CD4&lt;sup&gt;+&lt;/sup&gt;CD25&lt;sup&gt;high&lt;/sup&gt; Regulatory T Cells Are Markedly Decreased in Blood of Patients with Pemphigus Vulgaris

Sugiyama, Hideaki; Matsue, Hiroyuki; Nagasaka, Akiomi; Nakamura, Yuumi; Tsukamoto, Katsuhiko; Shibagaki, Naotaka; Kawamura, Tatsuyoshi; Kitamura, Reiko; Ando, Noriko; Shimada, Shinji

doi:10.1159/000099585

Cited by 61 publications

(48 citation statements)

References 93 publications

(85 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Taken together, the CD4+ CD25bright-FOXP3+ cells shown to be reduced in BP patients exhibited the Tregs characteristic phenotypic features. The Treg phenotypic modulation shown by our study in BP patients is similar to that reported in PV patients where a reduction in circulating Tregs and a preferential CCR4 and CD62L expression on the CD4+ CD25bright cells were reported [31].…”

Section: Discussionsupporting

confidence: 90%

Circulating CD4+ CD25brightFOXP3+ regulatory T-cells are significantly reduced in bullous pemphigoid patients

et al. 2012

View full text Add to dashboard Cite

Bullous pemphigoid (BP) is the most frequent autoimmune bullous skin disease, characterised by autoantibodies against the hemidesmosome complex. Recently, regulatory T cells (Tregs) have been implicated in the development of several autoimmune diseases; few data are available in BP, failing to demonstrate a role of this subset in disease pathogenesis. The aim of this study was to investigate the expression and phenotypes of different Tregs (CD4+ CD25brightFOXP3+ and CD8+ CD28-cells) in BP to clarify whether the depletion of this subset constitutes one mechanism of tolerance loss. The CD4+ CD25bright-FOXP3 and CD8+ CD28-circulating subsets were determined by flow-cytometry in 26 untreated BP patients and compared with a group of age-and sex-matched healthy controls (HC, n = 30). Absolute and percentage values of the CD4+ CD25brightFOXP3+ cells were significantly reduced in BP compared with HC (median CD25bright-FOXP3+ expression within CD4+ cells: 1.8 vs. 3.5%, p = 0.002); conversely, BP patients were characterised by a significant expansion of the CD25brightFOXP3-''activated'' T-cell subset. CCR4 and CD62L were expressed on the majority of CD4+ CD25brightFOXP3+ cells (75.2 and 82.3%, respectively). No differences in the CD8+ CD28-subset were found between BP and HC. This is the first report showing a significant reduction of circulating CD4+ CD25brightFOXP3+ Treg frequency in BP patients.

show abstract

Section: Discussionsupporting

confidence: 90%

Circulating CD4+ CD25brightFOXP3+ regulatory T-cells are significantly reduced in bullous pemphigoid patients

et al. 2012

View full text Add to dashboard Cite

show abstract

“…An earlier study demonstrated a decrease in Treg cells in the blood of pemphigus patients [57], while another showed increased Treg cells from patient lesional biopsy specimens [56]. It is possible that this discrepancy is reflective of the regulatory cells migrating from the blood to the skin lesions and regional lymph nodes.…”

Section: Tregmentioning

confidence: 99%

Cytokine networks in Pemphigus vulgaris: An integrated viewpoint

Giordano

Sinha

2012

Autoimmunity

View full text Add to dashboard Cite

Pemphigus vulgaris (PV) is an autoimmune bullous skin disease where tolerance to the desmosomal protein desmoglein 3 (Dsg3), and perhaps additional epidermal targets, is lost, leading to the production of autoantibodies directed against cellular adhesion molecules. As auto-reactive T cells are involved in the induction and maintenance of antibody production, it has been hypothesized that cytokines play a crucial role in disease pathogenesis. Qualitative and quantitative alterations in cytokine profiles have been previously reported; however, despite recent advancements, the characterization of the disease supporting cytokine network in PV has yet to be fully elucidated. It is overwhelmingly suggested that PV is a TH2-mediated disease, confirmed by the majority of studies demonstrating an increase in TH2-type cytokines. Recently, a focus has been placed on the contribution of the newly discovered TH17 subset to autoimmune states, and current evidence suggests that this inflammatory pathway may play a role in PV as well. Anti-cytokine medications are on the forefront as potential therapeutic options, and the growing number of reports of clinical benefit serves to confirm the major contribution of various inflammatory mediators in the development of disease phenotype. This work aimed to comprehend the complexity of cytokine and T cell involvement in pemphigus, taking account of known information and emphasizing the areas where additional research would be of great benefit, particularly in pharmacological development and expansion of the pemphigus therapeutic armamentarium.

show abstract

“…It has been postulated that active immune suppression operates in healthy individuals possessing Dsg 1- and Dsg 3-reactive T cells, and that an imbalance of the putative relationship between autoreactive Th and Tregs (Tr1) cells is critical to the development of pemphigus [159]. In support, the CD4 + CD25 + hi Tregs are decreased in peripheral blood of PV patients [160]. Furthermore, a subset of Dsg 3-reactive, interleukin (IL)-10-secreting Tr1 cells was found in the majority of healthy carriers of PV-associated HLA class II alleles and only in <20% of PV patients [161].…”

Section: Regulation Of Pemphigus Autoimmunitymentioning

confidence: 99%

Pemphigus autoimmunity: Hypotheses and realities

2011

View full text Add to dashboard Cite

The goal of contemporary research in pemphigus vulgaris and pemphigus foliaceus is to achieve and maintain clinical remission without corticosteroids. Recent advances of knowledge on pemphigus autoimmunity scrutinize old dogmas, resolve controversies, and open novel perspectives for treatment. Elucidation of intimate mechanisms of keratinocyte detachment and death in pemphigus has challenged the monopathogenic explanation of disease immunopathology. Over 50 organ-specific and non-organ-specific antigens can be targeted by pemphigus autoimmunity, including desmosomal cadherins and other adhesion molecules, PERP cholinergic and other cell membrane (CM) receptors, and mitochondrial proteins. The initial insult is sustained by the autoantibodies to the cell membrane receptor antigens triggering the intracellular signaling by Src, epidermal growth factor receptor kinase, protein kinases A and C, phospholipase C, mTOR, p38 MAPK, JNK, other tyrosine kinases, and calmodulin that cause basal cell shrinkage and ripping desmosomes off the CM. Autoantibodies synergize with effectors of apoptotic and oncotic pathways, serine proteases, and inflammatory cytokines to overcome the natural resistance and activate the cell death program in keratinocytes. The process of keratinocyte shrinkage/detachment and death via apoptosis/oncosis has been termed apoptolysis to emphasize that it is triggered by the same signal effectors and mediated by the same cell death enzymes. The natural course of pemphigus has improved due to a substantial progress in developing of the steroid-sparing therapies combining the immunosuppressive and direct anti-acantholytic effects. Further elucidation of the molecular mechanisms mediating immune dysregulation and apoptolysis in pemphigus should improve our understanding of disease pathogenesis and facilitate development of steroid-free treatment of patients.

show abstract

CD4<sup>+</sup>CD25<sup>high</sup> Regulatory T Cells Are Markedly Decreased in Blood of Patients with Pemphigus Vulgaris

Cited by 61 publications

References 93 publications

Circulating CD4+ CD25brightFOXP3+ regulatory T-cells are significantly reduced in bullous pemphigoid patients

Circulating CD4+ CD25brightFOXP3+ regulatory T-cells are significantly reduced in bullous pemphigoid patients

Cytokine networks in Pemphigus vulgaris: An integrated viewpoint

Pemphigus autoimmunity: Hypotheses and realities

Contact Info

Product

Resources

About