Masaki Suemura

Two species of human Fcε receptor II ( FcεRII CD23 ): Tissue-specific and IL-4-specific regulation of gene expression

The Fc epsilon receptor II (Fc epsilon RII, CD23) functions in B cell growth and differentiation and in IgE-mediated immunity. The Fc epsilon RII structure expressed on various cell types has been analyzed identifying two species, Fc epsilon RIIa and Fc epsilon RIIb. Sequence analysis of the cloned cDNAs revealed that they differ only at the N-terminal cytoplasmic region, but share the same C-terminal extracellular region. These Fc epsilon RII species appear to be generated utilizing different transcriptional initiation sites and alternative RNA splicing. Fc epsilon RIIa is constitutively expressed only in normal B cells and B cell lines, whereas Fc epsilon RIIb expression is detectable in various cell types, such as monocytes and eosinophils. Normally, Fc epsilon RIIb is undetectable in B cells and monocytes, and can be induced by interleukin-4. Moreover, Fc epsilon RIIb is expressed on peripheral blood lymphocytes in atopic individuals. These findings may explain the difference in Fc epsilon RIIa and Fc epsilon RIIb function in B cells and the effector phase of IgE-mediated immunity.

Molecular structure of human lymphocyte receptor for immunoglobulin E

We have isolated and sequenced a cDNA clone encoding the human lymphocyte receptor for IgE (Fc epsilon R). The deduced protein sequence reveals that Fc epsilon R consists of 321 amino acids, without any signal sequence, and is oriented with its N-terminus on the cytoplasmic side and its C-terminus on the outside of the cell. This molecule shows striking sequence homology with chicken asialoglycoprotein receptor (hepatic lectin), suggesting a possible role for Fc epsilon R in endocytosis. Fc epsilon R mRNA is expressed in B cells, B cell lines, and macrophage cell lines. It is not expressed in T cells or T cell lines, with the exception of an HTLV-transformed T cell line. mRNAs expressed in a macrophage line and in the latter T cell line differ in size from mRNA expressed in B cells. Human BSF-1 (or IL-4) induces the expression of Fc epsilon R mRNA in B cells, but not in T cells.

Delayed onset and reduced severity of collagen-induced arthritis in interleukin-6-deficient mice

OBJECTIVE To investigate the roles of interleukin-6 (IL-6) in the pathogenesis of rheumatoid arthritis (RA) by studying its effect on murine collagen-induced arthritis (CIA). METHODS IL-6-deficient (IL-6-/-) mice with a genetic background of susceptibility to CIA were generated by backcrossing them with DBA/1J mice for 8 generations. Clinical and immunologic features were compared between these mice and IL-6 wild-type (IL-6+/+) littermates with CIA. RESULTS Serum IL-6 levels increased during the development of CIA in IL-6+/+ mice. Two prominent peaks were observed. The first was coincident with the onset of arthritis, and the second one was observed during exacerbation of the disease. The onset of arthritis in IL-6-/- mice was delayed for 2 weeks compared with that in IL-6+/+ mice, and the severity of arthritis, as indicated by the arthritis score, remained significantly lower in IL-6-/- mice during the entire followup period (14 weeks), although all IL-6-/- mice developed definite arthritis as did the IL-6+/+ mice. Histologic severity was also reduced in IL-6-/- mice. In addition, radiologic changes such as osteopenia and bone erosion were reduced significantly in these animals. Both humoral and cellular responses to type II collagen (CII) in IL-6-/- mice were reduced to about half those in IL-6+/+ mice. In addition, enhanced production of IL-4 and IL-10 in response to concanavalin A stimulation was observed in IL-6-/- mice. CONCLUSION IL-6 plays an important role in the development of CIA, and both suppression of specific immune responses to CII and a tendency to a shift toward a Th2 cytokine profile might contribute in part to the attenuation of CIA in IL-6-/- mice. These findings suggest that blockade of IL-6 might be beneficial in the treatment of RA.

Interleukin-18 Is Elevated in the Sera from Patients with Atopic Dermatitis and from Atopic Dermatitis Model Mice, NC/Nga

Background: Several lines of in vitro and in vivo studies have demonstrated that interleukin-18 (IL-18) shows both antiallergic and allergy-promoting activities. But its expression in allergic diseases remains unknown. Methods: Serum IL-18 levels from atopic dermatitis (AD) model mice, NC/Nga and control mice and from patients with AD and healthy volunteers were measured by ELISA. The relationship between IL-18 levels and serum IgE levels or clinical severity was also examined. Results: Serum IL-18 levels from NC/Nga mice were significantly increased compared to those from control mice. The elevation of IL-18 in the sera was observed prior to the onset and during the development of dermatitis in NC/Nga mice. In addition, IL-18 levels in the sera from patients with AD were significantly (p < 0.05) elevated compared to those from healthy volunteers. However, serum IL-18 levels tended to correlate negatively with serum IgE levels in patients with AD and NC/Nga mice. Conclusion: IL-18 is overexpressed in AD.

Oral administration of persimmon leaf extract ameliorates skin symptoms and transepidermal water loss in atopic dermatitis model mice, NC/Nga

Summary Background  We have previously shown that persimmon leaf extract and its major flavonoid constituent, astragalin, inhibited histamine release by basophils and that oral administration of these substances prior to the onset into an atopic dermatitis (AD) model mouse, NC/Nga, prevented development of dermatitis.

Interleukin-18 enhances the production of interleukin-8 by eosinophils.

Interleukin‐18 (IL‐18), a proinflammatory cytokine, leads to IFN‐γ production by NK or T cells, induces Th1 differentiation and suppresses IgE synthesis by B cells when acting on responding cells together with IL‐12. IL‐18 also exhibits biological activities related to allergic inflammation such as histamine or IL‐4 release from basophils and accumulation of eosinophils in localized lesions in allergic model mice. In this study, Reverse transcription (RT)‐PCR analysis revealed that IL‐18 receptor α chain mRNA was expressed in both freshly prepared eosinophils and two eosinophilic cell lines (YY‐1 and EoL‐1 cells). Flow cytometry and RT‐PCR analyses revealed that the treatment of YY‐1 cells with n‐butyric acid promoted cell maturation and caused an enhancement of IL‐18 receptor α chain expression. IL‐18 had little effect on the survival of peripheral eosinophils, but it dose‐dependently augmented IL‐8 synthesis by YY‐1 cells. In addition, IL‐18‐mediated up‐regulation of IL‐8 expression in eosinophils from a patient suffering from hyper‐eosinophilic syndrome was confirmed. Our findings using peripheral blood eosinophils and eosinophilic cell line suggest the functional importance of IL‐18 in the induction of IL‐8 and a potential proinflammatory role in allergy.

Masked early symptoms of pneumonia in patients with rheumatoid arthritis during tocilizumab treatment: a report of two cases

Although reports of serious infections in clinical trials for rheumatoid arthritis (RA) with tocilizumab, anti-interleukin6 (IL-6) receptor antibody, have been relatively few, there is still some concern about infections. We report here two cases of patients who developed severe pneumonia during tocilizumab treatment for RA. Both patients initially presented with only minimal clinical symptoms and modest elevations in serum C-reactive protein. Tocilizumab might suppress the early inflammatory symptoms of pneumonia.

Remission of the Renal Involvement in a Patient with Primary Sjo¨gren’s Syndrome (SS) after Pulse High-Dose Corticosteroid Infusion Therapy

Abstract: We report the case of a young female patient with primary Sjo¨gren’s syndrome (SS). In addition to sicca symptoms she also suffered from progressive renal insufficiency and renal tubular acidosis (RTA). She was treated with three sets of pulse high-dose corticosteroid infusion and subsequent low-dose corticosteroid oral administration. When the efficacy was evaluated about 6 months after the start of the therapy, dramatic improvements were seen with no adverse effects, not only in laboratory tests but also histopathologically, as indicated by the repeat kidney biopsy. This suggests that renal involvements of SS might be reversible in some cases, and that there might be a clinical benefit of pulse high-dose corticosteroid infusion therapy in SS with progressive renal involvement.

Administration of anti-interleukin 18 antibody fails to inhibit development of dermatitis in atopic dermatitis-model mice NC/Nga

Summary Background Interleukin (IL)‐18 has been shown to activate basophils to produce histamine and IL‐4 and to induce naive T cells to differentiate into T‐helper (Th) 2 cells. However, when expressed together with IL‐12, IL‐18 induces Th1 cell development and inhibits IgE synthesis. Previously we reported that serum IL‐18 levels were elevated in the sera from atopic dermatitis‐model mice NC/Nga, prior to the onset and during the development of dermatitis.

Enhanced expression and DNA binding activity of two CCAAT/enhancer‐binding protein isoforms, C/EBPβ and C/EBPδ, in rheumatoid synovium

OBJECTIVE To investigate the activation and expression of CCAAT/enhancer-binding proteins (C/EBP), especially C/EBPbeta and -delta, in rheumatoid synovium, and their pathogenic implications in rheumatoid arthritis (RA). METHODS The activation of C/EBPbeta and -delta was assessed in synovial tissues from patients with RA by electrophoretic mobility shift assay (EMSA); DNA binding activity of C/EBPs was evaluated by measuring EMSA band density. The expression and distribution of C/EBPbeta and -delta in synovial tissues were examined by immunohistochemistry analysis. As a control, synovial tissues from patients with osteoarthritis (OA) were studied. RESULTS Enhanced DNA binding activity of C/EBPbeta and -delta, 2 major members of the C/EBP family, was detected in synovial tissues from RA patients, while synovial tissues from the patients with OA showed only faint or marginal activity (mean +/- SEM arbitrary units [AU] RA 23.3 +/- 11.7 in RA versus 4.5 +/- 1.3 in OA; P < 0.05). Moreover, the binding activities of the C/EBP proteins were correlated with both serum C-reactive protein levels (r = 0.62, P < 0.05) and synovial interleukin-6 messenger RNA levels (r = 0.60, P < 0.05). In immunohistochemistry studies, C/EBPbeta and -delta were detected predominantly in the rheumatoid synovial lining cells (both CD14+ and CD14- cells). CONCLUSION C/EBPbeta and -delta may contribute to the pathology of rheumatoid synovitis.