Overexpression of CD40 ligand in murine epidermis results in chronic skin inflammation and systemic autoimmunity.
Overexpression of CD40 ligand in murine epidermis results in chronic skin inflammation and systemic autoimmunity.
复制标题
鼠表皮中CD40配体的过表达会导致慢性皮肤炎症和全身自身免疫性。
DOI：
10.1084/jem.194.5.615
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发表时间：
2001-09-03
影响因子：
15.3
通讯作者：
Beissert, S
中科院分区：
文献类型：
--
作者：
Mehling, A;Loser, K;Varga, G;Metze, D;Luger, T A;Schwarz, T;Grabbe, S;Beissert, S
CD 40-CD 40配体（L）相互作用通过激活抗原呈递细胞（APC）在免疫介导的炎症反应中起关键作用。为了研究常驻组织APC（在这种情况下是皮肤的朗格汉斯细胞（LC））的连续活化的作用，使用角蛋白-14启动子将CD 40 L表达靶向小鼠表皮的基底角化细胞。约80%的转基因（Tg）小鼠在耳、面部、尾部和/或爪上自发地发生皮炎。与同窝仔相比，Tgs在表皮LC中具有>90%的减少，但在真皮内的数量增加，这表明CD 40活化的LC的迁移增强。Tgs还显示大量区域性淋巴结病，树突状细胞和B细胞数量增加。此外，可检测到IgM降低和IgG 1/IgG 2a/IgG 2b/IgE血清浓度升高。自身抗体筛查显示存在抗核抗体和抗dsDNA抗体，提示系统性自身免疫。因此，观察到肾IG沉积、蛋白尿和肺纤维化。T细胞从Tgs向nonTg受体的连续转移诱发了类似于Tgs中发现的皮肤病变的发展。在B细胞缺陷型CD 40 L Tg小鼠中也发生了皮炎。这些研究结果表明，在皮肤中的LC的原位激活CD 40 L不仅导致慢性炎性皮炎，而且还导致全身性混合结缔组织样自身免疫性疾病，可能是通过破坏对皮肤的免疫耐受。
CD40–CD40 ligand (L) interactions play a pivotal role in immune-mediated inflammatory responses via the activation of antigen-presenting cells (APCs). To investigate the effects of continuous activation of resident tissue APCs, in this case the Langerhans cells (LCs) of the skin, CD40L expression was targeted to the basal keratinocytes of the epidermis of mice using the keratin-14 promoter. Approximately 80% of the transgenic (Tg) mice spontaneously developed dermatitis on the ears, face, tail, and/or paws. Compared with littermates, Tgs had a >90% decrease in epidermal LCs yet increased numbers within the dermis suggestive of enhanced emigration of CD40-activated LCs. Tgs also displayed massive regional lymphadenopathy with increased numbers of dendritic cells and B cells. Moreover, a decrease in IgM and an increase in IgG1/IgG2a/IgG2b/IgE serum concentrations was detectable. Screening for autoantibodies revealed the presence of antinuclear antibodies and anti-dsDNA antibodies implicative of systemic autoimmunity. Accordingly, renal Ig deposits, proteinuria, and lung fibrosis were observed. Adoptive transfer of T cells from Tgs to nonTg recipients evoked the development of skin lesions similar to those found in the Tgs. Dermatitis also developed in B cell–deficient CD40L Tg mice. These findings suggest that in situ activation of LCs by CD40L in the skin not only leads to chronic inflammatory dermatitis but also to systemic mixed-connective-tissue-like autoimmune disorders, possibly by breaking immune tolerance against the skin.