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

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 (cno), 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 ␦-granule of platelets.Conclusion. The present findings suggest that platelet functions have a critical role in crescent formation in autoimmune GN.In systemic autoimmune disease, renal function is frequently impaired due to immune-mediated inflammation. An example is the occurrence of lupus nephritis in association with systemic lupus erythematosus (SLE). Immune complex (IC) deposition is detected in the affected glomeruli of patients with lupus nephritis, thus suggesting a pathogenic role of ICs in this manifestation. Animal models have further demonstrated the indispensable roles of some receptors such as the Fc receptor for IgG (Fc␥R) (1,2) and complement receptors (CRs) (3,4), proinflammatory factors such as cytokines and chemokines, and growth factors in the progression of glomerulonephritis (GN) following IC deposition. These findings readily confirm the existence of a longstanding pathogenic mechanism through which IC deposition initiates an inflammatory cascade by engaging Fc␥R and CRs and liberates a range of proinflammatory factors.

Extreme Thrombocytosis Presenting in Anti-Neutrophil Cytoplasmic Autoantibodies-Associated Crescentic Glomerulonephritis with Immune Complex Deposits: A Case Report

“…There have been a considerable number of articles researching the association between thrombocytosis and cytokines such as IL-6, IL-11, and thyroperoxidase (TPO) in inflammatory conditions such as infection and rheumatoid arthritis. With respect to CGN, however, there are only a few animal studies contradictorily showing a relation between the platelet count and nephritis and failing to mention ANCA ( 14 , 15 ). More clinical and basic studies are needed to uncover the association between extreme RT and the immune complex in ANCA-associated CGN and further reveal the possible mechanism.…”

Dynamics of platelet mobilisation into lungs in response to 5-hydroxytryptamine (serotonin) in mice

“…Animals and materials BALB/c male mice (6-7 weeks old) were provided by the animal facility of our university. Mutant mice defective in the cappuccino gene (cappuccino mice) (18) were provided by Masao Ono (an author of this study). 5HT hydrochloride, adenosine 5'-diphosphate (ADP) sodium salt, histamine hydrochloride, and ketanserin tartrate (Sigma, St. Louis, MO, USA) were dissolved in saline and injected either intravenously (i.v., via a tail vein) or intraperitoneally (i.p.)…”

“…Recently, Yoshida et al established a unique strain (called "cappuccino mice") from EOD mice (18). EOD mice are a strain established by brother-sister mating of F1 animals derived from the mating of female lpr x male BXSB (34).…”

“…The cappuccino protein in normal mice is a component of BLOC-1 (biogenesis of lysosome-related orga- nelles complex-1) (35), and BLOC-1 is involved in the biosynthesis of melanosomes and platelet dense granules (36). Thus, cappuccino mice exhibit diluted colours in the skin and eye, and they also have a profound defect in platelet dense bodies (inability to store 5HT and thus lacking 5HT) and reduced functions of platelets (18). Since both lpr and BXSB mice have a common C57BL/6 genetic background, we used C57BL/6J mice as normal control mice.…”

Dynamics of Platelet Behaviors as Defenders and Guardians: Accumulations in Liver, Lung, and Spleen in Mice

“…Mutations of the genes encoding the proteins named "biogenesis of lysosome-related organelles complex (BLOC)-1, -2 and -3" have been shown to cause both a dense-granule defect and albinism. 140,141) Various mice with such mutations have been established, 140) including "cappuccino mice" with cappuccino-like colors in the skin and eye. Our collaborators also established cappuccino mice, 142) and found that the mice exhibited a profound defect in platelet dense granules (i.e., lacking 5HT in platelets), although platelet levels were similar to those in control C57BL/6 mice.…”