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Summary Background Kimura's disease (KD) is a chronic inflammatory disorder characterized by tumours in the head and neck region, enlarged lymph nodes, increased eosinophil counts and high serum IgE. Mast cells are known to play a central role in IgE-mediated allergic diseases through the release of inflammatory mediators like IL-4, IL-5 and chemokines. We hypothesized that mast cells may play a role in the pathogenesis of KD by regulating eosinophilic infiltration and IgE synthesis. Objective In order to investigate the role of mast cells in the pathogenesis of KD, we examined the expression of cytokines/chemokines in the lesions of KD. Methods We examined the number of tryptase+ cells, EG2+ cells, CD3+ cells, IL-4+ cells, IL-5+ cells, eotaxin+ cells, RANTES+ cells and CCR3+ cells in five specimens of KD versus normal tissues by immunohistochemistry. The sources of IL-4, IL-5, eotaxin and RANTES and the expression of CCR3 were examined by immunostaining of serial sections with antibodies to IL-4, IL-5, eotaxin, RANTES and CCR3, and antibodies to tryptase, ECP (EG2) and CD3. Results Mast cells, activated eosinophils, T cells, IL-4+ cells, IL-5+ cells, eotaxin+ cells, RANTES+ cells and CCR3+ cells were all increased in the lesions of KD as compared with those in normal tissue. Mast cells and T cells were the major source of IL-4, whereas mast cells, T cells and activated eosinophils were the main source of IL-5. Mast cells, T cells and activated eosinophils were the main source of eotaxin and RANTES. Conclusions The number of IL-4, IL-5, eotaxin and RANTES-expressing mast cells and T cells were increased in the lesions of KD. As mast cells are lesional resident cells, these cells may play an important role in the pathogenesis of KD by regulating IgE synthesis and orchestrating eosinophilic infiltration. [ABSTRACT FROM AUTHOR]

The role of T cells for IL-4-induced IgE synthesis by peripheral blood mononuclear cells (PBMC) was investigated. The removal of monocytes from PBMC abolished IL-4-induced IgE synthesis. When PBMC were separated into T and non-T cells, non-T cells alone were not able lo secrete significant amounts of IgE in the presence of IL-4. Depending on the separation procedure, the reconstitution of non-T cells with T cells prepared by rosetting did not restore IgE secretion, whereas T cells obtained by the use of anti-CD3 antibodies could co-induce IgE formation. However, when the T cells were first irradiated, large amounts of IgE were produced, which strongly exceeded those found in unseparated PBMC cultures. IL-4-induced IgE synthesis was also obtained in co-cultures of formaldehyde-fixed T cells with non-T cells. Furthermore, not only autologous hut also allogeneic T cells, which have been irradiated or fixed, could provide the costimulatory effect on IgE formation by non-T cells in the presence of IL-4. Mitogenically pre-activated T cells, however, were not able to support IgE synthesis. Hydrocortisone (HC) potentiated the IL-4-induced IgE synthesis by PBMC and enabled non-T cells lo secrete IgE in the presence of IL-4. Adding both HC and T cells led lo a marked synergistic effect on IL-4-induced IgE production. We conclude that monocytes are required for the induction of IgE synthesis in PBMC in addition to T cells and IL-4. Our results support the view that the T cell signal is delivered via cognate and non-cognate T/B cell membrane interaction. Furthermore, active and proliferating T cells rather suppress IgE synthesis. Finally, HC appears to be a potent alternative stimulus, which bypasses the necessity for T cells in IL-4-induced IgE formation. [ABSTRACT FROM AUTHOR]

We measured the in vitro production of interferon-gamma (IFN-γ) in five cases of hyper-IgE syndrome (HIgE), induced by mitogens, calcium ionophores and phorbol ester. The biosynthesis of IFN-γ was severely reduced or undetectable in HIgE, while it was near normal in most atopic patients. The in vitro spontaneous production of IgE was increased overall in HIgE patients, although no correlation was found with serum IgE levels. Recombinant interleukin-4 (IL-4) induced a further increase in IgE synthesis, and its effect was totally antagonized by recombinant IFN-γ; the same pattern of response was also observed in atopic subjects with high production of IgE. IFN-α synergized with IL-4 on IgE synthesis, whereas recombinant IL-6 gave opposite changes in individual cases tested. We propose that IFN-γ deficiency may be responsible for some of the features of HIgE patients, including IgE levels and infections. [ABSTRACT FROM AUTHOR]

Neonatal B cells have been considered immature because of their impaired capacity to produce immunoglobulins in response to polyclonal activators in vitro. Here we demonstrate (hat cord blood mononuclear cells (MNC) produce normal levels of IgE in vitro when cultured in the presence of interleukin-4 (IL-4), indicating that the B cells are mature in their capacity to switch lo IgE-producing cells. However, in contrast to adult peripheral blood T cells, cord blood T cells failed to produce detectable levels of IL-4 upon activation by phytohaemagglutinin (PHA) concanavalin A (Con A) or combinations of PHA and the phorbol ester TPA. Interferon-gamma (IFN-γ) production by cord blood T cells following activation by Con A or PHA was also strongly reduced. However, high levels of IFN-γ, significantly higher than those produced by adult T cells, were synthesized in response to combinations of PHA and TPA, indicating that IFN-γ production by cord blood T cells is not intrinsically defective. In contrast, cord blood T cells produced levels of IL-2 that were significantly higher than those obtained by adult T cells tested in parallel. Collectively, our data indicate that the minimal levels of IgE production measured in cord blood (< 1 U/ml) are not due to immaturity of the cord blood B cells, but may be associated with the failure of cord blood T cells to produce detectable levels of IL-4, which has been shown to be responsible for induction of IgE synthesis both in vitro and in vivo. [ABSTRACT FROM AUTHOR]