CD4 T Cell-Dependent Autoimmunity against a Melanocyte Neoantigen Induces Spontaneous Vitiligo and Depends upon Fas-Fas Ligand Interactions

Abstract

Better understanding of tolerance and autoimmunity toward melanocyte-specific Ags is needed to develop effective treatment for vitiligo and malignant melanoma; yet, a systematic assessment of these mechanisms has been hampered by the difficulty in tracking autoreactive T cells. To address this issue, we have generated transgenic mice that express hen egg lysozyme as a melanocyte-specific neoantigen. By crossing these animals to a hen egg lysozyme-specific CD4 TCR transgenic line we have been able to track autoreactive CD4+ T cells from their development in the thymus to their involvement in spontaneous autoimmune disease with striking similarity to human vitiligo vulgaris and Vogt-Koyanagi-Harada syndrome. Our findings show that CD4-dependent destruction of melanocytes is partially inhibited by blocking Fas-Fas ligand interactions and also highlights the importance of local control of autoimmunity, as vitiligo remains patchy and never proceeds to confluence even when Ag and autoreactive CD4+ T cells are abundant. Immune therapy to enhance or suppress melanocyte-specific T cells can be directed at a series of semiredundant pathways involving tolerance and cell death.

Limited Peripheral T Cell Anergy Predisposes to Retinal Autoimmunity

“…Adjusting for the mean number of clonotype-specific cells had no effect on this result (data not shown). This is in stark contrast to the results from other HEL-expressing mice, including TCR-insHEL mice, which show significantly impaired T cell help due to anergy (27,28).…”

“…Similar experiments show vigorous proliferation of CD4 ϩ T cells in lymph nodes draining the insHEL-expressing pancreas (Ref. 29 and C. C. Goodnow, personal communication) and in the skin draining nodes of mice expressing HEL in melanocytes (28). However, after 3 days we found no significant proliferation of lymphocytes isolated from pooled submandibular and superficial cervical lymph nodes of rHEL recipients, despite a strong proliferative response to sHEL at 10 -20 ng/ml (Fig.…”

“…In this way, we have tracked retinal-specific autoreactive T cells during the development of spontaneous uveoretinitis, and by breeding to AIRE-KO mice we have been able to separate contributions due to central and peripheral tolerance. We demonstrate that central tolerance to retinal HEL (rHEL) is comparable to that seen in other models which express this neo-self Ag in a tissue-restricted manner (pancreas, thymus, and skin) (27,28). However, in rHEL double-transgenic mice, severe disease is seen at an early age, which despite a similar level of clonal deletion, is in striking contrast to that seen when HEL is expressed under the rat insulin promoter (insHEL) (27).…”

Pathological Aspects of Spontaneous Uveitis and Retinopathy in HLA-A29 Transgenic Mice and in Animal Models of Retinal Autoimmunity: Relevance to Human Pathologies

“…These dogs present an ocular inflammation with exudative retinal detachment, Dalen-Fuchs nodules and choroid thickening. HLA-A29-Tg mice also show a resemblance to the pathology observed in Tg mice expressing hen egg lysozyme as a melanocyte-specific neoantigen [20] . These Tg mice present a CD4-dependent destruction of melanocytes and show similar pathology as human vitiligo and VKH.…”

Behavior of Hair Follicles in Vitiligo: Clinical Presentation and Discussion

“…This destructive process may occasionally affect the active bulbar melanocytes too leading to the development of leukotrichia [5] (Figure 2). T-lymphocytes are well known pathological element during the development of vitiligo, expressing cytotoxic/apoptotic factors to induce melanocytic destruction [10,11]. These lymphocytes were also demonstrated perifollicularly in considerable density during disease activity in biopsies including black hairs within vitiligo patches.…”