Mice with early onset of death (EOD) due to lupus glomerulonephritis

Honda, Shuji; Nemoto, Kyuichi; Mae, Takako; Kinjoh, K; Kyogoku, Masahisa; Kawamura, Hiroki; Miyazawa, Shinobu; Weerashinghe, A.; Watanabe, Hirotaka; Narita, Junichi; Koya, Toshiyuki; Arakawa, Masaaki; Abo, Toru

doi:10.1046/j.1365-2249.1999.00847.x

Cited by 4 publications

(2 citation statements)

References 21 publications

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“…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). Cappuccino mice have a frame-shift mutation due to a single nucleotide deletion in the cappuccino gene.…”

Section: Effects Of 5ht In Cappuccino Micementioning

confidence: 99%

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

Yu¹,

Ohba²,

Nakamura

et al. 2009

Thromb Haemost

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In experimental animals, the lung rapidly removes intravenously injected 5-hydroxytryptamine (5HT), but the mechanism underlying this pulmonary 5HT removal (P-5HT-R) and the responsible cells remains unclear. 5HT reportedly induces rapid pulmonary platelet accumulation (P-PLT-A). Here, we examined the relationship between P-5HT-R and P-PLT-A in mice by comparing the platelet count in the blood with the endogenous 5HT in the tissues (a marker for platelets because the 5HT is largely contained within platelets). 5HT levels in murine blood and tissues were also examined after intravenous injection of 5HT. The data revealed that: (i) 5HT injection (at > or = 0.04 micromol/kg) induced a transient P-PLT-A (occurring within 6 seconds), (ii) platelets rapidly took up injected 5HT, (iii) the P-5HT-R was saturated following injection of 5HT at 1 micromol/kg, (iv) ketanserin (5HT(2)-receptor antagonist) strongly inhibited P-PLT-A, (v) under fluoxetine (5HT-uptake inhibitor), 5HT levels at 6 seconds after 5HT injection were markedly higher in blood, but significantly lower in lung (versus fluoxetine-untreated mice), (vi) P-5HT-R was barely detectable in mutant mice with platelets lacking dense bodies, and was much reduced in platelet-depleted mice, (vii) 5HT injected intravenously at 10 micromol/kg had a half-life in the lung of < 20 seconds, and (viii) unlike 5HT, injected histamine was largely excreted by the kidney. These results demonstrate that platelets rapidly translocate into the lung upon stimulation of 5HT(2) receptors, take up 5HT (and possibly swiftly metabolise it), and then return to the circulation. Hence, pulmonary platelet accumulation plays an important role in pulmonary 5HT removal in mice.

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Section: Effects Of 5ht In Cappuccino Micementioning

confidence: 99%

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

Yu¹,

Ohba²,

Nakamura

et al. 2009

Thromb Haemost

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“…Male WT‐EOD mice carry 2 autoimmune‐accelerating mutations, Fas lpr and Yaa , while female WT‐EOD mice carry only Fas lpr . As a result of selective breeding, the genetic background of the EOD strain was reconstituted such that the mice would die prematurely of severe GN with crescent formation and IC deposition (6). We have been using this strain as a model for IC CGN.…”

mentioning

confidence: 99%

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

Yoshida¹,

Saiga²,

Hato³

et al. 2006

Arthritis & Rheumatism

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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.

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Mast cell hyperplasia in the skin of Dsg4-deficient hypotrichosis mice, which are long-living mutants of lupus-prone mice

et al. 2008

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Desmosomal cadherins are essential cell adhesion molecules expressed in the epidermis. We identified a mutation of a cadherin superfamily member, namely, desmoglein 4 (Dsg4), in early onset of death (EOD)( hage ) mice with hypotrichosis. The mutation was induced by the insertion of an early transposon II-beta into intron 8 of Dsg4. Mast cell hyperplasia was observed in the skin of EOD( hage ) mice. The abnormally expanded population of lpr T cells, i.e., CD4(-)CD8(-)B220(+)Thy1.2(+) alphabetaT cells, in the splenocytes of EOD mice was reduced in EOD( hage ) mice. Therefore, it was suspected that the long-living mutant EOD( hage ) mice were selected from lupus-prone EOD mice because of their immunological immaturity. These findings clearly indicate that Dsg4 is an important molecule for the formation of hair follicles and hypothesize that unorganized hyperplastic hair follicles in anagen due to the Dsg4 mutation provide niches for mast cell precursors in the skin.

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Mice with early onset of death (EOD) due to lupus glomerulonephritis

Cited by 4 publications

References 21 publications

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

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

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

Mast cell hyperplasia in the skin of Dsg4-deficient hypotrichosis mice, which are long-living mutants of lupus-prone mice

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