Subunit-Specific Reactivity of Autoantibodies Against Laminin-332 Reveals Direct Inflammatory Mechanisms on Keratinocytes.
Subunit-Specific Reactivity of Autoantibodies Against Laminin-332 Reveals Direct Inflammatory Mechanisms on Keratinocytes.
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DOI：
10.3389/fimmu.2021.775412
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发表时间：
2021
影响因子：
7.3
通讯作者：
Amber KT
中科院分区：
文献类型：
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作者：
Bao L;Li J;Solimani F;Didona D;Patel PM;Li X;Qian H;Ishii N;Hashimoto T;Hertl M;Amber KT
层粘连蛋白-332类天疱疮是一种罕见而严重的自身免疫性起泡疾病，由靶向真皮-表皮基底层中层粘连蛋白-332的IgG自身抗体引起。层粘连蛋白-332类天疱疮的特征在于可变的炎性浸润和非补体结合抗体的优势。鉴于这些发现，我们假设层粘连蛋白-332的IgG自身抗体直接导致角质形成细胞表达炎症因子。我们对用来自层粘连蛋白-332类天疱疮患者的IgG处理的原代人角质形成细胞进行了RNA-seq。许多细胞因子和趋化因子的基因被上调，包括CSF 2、CSF 3、CXCL 1、CXCL 5、CXCL 3、CXCL 8、CXCL 10、CXCL 1、IL 6、IL 7、IL 15、IL 23、IL 32、IL 37、TGFB 2以及金属蛋白酶。考虑到在我们的初始实验中鉴定的来自层粘连蛋白-332类天疱疮患者的自身抗体的促炎和蛋白水解作用，我们接下来质疑针对特定层粘连蛋白亚基的反应性是否决定了炎症和蛋白水解角质形成细胞应答。然后，我们用来自单独一组患者的IgG处理角质形成细胞，这些患者对层粘连蛋白-332的各个亚基具有反应性。我们在蛋白质水平上鉴定了IL-1α、IL-6、IL-8、CXCL 1、MMP 9、TSLP和GM-CSF的上调，最显著的是在用来自层粘连蛋白β3反应性患者的IgG处理的角质形成细胞中。我们首次证明了促炎反应，类似于用来自大疱性类天疱疮患者的IgG自身抗体治疗的角质形成细胞中所述的促炎反应，为层粘连蛋白-332类天疱疮和层粘连蛋白-332生物学的发病机制提供了新的见解。
Laminin-332 pemphigoid is a rare and severe autoimmune blistering disease, caused by IgG autoantibodies targeting laminin-332 in the dermal-epidermal basement zone. Laminin-332 pemphigoid is characterized by variable inflammatory infiltrate and the predominance of non-complement-fixing antibodies. Given these findings, we hypothesized that IgG autoantibodies to laminin-332 directly resulted in keratinocyte expression of inflammatory factors. We performed RNA-seq on primary human keratinocytes treated with IgG from patients with laminin-332 pemphigoid. Genes for numerous cytokines and chemokines were upregulated, including CSF2, CSF3, CXCL1, CXCL5, CXCL3, CXCL8, CXCL10, CXCL1, IL6, IL7, IL15, IL23, IL32, IL37, TGFB2 as well as metalloproteases. Considering the pro-inflammatory and proteolytic effect of autoantibodies from patients with laminin-332 pemphigoid identified in our initial experiment, we next questioned whether the reactivity against specific laminin subunits dictates the inflammatory and proteolytic keratinocyte response. Then, we treated keratinocytes with IgG from a separate cohort of patients with reactivity against individual subunits of laminin-332. We identified upregulation of IL-1α, IL-6, IL-8, CXCL1, MMP9, TSLP, and GM-CSF at the protein level, most notably in keratinocytes treated with IgG from laminin β3-reactive patients. We for the first time demonstrated a pro-inflammatory response, similar to that described in keratinocytes treated with IgG autoantibodies from patients with bullous pemphigoid, providing novel insight into the pathogenesis of laminin-332 pemphigoid and laminin-332 biology.
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影响因子：
5.2
作者：
Meireles Da Costa N;Mendes FA;Pontes B;Nasciutti LE;Ribeiro Pinto LF;Palumbo Júnior A
通讯作者：
Palumbo Júnior A
影响因子：
14.9
作者：
Babicki S;Arndt D;Marcu A;Liang Y;Grant JR;Maciejewski A;Wishart DS
通讯作者：
Wishart DS
影响因子：
3.7
作者：
Chiorean R;Danescu S;Virtic O;Mustafa MB;Baican A;Lischka A;Hashimoto T;Kariya Y;Koch M;Sitaru C
通讯作者：
Sitaru C
影响因子：
4.8
作者：
Bao, Lei;Tessier, Christian;Gibori, Geula
通讯作者：
Gibori, Geula
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3
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