Mehran Ghoreishi

Expansion of Antigen-Specific Regulatory T Cells with the Topical Vitamin D Analog Calcipotriol

1,25-Dihydroxyvitamin D3 is immunosuppressive both in vivo and in vitro. Topical vitamin D analogs such as calcipotriol alter keratinocyte function, but their effects on cutaneous immune responses are less well understood. We demonstrate that exposure of the skin to calcipotriol before transcutaneous immunization with OVA protein and CpG adjuvant prevents Ag-specific CD8+ T cell priming coincident with Langerhans cell depletion in the skin. Immunization through calcipotriol-treated skin induces CD4+CD25+ regulatory T cells (Treg) that prevent subsequent Ag-specific CD8+ T cell proliferation and IFN-γ production. Treg induced by calcipotriol are able to inhibit the induction and the elicitation of protein contact hypersensitivity. Topical calcipotriol treatment also induces RANKL (receptor activator of NF-κB ligand) expression by keratinocytes, a TNF family member involved in modulation of skin dendritic cells. UV light B induces Ag-specific tolerance when it is applied before transcutaneous immunization. We suggest that UV light B-induced tolerance is induced via a vitamin D receptor-dependent mechanism as vitamin D receptor (VDR) knockout mice fail to increase FoxP3+ Treg in their peripheral draining lymph node following irradiation. Additionally, keratinocytes of VDR−/− mice fail to induce RANKL upon UV irradiation or calcipotriol treatment. The in vivo expansion of Ag-specific Treg with the topical application of the vitamin D analog calcipotriol followed by transcutaneous immunization is a simple method to augment functional Ag-specific CD4+CD25+Foxp3+ Treg populations and mimics Ag-specific UV-induced tolerance.

Tolerance Induction by Transcutaneous Immunization through Ultraviolet-Irradiated Skin Is Transferable through CD4+CD25+ T Regulatory Cells and Is Dependent on Host-Derived IL-10

UV radiation of the skin impairs immune responses to haptens and to tumor Ags. Transcutaneous immunization (TCI) is an effective method of inducing immune responses to protein and peptide Ag. We explore the effect of UV irradiation on TCI. The generation of Ag-specific CTL to OVA protein, but not class I MHC-restricted OVA peptide, is inhibited by TCI through UV-irradiated skin. Consequently, the induction of protein contact hypersensitivity and in vivo Ag-specific CTL activity following OVA protein immunization is prevented. Application of haptens to UV-exposed skin induces hapten-specific tolerance. We demonstrate that application of protein or class II MHC-restricted OVA peptide to UV-irradiated skin induces transferable Ag-specific tolerance. This tolerance is mediated by CD4+CD25+ T regulatory (Treg) cells. These Ag-specific Treg cells inhibit the priming of CTL following protein immunization in the presence of CpG adjuvant. IL-10 deficiency is known to prevent hapten-specific tolerance induction. In this study, we demonstrate, using IL-10-deficient mice and adoptive T cell transfer, that IL-10 is required for the direct inhibition of CTL priming following immunization through UV-irradiated skin. However, IL-10 is not required for the induction of Treg cells through UV-irradiated skin as IL-10-deficient Treg cells are able to mediate tolerance. Rather, host-derived IL-10 is required for the function of UV-generated Treg cells. These experiments indicate that protein and peptide TCI through UV-irradiated skin may be used to induce robust Ag-specific tolerance to neo-Ags and that UV-induced Treg cells mediate their effects in part through the modulation of IL-10.

Cutaneous GVHD is associated with the expansion of tissue-localized Th1 and not Th17 cells

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.

Type 1 interferon signature in the scalp lesions of alopecia areata

Background  Autoimmune attack of the bulbar region of anagen phase hair follicles by CD8+ T cells and Th1 cytokines has been proposed to result in hair loss in alopecia areata (AA). The initiating stimuli are unknown. As interferon‐α therapy may trigger AA, we propose that type 1 interferons are involved in the induction of disease.

Murine models of cutaneous involvement in lupus erythematosus

Skin manifestations of lupus erythematosus (LE) are common and are a significant source of morbidity. Lupus-specific skin disease includes chronic cutaneous lupus, subacute cutaneous lupus and acute cutaneous lupus. These conditions have in common a lichenoid tissue reaction. The best-characterized mouse model of spontaneous onset lupus-like skin disease is the MRL/lpr mouse. We review features of this mouse model pertinent to lupus skin disease. Transgenically altered mice indicate an important role for keratinocytes and skin dendritic cells in the development of cutaneous LE. Ultraviolet light (UV) is an environmental factor that has been implicated in exacerbation of systemic disease in LE. Two inbred mouse strains, BXSB and NOD, demonstrate UV accelerated, and UV induced, systemic LE-like disease respectively. We discuss mechanisms of UV-mediated acceleration of disease in these models. A better understanding of these mouse models will lead to an improved understanding of clinical cutaneous lupus erythematosus.

Type 1 IFN-induced protein MxA and plasmacytoid dendritic cells in lesions of morphea.

Abstract:  Morphea is an autoimmune sclerotic skin disease of unknown pathogenesis. As type 1 interferons (IFN) have been implicated in the pathogenesis of systemic sclerosis, we proposed that type 1 IFN promote localized inflammation and fibrosis in morphea. To investigate the expression of the type 1 IFN‐inducible protein myxovirus A (MxA) and the presence of plasmacytoid dendritic cells (pDC) in lesions of morphea, lesional skin of 10 patients with morphea was examined by immunohistochemistry for the presence of the type 1 IFN‐inducible protein, myxovirus A (MxA), and the pDC markers, CD123 and BDCA‐2, and was compared with lesional skin of cutaneous lupus erythematosus, lichen planus and keloid. Lesional and non‐lesional morphea skin was compared. MxA was expressed in the epidermis as well as the reticular dermis and subcutis in morphea. pDCs were abundant around vessels and between fibrous bundles. Non‐lesional biopsies demonstrated little or no expression of MxA and pDC markers. Keloid showed minimal expression of MxA and pDC markers. We demonstrate the expression of type 1 IFN‐related protein MxA and plasmacytoid DCs in lesional but not in non‐lesional biopsies of morphea. These findings suggest a potential role for type 1 interferons in the pathogenesis of morphea.