Altered gene copy number of inhibitory IgG receptors in Kawasaki Disease; consequences for coronary artery lesions
06 / 2006 - unknown
Background: Kawasaki Disease (KD) is a pediatric vasculitis of unknown etiology with an annual incidence rate of 5-20 per 100,000 children younger than 5 years of age in Europe and the USA. Coronary arteries are often affected, resulting in coronary artery aneurysms (CAA) in 25-30% of untreated children. Intravenous immunoglobulins (IVIG) reduce the incidence of CAA by 40-70%, by as yet unknown mechanisms. Fcgamma-receptors (FcyRs) are proteins on the surface of leukocytes that are able to bind immunoglobulin G (IgG), especially when these are bound to antigens in an immune complex. IgG is the predominant component in IVIG. The FcyRs exist in a number of isoforms, namely FcyR type I, type II (a and b) and type III (a and b). FcyRI is a receptor with a high affinity for IgG on macrophages, while FcyRII and FcyRIII have lower affinity but are expressed by many leukocytes, as well as platelets and endothelial cells. Kawasaki Disease (KD) is an acute systemic vasculitis occurring in young children. The diagnosis is based on clinical symptoms, including fever for at least five days, cervical lymphadenopathy, bilateral conjunctivitis, rash, inflammation of the mucous membranes and peripheral edema. The standard therapy for KD consists of high dose IVIG and oral aspirin. Without treatment in 25-30% of the cases CAA develop. Currently KD is the leading cause of acquired heart disease in children. Although the etiology of KD is enigmatic, most clinical and epidemiological data suggest an association with an infectious agent. The striking differences in annual incidence between Japan (135 per 100,000) and America and Europe (5-20 per 100,000) suggest that there is a genetic component as well, particularly since an increased risk has been observed in siblings and twins . The balance between activating and inhibitory FcyRs is crucial for immune reactivity. We have recent evidence that it is not only the SNPs but also the number of genes that is decisive for immune responsiveness and inflammation, and this may be wrong in auto-immune patients: the number of intact FCGR2B genes in the DNA from the patients may differ from that in healthy controls. We have developed new, ultra-specific PCR methods for quantifying the different genes for the various FcyRs. In 40 Kawasaki patients, we found 20 with only one intact FCGR2B gene and 2 with no intact FCGR2B gene at all. In 40 healthy controls, only 4 had one intact gene and 1 had no intact gene, whereas 4 controls had three or four intact FCGR2B genes (p less than 0.005). This last observation fits with a recent report about gene copy number polymorphisms in the human genome  KD is the most common acquired heart disease of childhood. Its etiology is unknown. It is a vasculitis occurring mostly in children younger than 5 years of age. In many of the affected children, coronary artery lesions are being observed, resulting in increased risk of sudden heart death, persistent vascular disease and long-term contribution to premature atherosclerosis. In an ongoing study in which most of the Academic Centers of Pediatric Cardiology as well as regional pediatricians participate we wish to elucidate why some children suffer from KD and why standard therapy of IVIG works in some and not in others. The Emma Children's Hospital at the AMC initiated in 1995 an ongoing collaboration with pediatricians from other academic and regional hospitals to prospectively study pathogenic mechanisms of infectious, inflammatory and immunological nature potentially involved in KD, funded by the Netherlands Heart Foundation from 1999 onward. The present study proposal represents a continuation of these studies on KD. Clinically, these studies are part of the pediatric cardiology follow-up program on KD of the Emma Children's Hospital AMC. All Dept of Pediatric Cardiology at the 8 academic centers in the Netherlands have again been approached in 2005, of which (at least) 6 have already expressed their willingness to collaborate on the aforementioned research plans.