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New Cell-based Targets For Treating Autoimmune Inflammatory Diseases

September 4, 2006
John Wiley & Sons, Inc.
A new study indicates the critical role of platelet function in this dire form of autoimmune kidney disease, crescentic glomerulonenephritis (CGN).

Patients with systemic autoimmune diseases such as lupus and rheumatoid arthritis (RA) often suffer loss of kidney function. When marked by a crescent formation in the glomerulus -- a tiny ball comprised of capillary blood vessels integral to forming urine -- kidney failure tends to be rapidly progressive, irreversible, and fatal. Little is known about the mechanism behind this crescent or its relationship to immune-mediated inflammation.

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To gain understanding, a team of researchers in Japan began by analyzing a spontaneous mutant strain of EOD mice. Their study, published in the September 2006 issue of Arthritis & Rheumatism, indicates the critical role of platelet function in this dire form of autoimmune kidney disease, crescentic glomerulonenephritis (CGN). It also sheds light on the involvement of Cno protein, a member of a large protein complex called biogenesis of lysosome-related organelle complex 1 (BLOC-1), in the development of an autoimmune disease.

Researchers isolated this mutant strain of mice from the autoimmune-prone strain EOD, which stably develops fatal CGN. Then, using blood samples, they thoroughly assessed blood cell count, immune function, platelet function, and properties of various cell types and genes in these mice, searching for clues to their marked improvement in CGN and ability to survive about twice as long as wild-type EOD mice. Among the surprising findings in the mutant mice was an ability to alter platelet functions. While wild-type EOD mice displayed massive accumulations of platelets in the glomerulus, the mutant mice did not, but they were more prone to bleeding. Further investigation revealed a mutation in the cappuccino gene, which encodes the Cno protein. Mutant platelets also showed abnormally low aggregation in response to collagen and abnormally low rates of serotonin storage.

These findings suggest links between the gene mutation, loss of Cno protein expression, defect in platelet function, and the regression of crescent formation in the glomerulus. What's more, these links are related to BLOC-1, which controls lysosomes, tiny organelles that contain digestive enzymes critical to maintaining healthy cell function.

"The profound role of BLOC-1 appears to be platelet-specific among immuno-inflammatory cell types," notes the study's lead author, Dr. Masao Ono from the Tohoku University Graduate School of Medicine. "BLOC-1 is a possible therapeutic target for suppression of platelet functions without compromising physiologic immune responses."

In another promising new study, using rats and gene-modified mice, researchers in Turku, Finland, uncovered a new type of adhesion molecule highly expressed on vessels of inflamed human synovial tissue. This molecule, AOC3 (amine oxidase, copper-containing 3; also known as vascular adhesion protein 1), works to spur inflammation by thwarting the infiltration of leukocytes, vital white blood cells, into rheumatoid joints. In an editorial describing the discovery and function of this adhesive enzyme, Dr. Beat A. Imhof of the University of Geneva School of Medicine and University Hospital, Geneva, Switzerland, indicates the potential therapeutic value for rheumatoid arthritis patients. "Antiadhesive therapies based on the use of small molecule inhibitors certainly represent an economically interesting alternative to expensive biologic treatments, such as humanized anti-adhesion molecule antibodies, which are currently being developed for the treatment of inflammatory diseases," Dr. Imhof notes.

Article: "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, and Masao Ono, Arthritis & Rheumatism, September 2006; (DOI: 10.1002/art.22059).

Article: "Vascular Amine Oxidases Are Needed for Leukocyte Extravasation Into Inflamed Joints In Vivo," Fumiko Marttila-Ichara, David J. Smith, Craig Stolen, Gennady G. Yegutkin, Kati Elima, Nathalie Mercier, Riku Kiviranta, Marjo Pihlavisto, Sakari Alaranta, Ulla Pentikäinen, Olli Pentikäinen, Ferenc Fölüp, Sirpa Jalkanen, and Marko Salmi, Arthritis & Rheumatism, September 2006; (DOI: 10.1002/art.22061).

Editorial: "Leukocyte Migration to Rheumatoid Joints: Enzymes Take Over," Gaby Palmer, Cem Gabay, and Beat A. Imhof, Arthritis & Rheumatism, September 2006; (DOI: 10.1002/art.22062).

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The above story is based on materials provided by John Wiley & Sons, Inc.. Note: Materials may be edited for content and length.

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John Wiley & Sons, Inc.. "New Cell-based Targets For Treating Autoimmune Inflammatory Diseases." ScienceDaily. ScienceDaily, 4 September 2006. <www.sciencedaily.com/releases/2006/08/060831084442.htm>.
John Wiley & Sons, Inc.. (2006, September 4). New Cell-based Targets For Treating Autoimmune Inflammatory Diseases. ScienceDaily. Retrieved January 24, 2015 from www.sciencedaily.com/releases/2006/08/060831084442.htm
John Wiley & Sons, Inc.. "New Cell-based Targets For Treating Autoimmune Inflammatory Diseases." ScienceDaily. www.sciencedaily.com/releases/2006/08/060831084442.htm (accessed January 24, 2015).

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