The induction of allergen-specific IgE synthesis requires the cognate interactions between B and T helper (Th) 2 cells. The B cell-activating signal for IgE synthesis is delivered through interleukin (IL)-4 or IL-13 and CD40 ligand, which are provided by activated Th2 cells. Signaling through the IL-4 receptor α chain (IL-4Rα) triggers IL-4- or IL-13-dependent germline Cε transcription by activating signal transducer and activator of transcription (STAT)-6 through members of the Janus kinase (JAK) family. In addition to the known JAK-STAT pathway, two adaptor molecules associated with the IL-4Rα, which include Src homologous and collagen (Shc ) and a product of the fes proto-oncogene family, are involved in the induction of germline Cε transcription. These adaptor molecules transmit the downstream signaling, leading to activation of PU.1, a product of the ets proto-oncogene family, which co-operates functionally with STAT-6 for germline Cε transcription. Ligation of CD40 in the presence of IL-4 or IL-13 leads to expression of activation-induced cytidine deaminase (AID). This novel RNA-editing enzyme plays a role upstream of the putative switch recom-binase, activation of which results in IgE isotype switching, mature Cε transcription and IgE synthesis. Although CD40 signaling activates multiple pathways that are critical for the activation of the switch recom-bination machinery, none of the known second messengers and transcription factors generated by CD40 ligation is involved in AID expression and isotype switching. Elucidation of the merging point of IL-4Rα and CD40 signaling pathways required for IgE switching will provide potential new strategies for the isotype-specific regulation of IgE synthesis.

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Background: Although eosinophils and fibroblasts are believed to play important roles in the patho-genesis of chronic allergic inflammation, the inter-action between eosinophils and fibroblasts has not been thoroughly elucidated. Stem cell factor (SCF) is one of the important cytokines produced by fibro-blasts. In the present study, we examined the effects of some cytokines and eosinophils on SCF production by human lung fibroblasts.
Methods: Fibroblasts were cultured with or without interleukin (IL)-4 for up to 48 h. In some experiments, eosinophils were added to the wells after incubation with or without IL-5 for 3 h and cells were cultured for up to 48 h. At the end of the culture period, SCF in the supernatants was measured by ELISA. In addition, the expression of SCF mRNA was examined using reverse transcription-polymerase chain reaction analysis.
Results: Interleukin-4 significantly enhanced SCF production, whereas tumor necrosis factor-α, interferon-γ and IL-1α showed suppressive effects on SCF pro-duction. When fibroblasts were cultured with IL-4 plus IL-5-activated eosinophils, SCF production was significantly enhanced in comparison with IL-4 alone. Experi-ments using polymerase chain reaction amplification revealed that IL-5-activated eosinophils enhanced SCF production by fibroblasts through transcriptional gene activation.
Conclusions: These results suggest that some factor from activated eosinophils may interact in a synergistic fashion with IL-4 to further augment SCF production by fibroblasts and that eosinophils may play an important role in the activation of fibroblasts in chronic allergic inflammation.

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Background: The relationship between the severity of atopic dermatitis (AD) and involvements of T helper (Th) 1 and Th2 cytokines has not yet been clarified yet. The aim of the present study was to understand the relationship between the severity of AD and the involvement of Th1 and Th2 cytokines. Thus, we determined cytokine production in vitro by peripheral blood mononuclear cells (PBMC) obtained from patients with AD before and after treatment.
Methods: Cytokine production by PBMC obtained from patients with AD following antigen stimulation in vitro were compared before and after treatment. Enzyme-linked immunosorbent assays were used to measure cytokines. Treatment was undertaken with topical steroids and oral antihistamines.
Results: Interferon-γ and interleukin (IL)-12 pro-duction increased significantly after 2 weeks treatment (P < 0.005 and P < 0.05, respectively), while IL-10 production decreased significantly after 2 and 4 weeks treatment (P < 0.01). Granulocyte-macrophage colony stimulating factor and tumor necrosis factor-α production increased significantly after treatment (P < 0.05 and P < 0.05, respectively). The production of IL-1β, IL-4 and IL-13 was not changed significantly.
Conclusions: The T cells obtained from patients that were involved in the active inflammation of atopic -dermatitis were predominately of the Th2 type and, in addition, the function of these T cells was likely to be affected by the intensity of the skin inflammation.

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Background: Previous studies have suggested that mice passively sensitized with anti-dinitrophenol (DNP) monoclonal IgE antibody exhibit a triphasic cutaneous reaction with an immediate-phase response (IPR) at 1 h, a late-phase response (LPR) at 24 h and a very late-phase reaction (vLPR) at 8 days after challenge with 2,4-dinitrofluorobenzene. The present study was conducted to elucidate the role of T cells in this tri-phasic cutaneous reaction.
Methods: Mice were passively senseitized by an intravenous injection of anti-DNP monoclonal IgE antibody. Allergic cutaneous reaction was caused by painting an antigen on the ears of mice and measured an enlargement of the ears.
Results: Whereas the magnitudes of IPR and LPR in BALB/c nu/nu T cell-deficient mice were similar to those in BALB/c +/+ mice, vLPR was not observed in nu/nu mice. In addition, FK 506 (3 and 5 mg/kg) and cyclosporin A (30 and 50 mg/kg) clearly suppressed the onset of vLPR without affecting IPR and LPR. Because these findings suggest the participation of T cells in the onset of vLPR, the character of the T cells was investigated by using anti-CD4 or anti-CD8 monoclonal antibody (mAb) and interleukin (IL)-4 and IL-5 receptor α chain gene-deficient mice. When mice were treated with anti-CD4 or anti-CD8 mAb, the magnitude of the vLPR was augmented by anti-CD4 mAb and suppressed by anti-CD8 mAb, without affecting IPR and LPR. Disruption of the IL-4 gene slightly suppressed IPR, LPR and vLPR, but the lack of the IL-5Rα chain gene did not affect these triphasic responses.
Conclusions: The present findings suggest that vLPR is mainly caused by CD8-positive T cells, probably Tc1 cells, and regulated by CD4-positive T cells.

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Sulfasalazine (salazosulfapyridine) has been used increasingly and successfully for the treatment of rheumatoid arthritis. Azulfidine^®EN (salazosulfapyridine; Pharmacia KK Diagnostics, Tokyo, Japan), which dissolves in the intestine, is an improvement over sulfasalazine in terms of diminishing adverse gastro-intestinal effects. We report herein on a case treated with salazosulfapyridine for rheumatoid arthritis who developed mild dyspnea on exertion, high fever and diffuse pulmonary infiltrates, reversible on discontinuation of the drug. A histologic diagnosis of acute organizing interstitial pneumonia was made by transbronchial lung biopsy. Because the results of a lymphocyte stimulation test against Azulfidine^®EN were negative, we allowed the patient to resume Azulfidine^®EN for pain in his elbows under informed consent. However, the patient developed symptoms of fever, dry cough and stomatitis and mild renal dysfunction after two doses. Salazosulfapyridine was permanently discontinued and the patient's symptoms subsided. Laboratory findings returned to normal within 2 weeks. Azulfidine^®EN should be added to the list of pharmacologic agents causing infiltrative pulmonary disease and renal dysfunction.

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