis
chemical_list: D053491:Proteinase Inhibitory Proteins, Secretory; D002403:Cathepsins; D020789:Cathepsin C; C533919:Ctsc protein, mouse; D056664:Cathepsin W; C534188:Ctsw protein, mouse; C028217:cathepsin S