interleukin-8 and Job-Syndrome

Autosomal-dominant hyper-IgE syndrome (AD-HIES) is a primary immunodeficiency caused by STAT3 mutations. This inherited condition is characterized by eczema, staphylococcal cold abscesses and recurrent pulmonary infections. Given that STAT3 is involved in IL-10 signaling, we examined the immunoregulatory role of IL-10 in inflammation by studying the effects of IL-10 on monocytes, neutrophils and monocyte-derived DCs from HIES subjects. Analysis of gene expression in PBMCs and neutrophils isolated from HIES patients and stimulated with LPS in the presence of IL-10 showed reduced expression of IL1RN, which encodes IL-1 receptor antagonist (IL-1ra), and SOCS3 mRNA but increased CXCL8 mRNA expression. Moreover, secretion of the anti-inflammatory protein IL-1ra was reduced in AD-HIES patients. DCs from HIES patients secreted higher levels of TNF-α, IL-6 and, to a lesser extent, IL-12 when these cells were cultured in the presence of IL-10. These results suggest that IL-10 activity is affected in myeloid cells (e.g. monocytes, DCs) of HIES patients. Impairment of IL-10 signaling in patients with AD-HIES might result in an altered balance between pro-inflammatory and anti-inflammatory signals and might lead to persistent inflammation and delayed healing after infections.

Topics: Adolescent; Adult; Base Sequence; Cells, Cultured; Child; Child, Preschool; Dendritic Cells; Female; Gene Expression Profiling; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-10; Interleukin-12; Interleukin-6; Interleukin-8; Job Syndrome; Lipopolysaccharides; Male; Monocytes; Myeloid Cells; Neutrophils; Phosphorylation; RNA, Messenger; Sequence Analysis, DNA; Signal Transduction; src Homology Domains; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Tumor Necrosis Factor-alpha

Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by atopic manifestations and susceptibility to infections with extracellular pathogens, typically Staphylococcus aureus, which preferentially affect the skin and lung. Previous studies reported the defective differentiation of T helper 17 (Th17) cells in HIES patients caused by hypomorphic STAT3 mutations. However, the apparent contradiction between the systemic Th17 deficiency and the skin/lung-restricted susceptibility to staphylococcal infections remains puzzling. We present a possible molecular explanation for this enigmatic contradiction. HIES T cells showed impaired production of Th17 cytokines but normal production of classical proinflammatory cytokines including interleukin 1beta. Normal human keratinocytes and bronchial epithelial cells were deeply dependent on the synergistic action of Th17 cytokines and classical proinflammatory cytokines for their production of antistaphylococcal factors, including neutrophil-recruiting chemokines and antimicrobial peptides. In contrast, other cell types were efficiently stimulated with the classical proinflammatory cytokines alone to produce such factors. Accordingly, keratinocytes and bronchial epithelial cells, unlike other cell types, failed to produce antistaphylococcal factors in response to HIES T cell-derived cytokines. These results appear to explain, at least in part, why HIES patients suffer from recurrent staphylococcal infections confined to the skin and lung in contrast to more systemic infections in neutrophil-deficient patients.

Topics: Animals; Antigens, Bacterial; Antigens, Fungal; beta-Defensins; Chemokines; Cytokines; Epithelial Cells; Humans; Interleukin-8; Job Syndrome; Keratinocytes; Lung Diseases; Receptors, Interleukin-1; Respiratory Mucosa; Staphylococcal Infections; Staphylococcal Skin Infections; STAT3 Transcription Factor; T-Lymphocytes, Helper-Inducer

Hyper IgE syndromes (HIES) are primary immunodeficiency disorders of unknown pathogenesis. Patients are typically affected with 'cold' abscesses of the skin, recurrent cyst-forming pneumonia, chronic mucocutaneous candidiasis and other less frequent features such as progressive skeletal abnormalities. Defective signaling in the Toll-like receptor (TLR) pathways has been suggested as a responsible pathologic mechanism, however, in previous reports, 10 patients revealed no defect in inflammatory cytokine responses to different TLR ligands. Here, we report the increase in pro-inflammatory cytokines TNF-alpha and IL-8, following TLR2 and TLR4 stimulation in a larger cohort of 25 additional patients with HIES, and provide a meta-analysis of the TLR data in HIES.

Topics: Cohort Studies; Female; Humans; Interleukin-8; Job Syndrome; Leukocytes, Mononuclear; Lipopolysaccharides; Male; Signal Transduction; Statistics, Nonparametric; Toll-Like Receptor 2; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Hyper-IgE syndrome is characterized by severe recurrent staphylococcal infections, eczema, bone abnormalities, and markedly elevated levels of immunoglobulin E (IgE). The genetic basis is not known and the central immunologic defect is largely undefined. Reduced neutrophil chemotaxis is often described, and variable T cell defects have been demonstrated in some patients. It has been hypothesized that hyper-IgE is associated with a Th1/Th2 imbalance. We wished to characterize cytokine and chemokine imbalances that might reflect the underlying disease process or reflect ongoing pathologic processes. Nine patients with hyper-IgE syndrome and six controls were studied. Radioimmunoassays, flow cytometry, and gene array analyses were performed to characterize cytokine and chemokine production. Hyper-IgE patients express more IL-12, while ENA-78, MCP-3, and eotaxin are markedly underexpressed. Underexpression of a set of chemokines could explain a number of features of hyper-IgE syndrome and may offer a new paradigm for the understanding of this disorder.

Topics: Adolescent; Adult; Cells, Cultured; Chemokine CCL11; Chemokine CCL7; Chemokine CXCL5; Chemokines; Chemokines, CC; Chemokines, CXC; Child; Child, Preschool; Cytokines; DNA, Complementary; Gene Expression Regulation; Humans; Interferon-gamma; Interleukin-12; Interleukin-8; Interleukins; Job Syndrome; Lymphocyte Activation; Monocyte Chemoattractant Proteins; Nicotinamide Phosphoribosyltransferase; Osteopontin; Phytohemagglutinins; Receptor, trkA; RNA, Messenger; Sialoglycoproteins; Tetradecanoylphorbol Acetate; Th1 Cells; Th2 Cells; Tumor Necrosis Factor-alpha

The hyper-IgE (HIE), or Job's, syndrome is a rare, complex disorder characterized by high levels of serum IgE in childhood and chronic dermatitis with recurrent, often severe sinopulmonary and skin infections. Although the etiology of HIE syndrome is unknown, there is evidence that patients with HIE have abnormalities in cellular immune responses, as well as in the production of polyclonal and antigen-specific antibodies. Furthermore, there appears to be a common (but still undefined) mechanism underlying the regulation of IgE and IgG4 in this condition.. We sought to assess the role of cytokines or cytokine receptor blockade in regulating IgE and IgG4 production in HIE.. PBMCs were isolated from patients with HIE (n = 9) and normal individuals (n = 8), and IgE and IgG4 production was assessed spontaneously, in the presence of recombinant IL-4, IL-13, IL-6, IL-8, IL-12, and IFN-gamma, under conditions in which the IL-4R was blocked or when these cytokines were neutralized by specific monoclonal or polyclonal antibodies.. In PBMCs from patients with HIE, a significant (P <.01) reduction in the spontaneously produced IgE (and IgG4) was induced by either IFN-gamma or IL-12, although neither cytokine could totally abrogate the immunoglobulin production. Whereas spontaneous IgE (and IgG4) production was not affected by exogenous IL-4 and IL-13, neutralizing antibodies to IL-4 and IL-13 also significantly (P <.01) reduced the production of IgE and IgG4, a finding supported by the observation of increased expression of IgE germline transcripts in these patients. In contrast to the neutralization of IL-4 and IL-13 protein, anti-IL-4R antibodies or soluble IL-4R completely suppressed IgE and IgG4 production in HIE. Similarly, IL-8 or antibodies to IL-6 and TNF-alpha, cytokines known to affect IL-4-dependent IgE production, completely inhibited both IgE and IgG4 production.. These data show that overproduction of IgE and IgG4 can be regulated by a number of cytokines affecting the IL-4-dependent pathway of IgE/IgG4 production in HIE and suggest new targets for therapeutic intervention.

Topics: Cytokines; Humans; Immunoglobulin E; Immunoglobulin G; Interferon-gamma; Interleukin-12; Interleukin-13; Interleukin-4; Interleukin-6; Interleukin-8; Job Syndrome; Leukocytes, Mononuclear; Tumor Necrosis Factor-alpha