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The Peri-islet Basement Membrane, a Barrier to Infiltrating Leukocytes in Type 1 Diabetes in Mouse and Human
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2013 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, no 2, 531-542 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2013. Vol. 62, no 2, 531-542 p.
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Immunology in the medical area
URN: urn:nbn:se:umu:diva-64530DOI: 10.2337/db12-0432PubMedID: 23139348OAI: diva2:602161
Available from: 2013-01-31 Created: 2013-01-31 Last updated: 2013-11-29Bibliographically approved

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Holmberg, Dan
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