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Richard Yu,
Raewyn Broady,
Yuanshen Huang,
Yang Wang,
Jie Yu,
Min Gao,
Megan Levings,
Shencai Wei,
Shengquan Zhang,
Aie Xu,
Mingwan Su, Jan Dutz,
Xuejun Zhang,
Youwen Zhou
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ABSTRACT: Vitiligo is characterized by the death of melanocytes in the skin. This is associated with the presence of T cell infiltrates in the lesional borders. However, at present, there is no detailed and systematic characterization on whether additional cellular or molecular changes are present inside vitiligo lesions. Further, it is unknown if the normal appearing non-lesional skin of vitiligo patients is in fact normal. The purpose of this study is to systematically characterize the molecular and cellular characteristics of the lesional and non-lesional skin of vitiligo patients.
Paired lesional and non-lesional skin biopsies from twenty-three vitiligo patients and normal skin biopsies from sixteen healthy volunteers were obtained with informed consent. The following aspects were analyzed: (1) transcriptome changes present in vitiligo skin using DNA microarrays and qRT-PCR; (2) abnormal cellular infiltrates in vitiligo skin explant cultures using flow cytometry; and (3) distribution of the abnormal cellular infiltrates in vitiligo skin using immunofluorescence microscopy.
Compared with normal skin, vitiligo lesional skin contained 17 genes (mostly melanocyte-specific genes) whose expression was decreased or absent. In contrast, the relative expression of 13 genes was up-regulated. The up-regulated genes point to aberrant activity of the innate immune system, especially natural killer cells in vitiligo. Strikingly, the markers of heightened innate immune responses were also found to be up-regulated in the non-lesional skin of vitiligo patients.
As the first systematic transcriptome characterization of the skin in vitiligo patients, this study revealed previously unknown molecular markers that strongly suggest aberrant innate immune activation in the microenvironment of vitiligo skin. Since these changes involve both lesional and non-lesional skin, our results suggest that therapies targeting the entire skin surface may improve treatment outcomes. Finally, this study revealed novel mediators that may facilitate future development of vitiligo therapies.
PLoS ONE 01/2012; 7(12):e51040. · 4.09 Impact Factor
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ABSTRACT: Antimalarial agents ameliorate disease in more than half of patients with cutaneous lupus erythematosus (CLE), regardless of smoking status. The major determinant of responsiveness appears to be severity: more extensive CLE and CLE in the setting of systemic lupus erythematosus (SLE) respond less well to antimalarial therapy. Prospective studies are needed to determine whether antimalarials are more likely to benefit patients--smokers and nonsmokers--who have milder cutaneous lupus. Agreement on a single, validated disease severity measure for CLE would permit comparisons among studies and thereby foster progress in the field.
Journal of Investigative Dermatology 10/2011; 131(10):1968-70. · 6.31 Impact Factor
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ABSTRACT: Studies in mice have shown that proinflammatory Th17 cells can cause acute graft-versus-host disease (aGVHD) related tissue damage; however, whether they play a role in human aGVHD remains unclear. In a prospective study, we measured the proportion of Th17 cells in the blood and skin of patients at the onset of aGVHD. We found no difference in the proportion or amount of IL-17 produced by T cells in the blood of patients with aGVHD (n = 20) compared with time-matched patients without GVHD (n = 14). Moreover, Th17 cells were not increased in the skin of patients with cutaneous aGVHD (n = 7) compared with healthy controls (n = 10). In contrast, we found significantly more interferon-γ-producing T cells in the skin of patients with aGVHD compared with controls. These data support the long-standing paradigm that tissue localized interferon-γ-producing cells are the perpetrators of aGVHD.
Blood 12/2010; 116(25):5748-51. · 9.90 Impact Factor
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Journal of Investigative Dermatology 07/2008; 128(6):1351-3. · 6.31 Impact Factor
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ABSTRACT: X-linked lymphoproliferative disease (XLP) is a fatal immunological disorder that typically manifests following EBV infection. XLP patients exhibit a number of immune defects including abnormal T, B, and NK lymphocyte function. These defects have been attributed to mutations of Src homology 2 domain-containing gene 1A (SH2D1A), the gene encoding signaling lymphocytic activation molecule-associated protein (SAP), an intracellular adaptor molecule expressed in lymphocytes. We have observed that SAP knockout (SAPKO) mice and humans with XLP have a complete lack of CD1d-restricted NKT cells. As expected, SAPKO mice injected with the NKT cell agonist, alpha-galactosylceramide failed to generate NKT cell IFN-gamma or IL-4. Furthermore, in contrast to wild-type littermates, SAPKO mice coinjected with OVA and alpha-galactosylceramide failed to mount OVA-specific CTL responses. These data suggest that an absence of NKT cells may underlie part of the immune dysregulation seen in SAPKO mice and in XLP patients.
The Journal of Immunology 04/2005; 174(6):3153-7. · 5.79 Impact Factor
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ABSTRACT: We have characterized a novel animal model of the common inflammatory skin disease seborrheic dermatitis (SD) that involves the expression of the self-specific 2C transgenic T cell receptor on the DBA/2 genetic background. Opportunistic fungal pathogens are present in the primary histological lesions and severe disease can be mitigated by the administration of fluconazole, demonstrating a role for infection in disease pathogenesis. Spontaneous disease convalescence occurs at 70-90 d of age and is preceded by an expansion of CD4+ T cells that partially restores the T cell lymphopenia that occurs in these animals. The adoptive transfer of syngeneic CD4+ T cells into pre-diseased DBA/2 2C mice completely abrogates the development of cutaneous disease. The pattern of disease inheritance in DBA/2 backcrosses suggests that one, or a closely linked group of genes, may control disease penetrance. Bone marrow reconstitution experiments demonstrated that the DBA/2 susceptibility factor(s) governing disease penetrance is likely non-hematopoietic since bone marrow from disease-resistant 2C mice can adoptively transfer the full disease phenotype to non-transgenic DBA/2 animals. This model implicates fungal organisms and CD4+ T cell lymphopenia in the development of a SD-like condition and, as such, may mimic the development of SD in acquired immunodeficiency syndrome.
Journal of Investigative Dermatology 02/2005; 124(1):151-9. · 6.31 Impact Factor
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ABSTRACT: Autoimmune (type 1) diabetes results from a loss of beta cells that is mediated by self-reactive T cells. Previous studies have shown that a single injection of CFA prevents diabetes in nonobese diabetic (NOD) mice, but the mechanism(s) of protection remain unknown. We show here that NOD mice immunized with CFA have a markedly reduced incidence of diabetes and that this reduced incidence is associated with a decrease in the number of beta cell-specific, autoreactive CTL. In addition, the adoptive transfer of diabetes into syngeneic NOD/SCID recipients was prevented by CFA immunization, and the protective effects of CFA were lost when cells expressing the NK cell marker, asialo GM1, were removed from both donor cells and recipient mice. Returning a population of CD3-DX5+ cells to the adoptive transfer restored the protective effects of CFA. Therefore, NK cells mediate the protective effects of CFA possibly through the down-regulation of autoreactive CTL and stimulation of NK cells represents a novel approach to the prevention of autoimmune diabetes.
The Journal of Immunology 02/2004; 172(2):937-42. · 5.79 Impact Factor
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ABSTRACT: Mycophenolate mofetil (MMF) is an immune suppressant that selectively inhibits activated lymphocytes. Its usefulness in treating psoriasis has not been systematically investigated.
To evaluate efficacy and safety of MMF as a monotherapy for psoriasis.
This is a two-center, prospective, open-label clinical trial.
Twenty-three patients with moderate to severe psoriasis [mean psoriasis area and severity index (PASI) of 21.7] were treated with MMF 2-3 g/day for 12 weeks. Eighteen patients completed the study. The PASI was reduced by 24% (p < 0.001) at 6 weeks, and by 47% (p < 0.001) at 12 weeks. At the end of the treatment phase, 77% of the patients had significant reduction of PASI while 22% did not respond. The treatment was well tolerated. Five patients experienced mild nausea. One patient each had periorbital edema and pruritus. One patient had transient leukopenia.
In this noncontrolled trial, the majority of patients with moderate to severe psoriasis responded to mycophenolate mofetil monotherapy with few adverse events. A randomized, controlled trial should be considered to confirm the usefulness of MMF as a monotherapy for psoriasis.
Journal of Cutaneous Maedicine and Surgery 7(3):193-7. · 0.98 Impact Factor
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Wency Ip,
Olivier Wellman-Labadie,
Liren Tang,
Mingwan Su,
Richard Yu, Jan Dutz,
Yuzhuo Wang,
Shengquan Huang,
Xuejun Zhang,
Changzheng Huang,
Youwen Zhou
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ABSTRACT: The extracellular protein collagen triple helix repeat containing 1 (CTHRC1) is aberrantly upregulated in melanoma and most human solid cancers. However, its role in cancer remains unknown.
In this study, we investigated the functional impact of CTHRC1 on melanoma cells in vitro.
Stable clones of cultured melanoma cells expressing different amounts of CTHRC1 protein were generated and evaluated to characterize their growth, survival, and attachment ability as well as their sensitivity to chemotherapy.
In cultured MMAN and MMRU melanoma cells, increased expression of CTHRC1 protein resulted in morphologic cell changes, enhanced cell adhesion to culture surfaces, increased cell proliferation, and decreased apoptosis. Furthermore, decreased CTHRC1 expression through antisense inhibition enhanced temozolomide sensitivity.
CTHRC1 expression influences cellular processes, including cell adhesion and survival. Additionally, CTHRC1 inhibition may represent a potential method for decreasing melanoma resistance to conventional chemotherapy.
Journal of Cutaneous Maedicine and Surgery 15(2):103-10. · 0.98 Impact Factor
