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Donald Y M Leung

Publications and source records attributed to Donald Y M Leung.

At least 19 recordsLinked to original sources
PubMed2006

Macrophage inflammatory protein 3alpha deficiency in atopic dermatitis skin and role in innate immune response to vaccinia virus.

BACKGROUND: Patients with atopic dermatitis (AD) are prone to disseminated viral skin infections and therefore are not vaccinated against smallpox because of potential complications. Macrophage inflammatory protein 3alpha (MIP-3alpha) is a C-C chemokine expressed by keratinocytes that exhibits antimicrobial activity against bacteria and fungi; however, its role in antiviral innate immunity is unknown. OBJECTIVE: Evaluate the level of MIP-3alpha in AD skin and its role in the innate immune response to vaccinia virus (VV). METHODS: Macrophage inflammatory protein 3alpha levels were evaluated using real-time RT-PCR, immunodot-blot, and immunohistochemistry. The antiviral activity of MIP-3alpha was determined using a standard viral plaque assay. RESULTS: Macrophage inflammatory protein 3alpha gene expression was significantly (P < .01) decreased in AD skin (0.21 +/- 0.05 ng MIP-3alpha/ng glyceraldehyde-3-phosphate dehydrogenase) compared with psoriasis skin (0.67 +/- 0.13). This was confirmed at the protein level using immunohistochemistry. We further demonstrate that T(H)2 cytokines downregulate MIP-3alpha expression. The importance of MIP-3alpha in the innate immune response against VV was established by first demonstrating that MIP-3alpha exhibits activity against VV. Second, VV replication was significantly increased (P < .01) in keratinocytes treated with an antibody to neutralize MIP-3alpha. CONCLUSION: The current study demonstrates that MIP-3alpha exhibits antiviral activity against VV and demonstrates the importance of MIP-3alpha in the innate immune response against VV. In addition, AD skin is deficient in MIP-3alpha, in part because of the overexpression of T(H)2 cytokines in AD skin. CLINICAL IMPLICATIONS: MIP-3alpha deficiency in AD skin contributes to patients' increased propensity toward eczema vaccinatum. Increasing MIP-3alpha or neutralizing T(H)2 cytokines could prevent adverse reactions in patients with AD after smallpox vaccination.

Adult↗
PubMed2006

Mechanism of HBD-3 deficiency in atopic dermatitis.

Extrinsic atopic dermatitis (EAD) and intrinsic atopic dermatitis (IAD) patients suffer from recurrent bacterial and viral infections. In this study, we demonstrate significantly decreased expression of human beta defensin (HBD)-3, a potent antimicrobial peptide (AMP), in lesional skin of both IAD (p<0.01) and EAD patients (p<0.01), as compared to psoriasis patients. Using primary keratinocytes from EAD and IAD patients, we determined that the deficiency in HBD-3 expression is an acquired rather than a constitutive defect. Furthermore, we demonstrate the down-regulatory effect of IL-4, IL-10, and IL-13 - which are over-expressed in the skin of AD patients - on HBD-3 expression in keratinocytes. Additionally, treatment of EAD skin explants with antibodies against IL-4, IL-10, and IL-13 augmented the expression of HBD-3. These studies suggest that neutralizing the Th2 cytokine milieu in AD skin may augment the innate immune response against bacterial and viral pathogens.

Adult↗
PubMed2006

Atopic dermatitis.

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Antibodies, Anti-Idiotypic↗
PubMed2006

Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects.

This review highlights some of the research advances in anaphylaxis; hypersensitivity reactions to foods, drugs, and insects; and allergic skin disease that were reported primarily in the Journal in 2005. Although studies documented deficiencies in community management of anaphylaxis, guidelines and National Institutes of Health summary reports provide direction toward improved research and education. At least 9% of young children "outgrow" a tree nut allergy. Advances in food allergy diagnosis include reports of probability of reactions to peanut at various peanut-specific IgE concentrations and skin test response size and the utility of evaluating IgE binding to specific epitopes. Future food allergy treatments might include selection of "less allergenic" fruit cultivars, genetic silencing of major allergens, and treatment of allergic patients with Chinese herbal remedies. Osteopontin might be a useful biomarker for success of venom immunotherapy. Progress in our understanding of the immunology of atopic dermatitis and autoimmune urticaria has also been made. These observations will likely contribute toward optimizing management of these common allergic disorders.

Anaphylaxis↗
PubMed2006

Cathelicidin deficiency predisposes to eczema herpeticum.

BACKGROUND: The cathelicidin family of antimicrobial peptides is an integral component of the innate immune response that exhibits activity against bacterial, fungal, and viral pathogens. Eczema herpeticum (ADEH) develops in a subset of patients with atopic dermatitis (AD) because of disseminated infection with herpes simplex virus (HSV). OBJECTIVE: This study investigated the potential role of cathelicidins in host susceptibility to HSV infection. METHODS: Glycoprotein D was measured by means of real-time RT-PCR as a marker of HSV replication in skin biopsy specimens and human keratinocyte cultures. Cathelicidin expression was evaluated in skin biopsy specimens from patients with AD (n = 10) without a history of HSV skin infection and from patients with ADEH (n = 10). RESULTS: The cathelicidin peptide LL-37 (human cathelicidin) exhibited activity against HSV in an antiviral assay, with significant killing (P < .001) within the physiologic range. The importance of cathelicidins in antiviral skin host defense was confirmed by the observation of higher levels of HSV-2 replication in cathelicidin-deficient (Cnlp-/-) mouse skin (2.6 +/- 0.5 pg HSV/pg GAPDH, P < .05) compared with that seen in skin from their wild-type counterparts (0.9 +/- 0.3). Skin from patients with ADEH exhibited significantly (P < .05) lower levels of cathelicidin protein expression than skin from patients with AD. We also found a significant inverse correlation between cathelicidin expression and serum IgE levels (r2 = 0.46, P < .05) in patients with AD and patients with ADEH. CONCLUSION: This study demonstrates that the cathelicidin peptide LL-37 possesses antiviral activity against HSV and demonstrates the importance of variable skin expression of cathelicidins in controlling susceptibility to ADEH. Additionally, serum IgE levels might be a surrogate marker for innate immune function and serve as a biomarker for which patients with AD are susceptible to ADEH. CLINICAL IMPLICATIONS: A deficiency of LL-37 might render patients with AD susceptible to ADEH. Therefore increasing production of skin LL-37 might prevent herpes infection in patients with AD.

Adult↗
PubMed2006

Divergent expression and function of glucocorticoid receptor beta in human monocytes and T cells.

Glucocorticoid (GC) insensitivity is a significant problem in the treatment of immune-mediated diseases. The current study examined whether T cells and monocytes differed in their response to GC and the potential molecular basis for their variation in response to steroids. Functional studies revealed that dexamethasone (DEX) inhibited phorbol 12-myristate 13-acetate/ionomycin-induced tumor necrosis factor alpha and interleukin-6 production to a significantly lesser extent in monocytes than T cells. In parallel, a significantly longer period of time was required for DEX to induce the steroid-responsive gene, mitogen-activated protein kinase phosphatase-1 (MKP-1), in human monocytes as compared with T cells. It is interesting that such differences were not observed between murine T cells and monocytes. GC receptor beta (GCRbeta) is a splicing variant of the classic GCR, GCRalpha, which functions as a dominant-negative inhibitor of GCRalpha in humans, not mice (as mice do not express GCRbeta mRNA as a result of a difference in the murine GCR 9b exon sequence). It was found that human monocytes had a significantly higher level of GCRbeta than T cells. Furthermore, GCRbeta was found in the cytoplasm and nucleus of monocytes, and GCRbeta was localized to the nucleus of T cells. This raised the possibility that GCRbeta in the cytoplasm could affect GCRalpha cellular shuttling in response to DEX. Indeed, we found that DEX-induced nuclear translocation of GCRalpha was decreased in monocytes as compared with T cells. Specific RNA silencing of GCRbeta in human monocytes resulted in enhanced steroid-induced GCRalpha transactivation and transrepression. Our data suggest that GCRbeta contributes to variation in the GC responses of monocytes versus T cells.

Animals↗
PubMed2006

Staphylococcal enterotoxin B inhibits regulatory T cells by inducing glucocorticoid-induced TNF receptor-related protein ligand on monocytes.

BACKGROUND: Superantigens inhibit naturally occurring CD4+CD25+ regulatory T-cell (nTreg) activity, yet the mechanism for this is unknown. OBJECTIVE: We tested the hypothesis that staphylococcal enterotoxin B (SEB), a prototypic superantigen, inhibits the ability of nTregs to suppress T-effector cell (Teff) proliferation by an antigen-presenting cell-dependent cell contact mechanism and the induction of glucocorticoid-induced TNF receptor-related protein ligand (GITR-L) on monocytes. METHODS: Cell proliferation assays were performed on immunomagnetic-bead separated CD4+CD25+, CD4+CD25- T cells and CD14+ monocytes using anti-CD3, SEB, or a neutralizing anti-GITR-L antibody for stimulation. A cytokine permeable membrane insert separating cells in culture was used to evaluate the role of cell contact. Proliferation was measured by [3H]-thymidine incorporation or a carboxyfluorescein diacetate succinimidyl ester assay. GITR-L expression was determined by RT-PCR and immunostaining. RESULTS: Antigen-presenting cell contact was required for proliferation of nTregs and loss of their ability to suppress Teff proliferation as confirmed by carboxyfluorescein diacetate succinimidyl ester. At baseline, monocytes expressed no GITR-L, but after SEB stimulation, GITR-L gene and protein expression increased significantly over a period of 24 hours (P<.05). When GITR-L activity was neutralized with blocking antibody, as opposed to isotype control, nTregs suppressed Teff proliferation despite the presence of SEB (P<.05). Likewise, loss of GITR-L at 48 hours was associated with restoration of nTreg activity (P<or=.05). CONCLUSION: Staphylococcal enterotoxin B upregulates GITR-L on monocytes and inhibits nTreg ability to suppress Teff proliferation via a cell contact interaction. CLINICAL IMPLICATIONS: Prevention of GITR-L induction on monocytes by SEB may be a novel target for control of inflammation in superantigen-driven diseases such as atopic dermatitis.

Adult↗
PubMed2006

Safety of topical calcineurin inhibitors in atopic dermatitis: evaluation of the evidence.

Topical calcineurin inhibitors (pimecrolimus, Elidel, East Hanover, NJ; and tacrolimus, Protopic, Tokyo, Japan) have been approved for the use in atopic dermatitis since the year 2000. These compounds represent a relatively safe class of topical anti-inflammatory, nonsteroidal therapy. However, in January of 2006, the US Food and Drug Administration issued a black box warning on these compounds about possible concerns of increased long-term malignancy risk due to systemic immunosuppression. To date, studies from clinical trials, systemic absorption, and post-marketing surveillance show no evidence for this systemic immunosuppression or increased risk for any malignancy.

Calcineurin Inhibitors↗
PubMed2006

Immune dysregulation in atopic dermatitis.

Atopic dermatitis is a chronic inflammatory skin disease that causes significant morbidity in affected individuals. It is characterized by dysregulated immune responses that consist of an increased systemic Th2 response and a combination of Th2 and Th1 responses in the skin lesions. In this article, we review factors that contribute to these abnormal responses, including key effector cells of the immune system, chemokines, defective skin barrier, genetic predisposition, and environmental triggers. Understanding these pathomechanisms may improve our current therapies for atopic dermatitis.

Allergens↗
PubMed2006

Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus.

Atopic dermatitis (AD) is associated with eczema vaccinatum (EV), a disseminated viral skin infection that follows inoculation with vaccinia virus (VV). This study examined whether AD skin can control VV replication, and the role of IL-4 and IL-13 in modulating the human cathelicidin LL-37, an antimicrobial peptide that kills VV. AD skin exhibited increased VV replication and decreased LL-37 expression compared to normal or psoriasis skin. IL-4/IL-13 enhanced VV replication while downregulating LL-37 in VV-stimulated keratinocytes. Neutralizing IL-4/IL-13 in AD skin augmented LL-37 and inhibited VV replication. Cathelicidins were induced via toll-like receptor-3 and were inhibited by IL-4/IL-13 through STAT-6. Skin from cathelicidin-deficient mice exhibited reduced ability to control VV replication. Exogenous LL-37 controlled vaccinia viral replication in infected keratinocytes and AD skin explants. The current study demonstrates that Th2 cytokines enhance VV replication in AD skin by subverting the innate immune response against VV in a STAT-6-dependent manner.

Adult↗
PubMed2006

10. Atopic dermatitis.

Atopic dermatitis is a common chronic inflammatory skin disease often preceding the development of asthma and allergic disorders, such as food allergy or allergic rhinoconjunctivitis. Pathophysiology involves a complex series of interactions between resident and infiltrating cells orchestrated by proinflammatory cytokines and chemokines. A deficiency of antimicrobial peptides might contribute to the propensity for colonization or infection by microbial organisms seen in atopic dermatitis. New treatment approaches include use of topical steroids as maintenance therapy and use of topical calcineurin inhibitors for early intervention with topical steroids used as rescue therapy.

Administration, Topical↗
PubMed2006

IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis.

BACKGROUND: IL-31 is a newly discovered T-cell cytokine that, when overexpressed in mice, results in pruritus and skin dermatitis resembling human atopic dermatitis (AD). OBJECTIVE: We sought to investigate the expression of IL-31 and IL-31 receptor A (IL-31RA) in skin biopsy specimens and peripheral blood cells from patients with AD and healthy individuals. METHODS: Expression of IL-31 and IL-31RA was evaluated in skin biopsy specimens from patients with AD and healthy individuals by means of immunohistochemistry and RT-PCR. IL-31 protein production by skin-homing cutaneous lymphocyte antigen (CLA)-positive T cells was also assessed. RESULTS: IL-31RA protein was expressed by keratinocytes and infiltrating macrophages in skin biopsy specimens from patients with AD. Comparisons between skin from patients with AD and healthy skin showed IL-31RA expression at higher levels on epidermal keratinocytes in AD samples. Infiltrating cells, more numerous in skin from patients with AD compared with that of healthy individuals, expressed IL31 mRNA. Histomorphometric analysis of these cells indicated they were of the lymphocytic lineage, with the majority of cells staining positive for CLA and CD3. IL31 mRNA and protein expression is largely restricted to CD45RO(+) (memory) CLA(+) T cells in peripheral blood of patients with AD and healthy volunteers. Moreover, circulating CLA(+) T cells from patients with AD, but not from patients with psoriasis, are capable of producing higher levels of IL-31 compared with CLA(+) T cells from healthy individuals. However, the average levels of IL-31 were not significantly different between patients with AD and healthy individuals. CONCLUSION: We provide evidence that IL-31 expression is associated with CLA(+) T cells and might contribute to the development of AD-induced skin inflammation and pruritus.

Adult↗