Cappuccino mutation in an autoimmune-prone strain of mice suggests a role of platelet function in the progression of immune complex crescentic glomerulonephritis

Minako Yoshida, Kan Saiga, Takaaki Hato, Shoko Iwaki, Toshiyuki Niiya, Norimasa Arita, Hiroaki Komori, Takahito Tsubaki, Hiroshi Furukawa, Miho Terada, Kazutaka Maeyama, Kyuichi Nemoto, Masato Nose, Masao Ono

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Objective. Crescent formation in the renal glomerulus is a typical manifestation of progressive glomerulopathy associated with fatal renal failure; therefore, its prevention is of clinical importance. Little is known about the pathogenic mechanism for crescent formation. This study was undertaken in an attempt to identify the events that are critical for crescent formation in immune complex crescentic glomerulonephritis (CGN) by analyzing a novel mutant strain of mice. Methods. A spontaneous mutant strain of mice was isolated from the autoimmune-prone strain EOD, which stably develops fatal CGN. The mutant phenotypes were assessed histopathologically, hematologically, and immunologically. The mutation was searched for with positional cloning using microsatellite markers. Results. Compared with wild-type EOD (WT-EOD) mice, mutant EOD (mut-EOD) mice showed marked improvement in CGN in conjunction with an improvement in spontaneous mortality. In WT-EOD mice, an inverse correlation between blood urea nitrogen concentration and blood platelet count and massive accumulation of platelets in the glomerulus were evident, suggesting that an accumulation of platelets in the glomerulus contributes to the progression of CGN. The mutant platelets showed an abnormal aggregation in response to collagen and thrombin, associated with a bleeding tendency in mut-EOD mice. Genetic analysis revealed a deleterious mutation in the cappuccino gene (CMO), which encodes a protein that belongs to a complex called the biogenesis of lysosome-related organelle complex 1 and is profoundly involved in platelet function. Morphologic examination revealed a partial defect in dense body formation in the δ-granule of platelets. Conclusion. The present findings suggest that platelet functions have a critical role in crescent formation in autoimmune GN.

Original languageEnglish
Pages (from-to)2934-2943
Number of pages10
JournalArthritis and Rheumatism
Volume54
Issue number9
DOIs
Publication statusPublished - 2006 Sep

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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