Abstract
The flaky tail mouse arose as a spontaneous recessive mutation in 1958. Homozygous mice (ft/ft) are characterized by dry, flaky skin and annular tail and paw constrictions that are present during the neonatal period. Histopathology of the skin shows mild, diffuse orthokeratotic hyperkeratosis and occasional acanthosis. These mice express truncated profilaggrin protein and lack the normal processed filaggrin protein. Filaggrin is a structural protein that is critical to epidermal terminal differentiation and formation of an intact skin barrier. Fallon and colleagues determined that the genetic defect in these mice results from a 1 basepair deletion in the filaggrin gene, and they have provided further evidence of how this contributes to the pathogenesis of excema and related atopic disorders such as excema-associated asthma. When they applied ovalbumin, an allergen, to the intact skin of ft/ft mice it induced cutaneous inflammation of predominantly lymphocytes, with some eosinophils and mononuclear cells. The mice also developed allergen-specific antibodies and cytokine responses very similar to those observed in humans with atopic excema. This supports the notion that disruption of the epidermal barrier allow exposure to allergens that result in systemic inflammatory responses. Although the mice did not develop inflammatory lung lesions following percutaneous allergen challenge in the absence of adjuvant, this could be due to the timing of the challenge, as the ft/ft mice were 6–8 weeks old and display a much less severe phenotype at that age than in the neonatal period.
Fallon PG, Sasaki T, Sandilands A, et al. A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nat Genet
Large, eosinophilic, cytoplasmic inclusions are sometimes seen in Clara cells of the rat lung. The authors of this study noticed an increase in the number of Clara cells containing these inclusions in rats treated with inhaled corticosteroids for 3–24 months. The inclusions were characterized by immunohistochemistry (IHC), in situ hybridization (ISH), and transmission electron microscopy (TEM). In both treated and untreated rats, the inclusions were strongly positive for surfactant protein D and weakly positive for Clara cell specific protein. TEM showed that the inclusions, which measured as large as 17 microns in diameter, contained moderately electron-dense amorphous material and had an irregular limiting membrane. There was a dose-dependent increase in the number of inclusions present. The mechanism for formation of increased inclusions during inhaled corticosteroid treatment was not determined, but since eosinophilic cytoplasmic inclusions are not observed in human bronchial epithelium, their presence in the rat was deemed unlikely to have relevance for human risk analyses.
Kambara T, McKevitt TP, Francis I, et al. Eosinophilic inclusions in rat Clara cells and the effect of an inhaled corticosteroid. Toxicol Pathol
Heart and skeletal muscle inflammation (HSMI) is a transmissible disease in farmed Atlantic salmon that has high morbidity and variable mortality. It was first characterized in 1999 in Norway. Cardiac lesions consist of epi-, endo- and myocarditis and necrosis, and skeletal muscle also shows myositis and necrosis. The cause of HSMI is unknown and no definitive etiologic agent has been isolated. The authors of this study conducted infection trials to better understand the infectivity, pathogenesis, and disease progression of HSMI. Putatively infected material (heart, liver, kidney, spleen and plasma) was injected intraperitoneally into salmon in fresh water and in sea water. All inoculates caused cardiac inflammation beginning with perivasculitis and endocarditis as early as 1–3 weeks post-challenge. Myocarditis and necrosis was evident after 3 weeks. Lesions occurred even when the inoculate was from derived from tissues that appeared histologically normal in diseased fish, such as the kidney, and also when the tissue used for the inoculate was harvested prior to a disease outbreak. Pretreatment of the inoculate with chloroform did not prevent disease, indicating that the organism may be non-enveloped. The authors speculate that since plasma appears to contain the infectious agent, this may allow the development of a non-lethal detection assay.
Kongtorp RT, Taksdal T. Studies with experimental transmission of heart and skeletal muscle inflammation in Atlantic salmon, Salmo salar L. J Fish Dis
The Coxsackievirus-adenovirus receptor (CAR) is one of the receptors for Coxsackievirus B3 (CVB3). This virus causes acute myocarditis, chronic cardiomyopathy, and contractile dysfunction in humans and experimental mice. Shi et al. developed a tamoxifen-inducible CAR knockout (KO) mouse to study the effects of CVB3 infection in the adult heart, as conventional KO models have cardiac malformations and/or embryonic lethality. The authors found that CAR KO mice had no signs of myocarditis or cardiomyopathy upon challenge with CVB3, nor did they have a cytokine response with increased interleukin-6 and -10 as did the wildtype controls. No virus was detectable in hearts from KO mice, while noncardiac tissues such as pancreas and spleen had the same viral load as wildtype mice. This study demonstrates that CAR is necessary for myocyte infection in vivo, and that direct infection of myocytes is required for myocarditis to occur during CVB3 infection.
Shi Y, Chen C, Lisewski U, et al. Cardiac deletion of the Coxsackievirus-adenovirus receptor abolishes Coxsackievirus B3 infection and prevents myocarditis in vivo. J Am Coll Cardiol