Th 1 / Th 2 cytokine imbalance in a family with hyper-IgE syndrome

Background: Hyperimmunoglobulin E (hyper-IgE) syndrome is a rare immunodeficiency characterised by recurrent skin and respiratory tract infections, skeletal and dental abnormalities, chronic eczema, and elevated serum IgE. We describe a family with four hyper-IgE syndrome patients (38, 37, 30 and 7 years old), in which we investigated the cytokine response to both specific and non-specific stimulation. Methods: Whole blood from patients and volunteers was stimulated for either 24 or 48h at 37°C with heat-killed Staphylococcus, C. albicans or a combination of IL-12 and IL-18. Cytokine concentrations in the plasma were measured by specific radioimmuno-assays or ELISA. Results: Serum IgE ranged from 5000 to 16,670 IU/ml, and neutrophil chemotaxis was normal in all four patients. Tumour necrosis factor, interleukin (IL)-1 , IL-6 and IL-8 production after stimulation of whole-blood cultures with lipopolysaccharide or heat-killed S. aureus did not differ between the adult patients and four healthy controls. In contrast, when blood from patients and controls was stimulated with heat-killed S. aureus or C. albicans, a severe imbalance towards a Th2 phenotype was found, with 10to 30-fold reduction in the IFN /IL-10 ratios in the hyper-IgE syndrome patients. The IFN production in the patients was less severely impaired when blood was non-specifically stimulated with a combination of IL-18 and IL-12. Conclusion: In this family with hyper-IgE syndrome, the imbalance in the Th1/Th2 cytokine production may have been involved in the pathogenesis of the recurrent infections and/or chronic eczema characteristic of this disease. I N T R O D U C T I O N Hyperimmunoglobulin E syndrome is a rare immunodeficiency characterised by recurrent staphylococcal skin abscesses, respiratory tract infections such as pneumonia with pneumatocele formation, mucocutaneous candidiasis, chronic eczematous dermatitis, and extremely elevated circulating IgE concentrations. The recent publication of the clinical characteristics of a large series of patients revealed important non-immunological features such as dental abnormalities (retained primary teeth, non-eruption of permanent teeth, double rows of teeth), anomalies in midline facial development, and skeletal abnormalities (bone fractures, hyperextensible joints, scoliosis). Most cases are sporadic, but the description of several families with clustering of hyper-IgE syndrome patients suggests an autosomal dominant transmission with variable expressivity. Although the precise genetic abnormality is not yet known, linkage of hyper-IgE syndrome to the proximal q region of the chromosome 4 has been demonstrated. It has been hypothesised that the increased susceptibility to infections and the skin hypersensitivity could be the result of an altered cytokine production pattern in hyper-IgE syndrome patients. IFN as a prototype of the Th1 cytokines activates the cellular immune responses, whereas IL-4 and IL-10 as cytokines of the Th2 family induce activation of the O R I G I N A L A R T I C L E Th1/Th2 cytokine imbalance in a family with hyper-IgE syndrome M.G. Netea, P.M. Schneeberger, E. de Vries, B. -J. Kullberg, J.W. M. van der Meer, M.I. Koolen Departments of Internal Medicine, Medical Microbiology, and Paediatrics, Bosch MediCentrum, ’s-Hertogenbosch, the Netherlands, Department of Medicine (541), University Medical Centre St Radboud, PO Box 9101, 6500 HB Nijmegen, the Netherlands, tel. : +31 (0)24-361 88 19, fax: +31 (0)24-354 17 34, * corresponding author ** J.W. M. van der Meer was not involved in the handling and review process of this paper.