Autoimmune Melanocyte Destruction in Vitiligo

Wijngaard, Renè van den; Wańkowicz-Kalińska, Anna; Pals, Steven T.; Weening, Jan J.; Das, Pranab K.

doi:10.1038/labinvest.3780318

Cited by 62 publications

(42 citation statements)

References 85 publications

(54 reference statements)

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“…[13][14][15][16][17][18][19][20] Experimental data support the role of T-cells within active inflammatory lesions of vitiligo in initiating apoptosis of melanocytes. [13][14][15] Abnormal interactions between melanocytes and surrounding keratinocytes resulting from a decrease in the melanogenic cytokines produced by the keratinocytes, or from downregulation of specific receptors on the surface of melanocytes have been considered as possible pathways in pathogenesis of hypopigmentation in vitiligo. 19,20 We hypothesized that as in vitiligo, the pigment loss in hypopigmented mycosis fungoides may be related to alterations in expression of CD117 (also known as stem cell factor receptor or c-KIT), which is present on epidermal melanocytes.…”

mentioning

confidence: 68%

“…The pathogenesis of hypopigmentation in vitiligo is also not completely understood; suggested mechanisms include autoimmune, neural, biochemical, oxidative stress, autocytotoxic, viral, and melanocyte detachment. [13][14][15][16][17][18][19][20] The survival and growth of melanocytes is regulated by binding of stem cell factor (SCF) produced by keratinocytes, to its receptor CD117 on the surface of melanocytes. 20 Melanocyte-specific microphthalmia-associated transcription factor (MITF-M) expression is regulated downstream of the SCF/SCF receptor linkage 21 and serves as a transcription factor controlling the expression of tyrosinase mRNA, which essentially leads to melanocyte differentiation.…”

Section: Discussionmentioning

confidence: 99%

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Decreased CD117 expression in hypopigmented mycosis fungoides correlates with hypomelanosis: lessons learned from vitiligo

et al. 2006

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Hypopigmented mycosis fungoides is an uncommon clinical variant of cutaneous T-cell lymphoma. We hypothesized that hypomelanosis in hypopigmented mycosis fungoides may have a similar mechanism as in vitiligo, a condition in which it is believed that alterations in expression of CD117 (stem cell factor receptor/KIT protein) on epidermal melanocytes and abnormal interactions between melanocytes and surrounding keratinocytes may play a pathogenic role. To test the hypothesis that similar mechanisms might also explain hypopigmentation in hypopigmented mycosis fungoides, skin specimens from five cases each of hypopigmented mycosis fungoides and vitiligo were studied immunohistochemically for immunophenotype of the infiltrating cells, CD117 (expressed by epidermal melanocytes), and pan melanoma cocktail of antigens (gp100, tyrosinase, and MART-1) expression; cases of conventional mycosis fungoides and normal skin were studied in parallel as controls. Our findings confirm a predominance of CD8 þ neoplastic T cells in hypopigmented mycosis fungoides. Similarly, the epidermal lymphocytic infiltrate in vitiligo was also composed of CD8 þ cytotoxic T cells, in contrast to an epidermal infiltrate composed of CD4 þ T cells in conventional mycosis fungoides. The average number of epidermal CD117 expressing cells followed the same pattern of decreased expression in hypopigmented mycosis fungoides as in vitiligo, whereas the levels in conventional mycosis fungoides were higher, and similar to that observed in normal skin. Furthermore, a decreased number of melanocytes per high-power field of the length of the biopsy was present in hypopigmented mycosis fungoides and vitiligo, as compared with either conventional mycosis fungoides or normal skin, suggesting a correlation between decreased expression of CD117 and decreased number of melanocytes. We propose that decreased expression of CD117 and its downstream events in melanocytes may be initiated by cytotoxic effects of melanosomal-antigen-specific CD8 þ neoplastic T lymphocytes, resulting in destabilization of CD117 and leading to dysfunction and/or loss of melanocytes in the epidermis of hypopigmented mycosis fungoides.

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confidence: 68%

Section: Discussionmentioning

confidence: 99%

Decreased CD117 expression in hypopigmented mycosis fungoides correlates with hypomelanosis: lessons learned from vitiligo

et al. 2006

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“…In NSV a discrete number of infiltrating T cells express the cutaneous lymphocyte antigen (CLA), which is consistent with a recruitment of locally infiltrating cells from the peripheral circulation to the affected skin (17). CLA+ cytotoxic T cells were detected in apposition to disappearing melanocytes in perilesional NSV, and at the same site a focal epidermal expression of ICAM-l and HLA-DR (involved in cell-cell interaction, antigen presentation and T cell activation) was observed (18). Infiltrating cells are either CD4+ or CD8+ T lymphocytes, often with an increased CD8/CD4 ratio, and CD68+ macrophages, with no B cells (19).…”

Section: "Classic" Pathogenic Hypotheses: Autoimmune Theorymentioning

confidence: 85%

Focus on Vitiligo: A Generalized Skin Disorder

et al. 2006

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Vitiligo is an acquired pigmentation disorder due to a disappearance of functioning melanocytes from the epidermis and clinically characterized by achromic patches, often spreading over time. It is still not fully understood how melanocytes disappear in vivo, inducing these peculiar lesions. There are three major hypotheses for the pathogenesis of the disease: the autoimmune hypothesis considers that the disappearance of melanocytes is due to an autoimmune effector mechanism, the neural hypothesis suggests that an accumulation of neurochemical substances is able to damage epidermal melanocytes, and the metabolic hypothesis indicates that an increased sensitivity of melanocytes to oxidative stress is the crucial factor of the disease. Besides these well accepted hypotheses there are also some new interpretations based on a defective adhesion of melanocytic cells, an imbalance in the epidermal production of cytokines and an altered expression of melanocyte receptors. All these theories seem to be based on convincing evidence, indicating that they may contribute in variable proportions to the disease. There is also reasonable evidence at present that vitiligo potentially involves the whole integument, suggesting that it is a generalized skin disorder probably including different cell types during the active phase of the disease. It appears that the different theories may integrate with each other, supporting the concept that in vitiligo there is a final common step, i.e. a loss of pigment in the epidermis as well as different, possibly interacting, pathways leading up to this conclusive result.

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“…One of the most popular hypotheses considers vitiligo as an autoimmune disease. Previous investigations have proven that the anti-melanocyte antibody, which destroys the skin melanocyte, is one of the important autoantibodies causing vitiligo (11)(12)(13). The important antigens detected in vitiligo patients include, but may not be limited to, tyrosinase (5), tyrosinase-related protein-1 (TRP-1) (7), tyrosinaserelated protein-2 (TRP-2) (6), Pmel17 (14), the transcription factor SOX10 (8) and MCHR1 (9).…”

Section: Discussionmentioning

confidence: 99%