Regulation of immunoglobulin production in hyper-IgE (Job's) syndrome

Background: The hyper-IgE (HIE), or Job's, syndrome is a rare, complex diso rder characterized by high levels of serum IgE in childhood and chronic der matitis with recurrent, often severe sinopulmonary and skin infections. Alt hough the etiology of HIE syndrome is unknown, there is evidence that patie nts 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 th e regulation of IgE and IgG4 in this condition. Objective: We sought to assess the role of cytokines or cytokine receptor b lockade in regulating IgE and IgG4 production in HIE. Methods: PBMCs were isolated from patients with HIE (n = 9) and normal indi viduals (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 n-4R was blocked or when these cytokines wer e neutralized by specific monoclonal or polyclonal antibodies. Results: In PBMCs from patients with HIE, a significant (P <.01) reduction in the spontaneously produced IgE (and IgG4) was induced by either IFN-gamm a or IL-12, although neither cytokine could totally abrogate the immunoglob ulin production, Whereas spontaneous IgE land IgG4) production was not affe cted 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 fin ding supported by the observation of increased expression of IgE germline t ranscripts in these patients. In contrast to the neutralization of IL-4 and IL-13 protein, anti-IL-4R antibodies or soluble n-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, complet ely inhibited both IgE and IgG4 production. Conclusion: These data show that overproduction of IgE and IgG4 can be regu lated by a number of cytokines affecting the IL-4-dependent pathway of IgE/ IgG4 production in HIE and suggest new targets for therapeutic intervention .