Therapeutic implications of autoimmune vitiligo T cells

Oyarbide-Valencia, Kepa; Boorn, Jasper G. van den; Denman, Cecele J.; Li, Mingli; Carlson, Jeremy M.; Hernandez, Claudia; Nishimura, Michael I.; Das, Pranab K.; Luiten, Rosalie M.; Poole, I. Caroline Le

doi:10.1016/j.autrev.2006.03.012

Cited by 79 publications

(44 citation statements)

References 42 publications

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“…Whatever their role in vitiligo, these antibodies have the capacity to injure pigment cells in vivo and in vitro. Even if they are not pathogenic, study of melanocyte antibodies and target antigens might refine the diagnostic and prognostic testing of vitiligo, reveal putative T-cell targets and add to the therapeutic armamentarium [153]. Circulating anti-parietal cell, thyroid and adrenal antibodies have been detected in vitiligo patients, as well as antinuclear antibodies and rheumatoid factor, again suggesting an autoimmune pathomechanism for the disease [151].…”

Section: Vitiligo and Autoimmunitymentioning

confidence: 98%

Vitiligo, reactive oxygen species and T-cells

2010

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The acquired depigmenting disorder of vitiligo affects an estimated 1% of the world population and constitutes one of the commonest dermatoses. Although essentially asymptomatic, the psychosocial impact of vitiligo can be severe. The cause of vitiligo remains enigmatic, hampering efforts at successful therapy. The underlying pathogenesis of the pigment loss has, however, been clarified to some extent in recent years, offering the prospect of effective treatment, accurate prognosis and rational preventative strategies. Vitiligo occurs when functioning melanocytes disappear from the epidermis. A single dominant pathway is unlikely to account for all cases of melanocyte loss in vitiligo; rather, it is the result of complex interactions of biochemical, environmental and immunological events, in a permissive genetic milieu. ROS (reactive oxygen species) and H2O2 in excess can damage biological processes, and this situation has been documented in active vitiligo skin. Tyrosinase activity is impaired by excess H2O2 through oxidation of methionine residues in this key melanogenic enzyme. Mechanisms for repairing this oxidant damage are also damaged by H2O2, compounding the effect. Numerous proteins and peptides, in addition to tyrosinase, are similarly affected. It is possible that oxidant stress is the principal cause of vitiligo. However, there is also ample evidence of immunological phenomena in vitiligo, particularly in established chronic and progressive disease. Both innate and adaptive arms of the immune system are involved, with a dominant role for T-cells. Sensitized CD8+ T-cells are targeted to melanocyte differentiation antigens and destroy melanocytes either as the primary event in vitiligo or as a secondary promotive consequence. There is speculation on the interplay, if any, between ROS and the immune system in the pathogenesis of vitiligo. The present review focuses on the scientific evidence linking alterations in ROS and/or T-cells to vitiligo.

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Section: Vitiligo and Autoimmunitymentioning

confidence: 98%

Vitiligo, reactive oxygen species and T-cells

2010

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“…The skin-infiltrating cytotoxic T cells were found to be juxtaposed with melanocytes and were enriched for melanocyte antigen recognition [7], [8]. T cells isolated from peri-lesional skin of vitiligo patients also showed cytotoxicity against autologous melanocytes in vitro [9].…”

Section: Introductionmentioning

confidence: 99%

Th17 Cells and Activated Dendritic Cells Are Increased in Vitiligo Lesions

et al. 2011

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BackgroundVitiligo is a common skin disorder, characterized by progressive skin de-pigmentation due to the loss of cutaneous melanocytes. The exact cause of melanocyte loss remains unclear, but a large number of observations have pointed to the important role of cellular immunity in vitiligo pathogenesis.Methodology/Principal FindingsIn this study, we characterized T cell and inflammation-related dermal dendritic cell (DC) subsets in pigmented non-lesional, leading edge and depigmented lesional vitiligo skin. By immunohistochemistry staining, we observed enhanced populations of CD11c+ myeloid dermal DCs and CD207+ Langerhans cells in leading edge vitiligo biopsies. DC-LAMP+ and CD1c+ sub-populations of dermal DCs expanded significantly in leading edge and lesional vitiligo skin. We also detected elevated tissue mRNA levels of IL-17A in leading edge skin biopsies of vitiligo patients, as well as IL-17A positive T cells by immunohistochemistry and immunofluorescence. Langerhans cells with activated inflammasomes were also noted in lesional vitiligo skin, along with increased IL-1ß mRNA, which suggest the potential of Langerhans cells to drive Th17 activation in vitiligo.Conclusions/SignificanceThese studies provided direct tissue evidence that implicates active Th17 cells in vitiligo skin lesions. We characterized new cellular immune elements, in the active margins of vitiligo lesions (e.g. populations of epidermal and dermal dendritic cells subsets), which could potentially drive the inflammatory responses.

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“…21 As T cells also mediate autoimmune responses in vitiligo, boosting immune responses directed toward the gp100 and MART-1 antigens may be an effective strategy to eradicate LAM cells. 19 However, expression of gp100 as well as MART-1 is observed in only a subset of LAM cells. This prompted a wider investigation of melanoma-associated antigen expression, comparing expression within LAM tissue to normal lung and metastatic melanoma, and in vitro to melanoma cells and smooth muscle cells.…”

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confidence: 99%

“…18 Both MART-1 and gp100 are also recognized by T cells that infiltrate the skin of patients with autoimmune vitiligo, further supporting the notion that expression can prime host cells for immune destruction. 19 Vaccines boosting immune responses melanoma-associated antigens have since been developed and tested in clinical trials for the treatment of malignant melanoma. 20 Besides adoptive transfer of autologous T cells, identification of T-cell epitopes and reactive T cell receptor (TCR) molecules have enabled additional vaccine strategies including administration of adjuvant-supported antigen preparations or TCR transgenic T cells.…”

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confidence: 99%

Melanoma-Associated Antigen Expression in Lymphangioleiomyomatosis Renders Tumor Cells Susceptible to Cytotoxic T Cells

Klarquist

Barfuss

Kandala

et al. 2009

The American Journal of Pathology

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The antibody HMB45 is used to diagnose lymphangioleiomyomatosis, a hyperproliferative disorder of lung smooth muscle cells with mutations in both alleles of either TSC1 or TSC2. A subset of these tumor cells expresses the melanoma-associated antigens gp100 and melanoma antigen recognized by T cells (MART-1). To explore the feasibility of targeting tumors in lymphangioleiomyomatosis by melanoma immunotherapy, we therefore assessed melanoma target antigen expression and existing immune infiltration of affected tissue compared with normal lung and melanoma as well as the susceptibility of cultured lymphangioleiomyomatosis cells to melanoma reactive cytotoxic T lymphocytes in vitro. Tumors expressed tyrosinase-related proteins 1 and 2 but not tyrosinase, in addition to gp100 and MART-1, and were densely infiltrated by macrophages, but not dendritic cells or T cell subsets. Although CD8 ؉ lymphocytes were sparse compared with melanoma, cells cultured from lymphangioleiomyomatosis tissue were susceptible to cytotoxic, gp100 reactive, and major histocompatibility complex class I restricted CD8 ؉ T cells in functional assays. Responder T cells selectively clustered and secreted interferon-␥ in response to HLA-matched melanocytes and cultured lymphangioleiomyomatosis cells. This reactivity exceeded that based on detectable gp100 expression; thus , tumor cells in lymphangioleiomyomatosis may process melanosomal antigens different from melanocytic cells. Therefore , boosting immune responses to gp100 in lymphangioleiomyomatosis may offer a highly desirable treatment option for this condition.

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Therapeutic implications of autoimmune vitiligo T cells

Cited by 79 publications

References 42 publications

Vitiligo, reactive oxygen species and T-cells

Vitiligo, reactive oxygen species and T-cells

Th17 Cells and Activated Dendritic Cells Are Increased in Vitiligo Lesions

Melanoma-Associated Antigen Expression in Lymphangioleiomyomatosis Renders Tumor Cells Susceptible to Cytotoxic T Cells

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