Yi-Giien Tsai

TLR2 Agonists Enhance CD8+Foxp3+ Regulatory T Cells and Suppress Th2 Immune Responses during Allergen Immunotherapy

Pam3CSK4, a synthetic TLR2 ligand, has been shown to expand CD4+ regulatory T cells (Treg cells). Less is known about the function of CD8+ Treg cells than about the function of CD4+ Treg cells generated during allergen-specific immunotherapy (IT). This study investigated whether Dermatophagoides pteronyssinus-specific IT could expand the CD8+CD25+Foxp3+ Treg population and whether Pam3CSK4 could enhance the Treg population. PBMCs were isolated from healthy control subjects and from mite-sensitive asthmatic patients during IT at three specific times: before IT and 6 mo and 1 y after the maximum-tolerated dose. This study was performed without a placebo-controlled group. D. pteronyssinus-specific IT induced a significant increase in CD8+Foxp3+ Treg cells expressing intracellular IL-10 and granzyme B. Costimulation of PBMCs with Pam3CSK4 and D. pteronyssinus 2 expanded the CD8+CD25+Foxp3+ Treg population and inhibited D. pteronyssinus 2-induced IL-4 production. Pam3CSK4-treated CD8+CD25+ Treg cells directly suppressed CD4+ T cell proliferation by cell-contact inhibition. TUNEL revealed that CD8+CD25+ Treg cells, but not CD4+CD25+ Treg cells, directly induced CD4+CD45ROhi+ apoptosis. Our results provide direct evidence that Pam3CSK4 induces an immunomodulatory effect by inducing CD8+ Treg cells; therefore, it may be a good adjuvant for the treatment of mite allergies.

Increased IL-17A secreting CD4+ T cells, serum IL-17 levels and exhaled nitric oxide are correlated with childhood asthma severity.

Measuring fractional exhaled nitric oxide (FeNO) is a simple and non‐invasive method for assessing airway inflammation. IL‐17 plays an important role in T cell‐dependent inflammatory response that occurs in allergic asthma, it could act as a potent activator of inducible nitric oxide synthase (iNOS) to amplify FeNO levels.

Significant factors associated with severity and outcome of an initial episode of acute urticaria in children

Liu T‐H, Lin Y‐R, Yang K‐C, Tsai Y‐G, Fu Y‐C, Wu T‐K, Wu H‐P. Significant factors associated with severity and outcome of an initial episode of acute urticaria in children.
Pediatr Allergy Immunol 2010: 21: 1043–1051.
© 2010 John Wiley & Sons A/S

CD8+ Treg Cells Associated with Decreasing Disease Activity after Intravenous Methylprednisolone Pulse Therapy in Lupus Nephritis with Heavy Proteinuria

We focus on the role of CD8+ Treg cell in Intravenous methyl-prednisolone (IVMP) pulse therapy in forty patients with active Class III/IV childhood lupus nephritis (LN) with heavy proteinuria. IVMP therapy for five days. From peripheral blood mononuclear cells (PBMCs) and renal tissues, we saw IVMP therapy definitely restoring both CD4+CD25+FoxP3+ and CD8+CD25+Foxp3+ Treg cell number plus greater expression with intracellular IL-10 and granzyme B in CD8+FoxP3+ Treg from PBMCs. IVMP-treated CD8+CD25+ Treg cells directly suppressed CD4+ T proliferation and induced CD4+CD45RO+ apoptosis. Histologically, CD4+FoxP3+ as well as CD8+FoxP3+ Treg cells appeared in renal tissue of LN patients before IVMP by double immunohistochemical stain. CD8+FoxP3+ Treg cells increased in 10 follow-up renal biopsy specimens after IVMP. Reverse correlation of serum anti-C1q antibody and FoxP3+ Treg cells in PBMNCs (r = −0.714, P<0.01). After IVMP, serum anti-C1q antibody decrease accompanied increase of CD4+FoxP3+ Treg cells. CD8+Treg cells reduced interferon-r response in PBMCs to major peptide autoepitopes from nucleosomes after IVMP therapy; siRNA of FoxP3 suppressed granzyme B expression while decreasing CD8+CD25+Treg-induced CD4+CD45RO+ apoptosis. Renal activity of LN by SLEDAI-2k in childhood LN was significantly higher than two weeks after IVMP (P<0.01). CD8+FoxP3+ Treg cells return in post-IVMP therapy and exert crucial immune modulatory effect to control autoimmune response in LN. Trial Registration DMR97-IRB-259

Functional defects of CD46-induced regulatory T cells to suppress airway inflammation in mite allergic asthma

Defective recruitment of regulatory T cells (Treg) function to the airway is important in the pathogenesis of allergic asthma. Complement regulatory protein (CD46) is a newly defined costimulatory molecule for Treg activation, which together with IL-10/granzyme B production may aid in suppressing asthmatic inflammation. This study examines chemotaxis and adhesion molecule expression on CD3/CD46-activated CD4+ T cells (Tregs) from patients with and without asthma to suppress mite allergen-induced respiratory epithelial cells inflammation and to elucidate the mechanism of CD46-mediated Treg activation. Diminished IL-10/granzyme B and CCR4 expression from CD3/CD46-activated Tregs appeared in asthmatic subjects. CD3/CD46-activated Tregs from asthma patients co-cultured with BEAS-2B cells suppressed Dermatophagoides pteronyssinus 2 induced nuclear factor-κB/p65 by cell contact inhibition. Decreased interaction of CD3/CD46-mediated Tregs and BEAS-2B cells from asthmatics was associated with downregulated phosphorylation of protein kinase B (AKT) expression. Results provide the first evidence that decreased interaction between CD46-mediated Tregs and lung epithelial cells with less IL-10/granzyme B production may cause airway inflammation in allergic asthma.

An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity

Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria) to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS), or Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). The associations identified by these studies are usually drug, phenotype, and ethnic specific. The drug presentation models that explain how small drug antigens might interact with HLA and T cell receptor (TCR) molecules in drug hypersensitivity include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of drug hypersensitivity involving different drugs, as well as the various pathomechanisms involved, makes the diagnosis and management of it more challenging. This review highlights recent advances in our understanding of the predisposing factors, immune mechanisms, pathogenesis, diagnostic tools, and therapeutic approaches for drug hypersensitivity.

Heat-shock pretreatment reduces expression and release of TSLP from keratinocytes under Th2 environment.

Atopic dermatitis is a chronic, relapsing inflammatory disease of the skin. Current therapy is not curative, and recalcitrant disease is a big stress and challenge for parents and physicians. This study explored the potential role of heat‐shock protein 70 (HSP‐70) and its anti‐inflammatory effects on keratinocyte under TH2 environment.

Complement regulatory protein CD46 induces autophagy against oxidative stress-mediated apoptosis in normal and asthmatic airway epithelium

Autophagy plays a major role in defending against oxidative stress in respiratory epithelial cells. The complement regulatory protein CD46 can enhance autophagy and decrease local complement activation at sites of inflammation. This study investigated the mechanism by which CD46 protects against oxidative stress-mediated apoptosis in respiratory epithelium in asthmatic patients. Nasal mucosa samples were obtained from 60 adults with mild asthma who received turbinectomy and 30 controls. A decreased expression of CD46 and increased apoptosis were noted in the damaged nasal epithelium from the asthmatic patients. Primary epithelial cells cultured with Dermatophagoides pteronyssinus 2 showed decreased CD46 and increased cleaved CASPASE-3A expressions. Crosslinking CD46 mAb could induce the formation of autophagosomes and LC3-II expression in primary epithelial cells. CD46 engagement could induce autophagy against hydrogen peroxide-induced epithelial cell death, whereas the autophagy inhibitor 3-methyladenine decreased this effect. In addition, CD46 engagement decreased the expressions of PRO-IL-1β and NLRP3, enhanced the expression of scaffold protein GOPC, and diminished hydrogen peroxide-induced 8-OHdG, IL-1β and IL-6 production. Silencing ATG5 in human lung epithelial A549 cells decreased CD46-activated autophagy with LC3-II. CD46 induced autophagy and decreased the oxidative stress-mediated apoptosis of respiratory epithelium, and this may offer a new therapeutic strategy to treat asthma.

Long-acting β2-adrenoreceptor agonists suppress type 1 interferon expression in human plasmacytoid dendritic cells via epigenetic regulation

The combination of inhaled long-acting β2-adrenoreceptor (LABA) and inhaled glucocorticoid (ICS) is a major therapy for asthma. However, the increased risk of infection is still a concern. Plasmacytoid dendritic cells (pDCs) are the predominant cells producing type 1 interferon (IFN) against infection. The effect of LABA/ICS on type 1 IFN expression in human pDCs is unknown. Circulating pDCs were isolated from healthy human subjects and were pretreated with glucocorticoid (GCS), LABA or a cAMP analog, and were stimulated with Toll-like receptor (TLR) agonist CpG (TLR9) or imiquimod (TLR7) in the presence of IL-3. The expression of type 1 IFN (IFN-α/β) were measured by ELISA. The mechanisms were investigated using receptor antagonists, pathway inhibitors, Western blotting and chromatin immunoprecipitation. GCS suppressed TLR-induced IFN-α expression, and LABA enhanced the suppressive effect. LABA alone also suppressed TLR-induced IFN-α/β expression, and the effect was reversed by the β2-adrenoreceptor antagonist ICI118551. Dibutyryl-cAMP, a cAMP analog, conferred a similar suppressive effect, and the effect was abrogated by the exchange protein directly activated by cAMP (Epac) inhibitor HJC0197 or intracellular free Ca2+ chelator BAPTA-AM. Formoterol suppressed TLR-induced phosphorylation of mitogen-activated protein kinase (MAPK)-p38/ERK. Formoterol suppressed interferon regulatory factor (IRF)-3/IRF-7 expression. Formoterol suppressed CpG-induced translocation of H3K4 specific methyltransferase WDR5 and suppressed H3K4 trimethylation in the IFNA and IFNB gene promoter region. LABA suppressed TLR7/9-induced type 1 IFNs production, at least partly, via the β2-adrenoreceptor-cAMP-Epac-Ca2+, IRF-3/IRF-7, the MAPK-p38/ERK pathway, and epigenetic regulation by suppressing histone H3K4 trimethylation through inhibiting the translocation of WDR5 from cytoplasm to nucleus. LABA may interfere with anti-viral immunity.

New Advances in Drug Hypersensitivity Research and Treatment

Division of Pediatric Allergy and Immunology, Changhua Christian Hospital, Changhua City, Taiwan School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan School of Medicine, Chung Shan Medical University, Taichung, Taiwan Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei and Linkou, Taiwan Chang Gung Immunology Consortium, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan College of Medicine, Chang Gung University, Taoyuan, Taiwan Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand