TNF-alpha is necessary for induction of coronary artery inflammation and aneurysm formation in an animal model of Kawasaki disease

Kawasaki disease is the most common cause of multisystem vasculitis in childhood. The resultant coronary artery lesions make Kawasaki disease the leading cause of acquired heart disease in children in the developed world. TNF-alpha is a pleiotropic inflammatory cytokine elevated during the acute phase of Kawasaki disease. In this study, we report rapid production of TNF-alpha in the peripheral immune system after disease induction in a murine model of Kawasaki disease. This immune response becomes site directed, with migration to the coronary arteries dependent on TNF-alpha-mediated events. Production of TNF-alpha in the heart is coincident with the presence of inflammatory infiltrate at the coronary arteries, which persists during development of aneurysms. More importantly, inflammation and elastin breakdown in the coronary vessels are completely eliminated in the absence of TNF-alpha effector functions. Mice treated with the TNF-alpha-blocking agent etanercept, as well as TNFRI knockout mice, are resistant to development of both coronary arteritis and coronary aneurysm formation. Taken together, TNF-alpha is necessary for the development of coronary artery lesions in an animal model of Kawasaki disease. These findings have important implications for potential new therapeutic interventions in children with Kawasaki disease.     

Kawasaki disease: Canadian update.

Kawasaki disease, or mucocutaneous lymph node syndrome, is a multisystem disorder that affects young children. Between 1979 and 1982, 357 patients from 15 university pediatric centres in Canada were reported to have the disease. The diagnosis of Kawasaki disease is based on six clinical features, including fever, conjunctivitis, cracked lips, reddening and swelling of the hands and feet, rash and cervical lymphadenopathy. A scoring system is described that may help predict the development of cardiovascular complications. Coronary artery involvement can be recognized early by two-dimensional echocardiography. Anti-inflammatory therapy, principally with acetylsalicylic acid, is indicated in the acute phase and antithrombotic treatment in the subacute and chronic phases of the disease if coronary artery aneurysms have developed. Prolonged follow-up for patients with aneurysms is necessary. The length of follow-up for patients without aneurysms will depend on the results of studies on patients with Kawasaki disease after they reach adulthood.     

Zebrafish: a model system for the study of human disease

The zebrafish (Danio rerio) is a powerful model organism for the study of vertebrate biology, being well suited to both developmental and genetic analysis. Large-scale genetic screens have identified hundreds of mutant phenotypes, many of which resemble human clinical disorders. The creation of critical genetic reagents, coupled with the rapid progress of the zebrafish genome initiative directed by the National Institutes of Health, are bringing this model system to its full potential for the study of vertebrate biology, physiology and human disease.     

Chagas disease: a model for the study of autoimmune diseases

There are few natural animal model systems to study autoimmune disease caused by infectious agents; however, Trypanosoma cruzi infection of the mouse offers an excellent model for the induction of autoimmunity and its consequences. In this article Klaus Petty and Harvey Eisen explain that it is probably during the acute phase of the infection that the stage is set for the long-term pathology.     

Anti-human cardiac myosin autoantibodies in Kawasaki syndrome.

Kawasaki syndrome (KS) is the major cause of acquired heart disease in children. Although acute myocarditis is observed in most patients with KS, its pathogenesis is unknown. Because antimyosin autoantibodies are present in autoimmune myocarditis and rheumatic carditis, the purpose of the current study was to determine whether anticardiac myosin Abs might be present during the acute stage of KS. Sera from KS patients as well as age-matched febrile controls and normal adults were compared for reactivity with human cardiac myosin in ELISAs and Western blot assays. A total of 5 of 13 KS sera, as compared with 5 of 8 acute rheumatic fever sera, contained Ab titers to human cardiac myosin that were significantly higher than those found in control sera. Both cardiac and skeletal myosins were recognized in the ELISA by KS sera, although stronger reactivity was observed to human cardiac myosin. Only IgM antimyosin Abs from KS sera were significantly elevated relative to control sera. KS sera containing antimyosin Abs recognized synthetic peptides from the light meromyosin region of the human cardiac myosin molecule and had a different pattern of reactivity than acute rheumatic fever sera, further supporting the association of antimyosin Ab with KS. These Abs may contribute to the pathogenesis of acute myocarditis found in patients with KS.     

Isoprenoid biosynthesis is not compromised in a Zellweger syndrome mouse model.

Because several studies indicated that peroxisomes are important for the biosynthesis of isoprenoids, we wanted to investigate whether a reduced availability of isoprenoids could be one of the pathogenic factors contributing to the severe phenotype of the Pex5(-/-) mouse, a model for Zellweger syndrome. Total cholesterol was determined in plasma, brain and liver of newborn mice. In none of these tissues a significant difference was observed between Pex5(-/-) and wild type or heterozygous mice. The hepatic ubiquinone content was found to be even higher in Pex5(-/-) mice as compared to wild type or heterozygous littermates. To investigate whether the Pex5(-/-) fetuses are able to synthesise their own isoprenoids, fibroblasts derived from these mice were incubated with radiolabeled mevalonolactone as a substrate for isoprenoid synthesis. No significant difference was observed between the cholesterol production rates of Pex5(-/-) and normal fibroblasts. Our results show that there is no deficiency of isoprenoids in newborn Pex5(-/-) mice, excluding the possibility that a lack of these compounds is a determinant factor in the development of the disease state before birth.     

The Rhesus monkey as a model for the study of infectious disease

Models for bacterial and viral infections and intoxication were developed in rhesus macaques (Macaca mulatta). Manifestations of acute-phase illnesses, e.g., temperature, white blood cell (WBC) counts, blood cultures, etc., were monitored at regular intervals. Viral infection was established by inoculating subcutaneously 412 plaque-forming units of Trinidad strain, Venezuelan equine encephalomyelitis virus. A diphasic febrile response developed, with the first fever peak on days 1 to 2 and a second peak on days 3 to 5. Viremia occurred within 12 hours and persisted in some animals for as long as five days. WBC responses were typical of viral infection. Gram-positive infections were induced by intravenous (IV) inoculation of 10⁸ Type I Diplococcus pneumoniae. Peak febrile response and bacteremia (10² to 10⁶ pneumococci per milliliter) occurred within 48 hours. Gram-negative infections, obtained by IV inoculation with 10⁹ Salmonella typhimurium, induced maximal febrile responses within 24 to 48 hours. Leukopenia occurred in 75% of animals; all were bacteremic. Mortality was 40% at 72 hours. Manifestations of intoxication following IV administration of purified staphylococcal enterotoxin B (10 μg per kg body weight) consisted of vomiting, diarrhea, leukopenia, and fever within one to three hours and resembled nonlethal staphylococcal food poisoning of man. These studies indicate that the rhesus macaque has reproducible and characteristic responses to a variety of microbial stimuli and therefore is eminently suitable for studying pathophysiologic, metabolic, and immunologic parameters of infectious or toxic disease processes.