CD4 T cell-dependent autoimmunity against a melanocyte neoantigen induces spontaneous vitiligo and depends upon Fas-Fas ligand interactions
CD4 T cell-dependent autoimmunity against a melanocyte neoantigen induces spontaneous vitiligo and depends upon Fas-Fas ligand interactions
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DOI：
10.4049/jimmunol.177.5.3055
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发表时间：
2006-09-01
影响因子：
4.4
通讯作者：
Cornall, Richard J.
中科院分区：
文献类型：
--
作者：
Lambe, Teresa;Leung, Janson C. H.;Cornall, Richard J.
需要更好地了解对黑素细胞特异性抗原的耐受性和自身免疫性，以开发白癜风和恶性黑色素瘤的有效治疗方法;然而，对这些机制的系统评估受到难以追踪自身反应性T细胞的阻碍。为了解决这个问题，我们已经产生了转基因小鼠，表达鸡蛋溶菌酶作为黑素细胞特异性新抗原。通过将这些动物与鸡卵溶菌酶特异性CD 4 TCR转基因系杂交，我们已经能够追踪自身反应性CD 4（+）T细胞从它们在胸腺中的发育到它们参与自发性自身免疫性疾病的过程，这些自发性自身免疫性疾病与人类寻常型白癜风和Vogt-Koyanagi-Harada综合征惊人的相似。我们的研究结果表明，黑素细胞的CD 4依赖性破坏部分被阻断Fas-Fas配体相互作用所抑制，同时也强调了局部控制自身免疫的重要性，因为白癜风仍然是斑片状的，即使在Ag和自身反应性CD 4（+）T细胞丰富的情况下也不会进行融合。增强或抑制黑素细胞特异性T细胞的免疫疗法可以针对一系列涉及耐受和细胞死亡的半冗余途径。
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.