Birth, life, and death of the MAGE3 hypothesis of alopecia areata pathobiology

Ito, Taisuke; Bertolini, Marta; Funakoshi, Akihiro; Ito, Natsuho; Takayama, Tatsuya; Bı́ró, Tamás; Paus, Ralf; Tokura, Y.

doi:10.1016/j.jdermsci.2013.07.014

Cited by 12 publications

(10 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As expected from the literature [14], [19], [21], [24], [78], [79], the number of CD8+ T-cells in the perifollicular mesenchyme was significantly higher in lesional compared to non-lesional AA (data not shown) and to healthy anagen HFs (Figure 3A–C). …”

Section: Resultssupporting

confidence: 87%

Abnormal Interactions between Perifollicular Mast Cells and CD8+ T-Cells May Contribute to the Pathogenesis of Alopecia Areata

Bertolini

Zilio²,

Rossi³

et al. 2014

PLoS ONE

Self Cite

129

130

View full text Add to dashboard Cite

Alopecia areata (AA) is a CD8+ T-cell dependent autoimmune disease of the hair follicle (HF) in which the collapse of HF immune privilege (IP) plays a key role. Mast cells (MCs) are crucial immunomodulatory cells implicated in the regulation of T cell-dependent immunity, IP, and hair growth. Therefore, we explored the role of MCs in AA pathogenesis, focusing on MC interactions with CD8+ T-cells in vivo, in both human and mouse skin with AA lesions. Quantitative (immuno-)histomorphometry revealed that the number, degranulation and proliferation of perifollicular MCs are significantly increased in human AA lesions compared to healthy or non-lesional control skin, most prominently in subacute AA. In AA patients, perifollicular MCs showed decreased TGFβ1 and IL-10 but increased tryptase immunoreactivity, suggesting that MCs switch from an immuno-inhibitory to a pro-inflammatory phenotype. This concept was supported by a decreased number of IL-10+ and PD-L1+ MCs, while OX40L+, CD30L+, 4–1BBL+ or ICAM-1+ MCs were increased in AA. Lesional AA-HFs also displayed significantly more peri- and intrafollicular- CD8+ T-cells as well as more physical MC/CD8+ T-cell contacts than healthy or non-lesional human control skin. During the interaction with CD8+ T-cells, AA MCs prominently expressed MHC class I and OX40L, and sometimes 4–1BBL or ICAM-1, suggesting that MC may present autoantigens to CD8+ T-cells and/or co-stimulatory signals. Abnormal MC numbers, activities, and interactions with CD8+ T-cells were also seen in the grafted C3H/HeJ mouse model of AA and in a new humanized mouse model for AA. These phenomenological in vivo data suggest the novel AA pathobiology concept that perifollicular MCs are skewed towards pro-inflammatory activities that facilitate cross-talk with CD8+ T-cells in this disease, thus contributing to triggering HF-IP collapse in AA. If confirmed, MCs and their CD8+ T-cell interactions could become a promising new therapeutic target in the future management of AA.

show abstract

Section: Resultssupporting

confidence: 87%

Abnormal Interactions between Perifollicular Mast Cells and CD8+ T-Cells May Contribute to the Pathogenesis of Alopecia Areata

Bertolini

Zilio²,

Rossi³

et al. 2014

PLoS ONE

Self Cite

129

130

View full text Add to dashboard Cite

show abstract

“…This does not discount the relevance of these peptides for subsets of patients with AA. For example, melanoma-associated antigen 3 elicited responses in HLA-A*2402 positive patients' CTLs (Ito et al, 2013); the same peptide may have higher affinity for HLA-A*2402, but not for HLA-A*0201.…”

Section: Resultsmentioning

confidence: 99%

“…purity, controlled by high-performance liquid chromatography and mass spectrometry (Ouyang et al, 2006). Epitope peptide sequences for selected antigens, TCHH peptides (TCHH-1e8), cytokeratin-16-1e3 peptides, melanoma-associated antigen 3 (Ito et al, 2013), pro-opiomelanocortin-1, 2, and tyrosine hydroxylase-B-1e3 were predicted from full-length protein sequences. MelanA/MART1 analogs (MART1, MEL-1, 2) (Mehrotra et al, 2004;Valmori et al, 1998aValmori et al, , 1998b, TYR-1, 2 (Wolfel et al, 1994), TYRP2 (Kawakami et al, 2000), modified GP100 (GP100-1, 2) (Parkhurst et al, 1996), cytomegalovirus pp65, Epstein-Barr virus BMFL1, influenza matrix (Cellerai et al, 2010), human immunodeficiency virus p17 (Ferrari et al, 2004), and hepatitis C virus (Spangenberg et al, 2005) sequences were obtained from the published literature.…”

Section: Peptide Sequence Predictionmentioning

confidence: 99%

Identification of Autoantigen Epitopes in Alopecia Areata

Wang

Breitkopf

et al. 2016

Journal of Investigative Dermatology

View full text Add to dashboard Cite

Alopecia areata (AA) is believed to be a cell-mediated autoimmune hair loss disease. Both CD4 and cytotoxic CD8 T cells (CTLs) are important for the onset and progression of AA. Hair follicle (HF) keratinocyte and/or melanocyte antigen epitopes are suspected potential targets of autoreactive CTLs, but the specific epitopes have not yet been identified. We investigated the potential for a panel of known epitopes, expressed by HF keratinocytes and melanocytes, to induce activation of CTL populations in peripheral blood mononuclear cells. Specific synthetic epitopes derived from HF antigens trichohyalin and tyrosinase-related protein-2 induced significantly higher frequencies of response in AA CTLs compared with healthy controls (IFN-gamma secretion). Apoptosis assays revealed conditioned media from AA peripheral blood mononuclear cells stimulated with trichohyalin peptides elevated the expression of apoptosis markers in primary HF keratinocytes. A cytokine array revealed higher expression of IL-13 and chemokine ligand 5 (CCL5, RANTES) from AA peripheral blood mononuclear cells stimulated with trichohyalin peptides compared with controls. The data indicate that AA affected subjects present with an increased frequency of CTLs responsive to epitopes originating from keratinocytes and melanocytes; the activated CTLs secreted soluble factors that induced apoptosis in HF keratinocytes. Potentially, CTL response to self-antigen epitopes, particularly trichohyalin epitopes, could be a prognostic marker for human AA.

show abstract

“…It is considered that the comorbidity of AD and leukoderma takes place as a result of the preponderant local immune reaction to Th1/Tc1 and/or Th17 cells. In this concept, the simultaneous occurrence of alopecia areata with AD provides the same ambivalent condition . The mechanism underlying the concurrence of local Th1/Tc1 disease in systemic Th2 disease is an issue to be clarified in the future.…”

Section: Discussionmentioning

confidence: 99%

Leukoderma in patients with atopic dermatitis

Kuriyama

Kasuya

Fujiyama

et al. 2014

The Journal of Dermatology

Self Cite

View full text Add to dashboard Cite

Atopic dermatitis (AD) is occasionally associated with vitiligo, however, the incidence and conditions of vitiligo or leukoderma, and the characteristics of concurrent AD, remain unclear. We conducted a prospective observational study to investigate the leukoderma-related clinical manifestations and bioparameters of AD. Because vitiligo in AD lesions is occasionally associated with inflammation, we used leukoderma in this study. Enrolled were all AD patients who had been followed up in our AD outpatient clinic and visited within the previous 4 months. During this period, we carefully inspected whether the patients had leukoderma. Eight of 52 patients had leukoderma (15.4%) and were designated as the leukoderma group, and the remaining 44 patients comprised the non-leukoderma group. While the ages were statistically not different between the two groups, female preponderance was significantly observed in the leukoderma group. The leukoderma patients tended to have higher values of SCORAD, CCL17/thymus and activation regulated chemokine and lactate dehydrogenase than the non-leukoderma patients. The leukoderma group was also characterized by a lower frequency of allergic rhinitis and a higher frequency of prurigo lesions. Thus, despite the possession of high AD severity, the leukoderma patients may possibly retain a relatively T-helper 1-skewing state in relation to the development of leukoderma and less association with rhinitis.

show abstract

Birth, life, and death of the MAGE3 hypothesis of alopecia areata pathobiology

Cited by 12 publications

References 11 publications

Abnormal Interactions between Perifollicular Mast Cells and CD8+ T-Cells May Contribute to the Pathogenesis of Alopecia Areata

Abnormal Interactions between Perifollicular Mast Cells and CD8+ T-Cells May Contribute to the Pathogenesis of Alopecia Areata

Identification of Autoantigen Epitopes in Alopecia Areata

Leukoderma in patients with atopic dermatitis

Contact Info

Product

Resources

About