Increased chemoattractant induced neutrophil oxidative burst, accelerated apoptosis, and dysregulated tyrosine phosphorylation associated with lifelong bacterial infections.
A boy with lifelong recurrent bacterial infection at cutaneous and mucosal sites was investigated. PMN oxidative burst to phorbol myristate acetate (PMA) and zymosan was normal but was increased 20- to 50-fold upon C5a or formyl-met-leu-phe (fMLP) chemoattractant stimulation, accompanied by accelerated PMN apoptosis. His PMNs showed increased constitutive tyrosine phosphorylation of 21-, 25-, and 44-kDa proteins, and of src-family kinases (p59(hck), p58(fgr), and p53/56(lyn)). Phosphorylation was abnormally enhanced following fMLP stimulation. Expression and activity of the major PMN tyrosine phosphatases, i.e., CD45, CD148, and SHP-1 and -2, was normal. However, dephosphorylation of phospho-p58(fgr) and phospho-p53/56(lyn) by lysates of patient's PMNs was enhanced. Thus, another phosphatase may be overactive, perhaps dephosphorylating a regulatory (inhibitory) site on a protein tyrosine kinase, accounting for the abnormal PMN tyrosine phosphorylation and function. With age (now 13 years), T-cell lymphopenia and loss of T-cell responses developed. This appears to be a unique primary immunodeficiency with abnormal PMN oxidative and apoptotic responses to chemoattractants, dysregulated protein tyrosine phosphorylation, serious bacterial infection, and T-lymphocyte attrition.
Yan
Sen Rong
SR
Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.
Bortolussi
Robert
R
Issekutz
Thomas B
TB
Issekutz
Andrew C
AC
D000293:Adolescent; D017209:Apoptosis / Q000276:immunology*; D001424:Bacterial Infections / Q000276:immunology*; D002630:Chemotactic Factors / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis / Q000276:immunology / Q000503:physiopathology; D007223:Infant; D008297:Male; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D016897:Respiratory Burst / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014443:Tyrosine / Q000276:immunology / Q000378:metabolism*
D002630:Chemotactic Factors; D014443:Tyrosine