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A quantitative increase in regulatory T cells controls development of vitiligo.

ABSTRACT: T-cell cytolytic activity targeting epidermal melanocytes is shown to cause progressive depigmentation and autoimmune vitiligo. By using the recently developed transgenic mice h3TA2 that carry T cells with a HLA-A2-restricted human tyrosinase peptide (h-Tyr)-reactive TCR and develop spontaneous vitiligo from an early age, we addressed the mechanism regulating autoimmune vitiligo. Depigmentation was significantly impaired only in IFN-?-knockout h3TA2 mice but not in TNF-?- or perforin-knockout h3TA2 mouse strains, confirming a central role for IFN-? in vitiligo development. In addition, regulatory T cells (Tregs) were relatively abundant in h3TA2-IFN-?(-/-) mice, and depletion of the Treg-engaging anti-CD25 antibody fully restored the depigmentation phenotype in h3TA2-IFN-?(-/-) mice, mediated in part through the upregulation of proinflammatory cytokines such as IL-17 and IL-22. Further therapeutic potential of Treg abundance in preventing progressive depigmentation was evaluated by adoptively transferring purified Treg or using rapamycin. Both the adoptive transfer of Tregs and the use of rapamycin induced a lasting remission of vitiligo in mice treated at the onset of disease, or in mice with established disease. This leads us to conclude that reduced regulatory responses are pivotal to the development of vitiligo in disease-prone mice, and that a quantitative increase in the Treg population may be therapeutic for vitiligo patients with active disease.

SUBMITTER: Chatterjee S

PROVIDER: S-EPMC3989443 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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A quantitative increase in regulatory T cells controls development of vitiligo.

Chatterjee Shilpak S Eby Jonathan M JM Al-Khami Amir A AA Soloshchenko Myroslawa M Kang Hee-Kap HK Kaur Navtej N Naga Osama S OS Murali Anuradha A Nishimura Michael I MI Caroline Le Poole I I Mehrotra Shikhar S

The Journal of investigative dermatology 20131223 5

T-cell cytolytic activity targeting epidermal melanocytes is shown to cause progressive depigmentation and autoimmune vitiligo. By using the recently developed transgenic mice h3TA2 that carry T cells with a HLA-A2-restricted human tyrosinase peptide (h-Tyr)-reactive TCR and develop spontaneous vitiligo from an early age, we addressed the mechanism regulating autoimmune vitiligo. Depigmentation was significantly impaired only in IFN-γ-knockout h3TA2 mice but not in TNF-α- or perforin-knockout h3 ...[more]

PMID: 24366614

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Project description:Vitiligo is a noncontagious autoimmune skin depigmenting disease. Regulatory T cells (Tregs) play a key role in maintaining peripheral tolerance; however, Tregs' number, suppressive function, and associated suppressive molecules (FOXP3, IL-10, and TGF-β) are found to be reduced in vitiligo patients. Although, the role of Tregs in vitiligo pathogenesis is well established, there are several contrary findings which suggest a controversial role of Tregs in vitiligo. Therefore, to clarify the role of Tregs in vitiligo pathogenesis, we aimed to study Tregs' frequency, suppressive capacity, and associated suppressive molecules (FOXP3, IL-10, and TGF-β) in vitiligo patients through meta-analysis approach. A total of 30 studies involving 1223 vitiligo patients and 1109 controls were included in the study. Pooled results from our meta-analysis suggested significantly reduced Treg cells' frequency in vitiligo patients (p = 0.002). Interestingly, Tregs' suppressive capacity was also significantly reduced in vitiligo patients (p = 0.0002); specifically, Treg-mediated suppression of CD8+T cells was impaired in vitiligo patients (p < 0.00001). Moreover, FOXP3, a key Tregs' transcription factor, was significantly reduced in blood and skin of vitiligo patients (p < 0.00001). Intriguingly, the FOXP3 expression was significantly reduced in the lesional skin as compared to perilesional and nonlesional skin (p = 0.007 and p = 0.04). Furthermore, the expression of key Treg-associated suppressive cytokines IL-10 and TGF-β were significantly reduced in vitiligo patients (p = 0.0005 and p = 0.01). The disease activity-based analysis suggested for reduced Tregs' frequency and FOXP3 expression in active vitiligo patients (p = 0.05 and p = 0.01). We also studied the effect of microRNA-based treatment, narrow band–UVB phototherapy, and Treg-associated treatments on Tregs' frequency, FOXP3, and IL-10 expression. Interestingly, we found increased Tregs' frequency, FOXP3, and IL-10 expression after the treatment (p = 0.007, p < 0.0001, and p = 0.002). Overall, our meta-analysis suggests that the Tregs play a crucial role in pathogenesis and progression of vitiligo, and hence, Treg-based therapeutic interventions could be effective in vitiligo patients.

Project description:ObjectiveTo find out if the failure in immunotolerance of myasthenia gravis (MG) is a possible aspect of deduction in Breg cells and to characterize B cell subsets in MG.MethodsFlow cytometry detection and enzyme-linked immunosorbent assays in peripheral blood films of 10 MG patients and 10 healthy controls (HCs) were performed after isolation of B cells. The CD19+CD5+CD1d+ Breg cells percentages were measured to complement a B cell phenotype assay and frequencies of B cell subsets. The clinical outcome measures and immunological variables of patients with MG were compared with HCs.ResultsPatients with MG had relatively lowered percentages of CD19+CD5+CD1d+ Breg cells as compared to HCs. The production of interleukin (IL)-10 and transforming growth factor (TGF)-?1 was relatively lesser in patients with MG than HCs, which were linked with more severe of MG disease status according to Myasthenia Gravis Foundation of America (MGFA) clinical classification. The reduction of cytokine production was more significant for IL-10 than TGF-?1 when compared to HCs.ConclusionIt has been observed that the reduced number of B cells is able to produce IL-10 in MG patients but lesser than compared to HCs. The Bregs reduction mainly was regarded by the severity of disease status, which was highly significant and also by disease duration which was statistically significant as well. The findings of the measurement of B cell phenotype assay and frequencies of B cell subsets between MGs and HCs give us new ideas to develop B cell-mediated therapies of MG such as (1) isolated B cells of MGs could be cultured with steroids, e.g., dexamethasone in vitro to see if it induces the CD19+CD5+CD1d+ Breg cells, (2) it may observe whether induced CD19+CD5+CD1d+ Bregs have higher production of IL-10 and TGF-?1, as both are linked with disease severity, and (3) after completion in vitro steps, through further research in vivo to observe whether it improves the function of MG disease status.

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A quantitative increase in regulatory T cells controls development of vitiligo.

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A quantitative increase in regulatory T cells controls development of vitiligo.

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