ABSTRACT
The cause of Kawasaki disease (KD), the leading cause of acquired heart disease in children, is currently unknown. Epidemiology studies support that an infectious disease is involved in at least starting the inflammatory cascade set off during KD. Clues from epidemiology support that humoral immunity can have a protective effect. However, the role of the immune system, particularly of B cells and antibodies, in pathogenesis of KD is still unclear. Intravenous immunoglobulin (IVIG) and other therapies targeted at modulating inflammation can prevent development of coronary aneurysms. A number of autoantibody responses have been reported in children with KD and antibodies have been generated from aneurysmal plasma cell infiltrates. Recent reports show that children with KD have similar plasmablast responses as other children with infectious diseases, further supporting an infectious starting point. As ongoing studies are attempting to identify the etiology of KD through study of antibody responses, we sought to review the role of humoral immunity in KD pathogenesis, treatment, and recovery.
ABSTRACT
BACKGROUND: During HIV infection, fusion of the viral and cellular membranes is dependent on folding of the gp41 trimer into a six-helix bundle. Fusion inhibitors, such as the antiretroviral Enfuvirtide (T20), interfere with the formation of the gp41 six-helix bundle. Recent in vitro studies reveal that the gp41 immunodominant region one targeting antibody 3D6 can block T20 interference, but the clinical and pathophysiologic significance of this finding is unclear. OBJECTIVE/METHOD: We have previously characterized a number of antibodies that target conformational epitopes on gp41and herein characterized their ability to interfere with T20 in multiple assays and assess their prevalence in HIV infected subjects. RESULTS: The T20 interference by antibody 3D6 was confirmed in a CHO-HXB2 envelope/ HeLaT4+ cell culture assay. Antibodies that target an immunodominant region one epitope, as well as a gp41 discontinuous epitope, also interfered in this assay, however, not all antibodies that targeted these epitopes showed T20 interference. This response was not due to the direct binding of T20 by the antibodies and could not be replicated utilizing TZM-bl and HL2/3 cells. Notably, serum competition studies on a panel of HIV subjects demonstrate that these conformational targeting antibodies are common in the HIV population. CONCLUSION: The relatively common nature of antibodies targeting these epitopes, the disparate in vitro results, and lack of reported clinical failures ascribed to such antibodies leads us to conclude that antibody interference of T20 is likely not clinically relevant. However, this warrants continued consideration with the advancement of other fusion inhibitors.
Subject(s)
Drug Interactions , Enfuvirtide/pharmacology , HIV Antibodies/immunology , HIV Envelope Protein gp41/immunology , HIV Fusion Inhibitors/pharmacology , HIV Infections/drug therapy , Animals , Cell Line , HumansABSTRACT
BACKGROUND: Kawasaki disease (KD) is a febrile childhood vasculitis of unknown etiology. The diagnosis is highly concerning as over a quarter of children who fail to receive timely treatment with intravenous immunoglobulin (IVIG) will develop coronary aneurysms. Diagnosis relies on proper symptomatology and is supported by non-specific markers of inflammation. Previous studies have identified elevated plasma levels of interleukin-21 (IL-21) as a sensitive and specific biomarker in KD. The aim of this study is to assess the validity of IL-21 as a diagnostic biomarker for KD in febrile children in North America. METHODS: Plasma samples were collected from children who presented to an urban Emergency Department in North America. IL-21 levels were measured using commercial ELISA kits in 12 KD versus 60 controls subjects. RESULTS: Our study shows that IL-21 levels were non-specifically elevated across all febrile children, irrespective of KD diagnosis. Length of fever prior to sample collection does not correlate with IL-21 levels. Other inflammatory markers and laboratory values were also compared to IL-21 and show no significant correlation. CONCLUSIONS: Since IL-21 is elevated non-specifically in this cohort, our data supports that IL-21 is not an appropriate biomarker for diagnosis of KD in North American pediatric populations.