Lack of IL-17 Receptor A signaling aggravates lymphoproliferation in C57BL/6 lpr mice
Lack of IL-17 Receptor A signaling aggravates lymphoproliferation in C57BL/6 lpr mice
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DOI：
10.1038/s41598-019-39483-w
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发表时间：
2019-03-11
影响因子：
4.6
通讯作者：
Lubberts, Erik
中科院分区：
文献类型：
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作者：
Corneth, Odilia B. J.;Schaper, Fleur;Lubberts, Erik
Fas功能缺陷与系统性自身免疫性疾病的易感性有关，如自身免疫淋巴增殖性综合征(ALPS)和系统性红斑狼疮(SLE)。用C57BL/6 LPR(B6/LPR)小鼠作为阿尔卑斯综合征的动物模型，发展成轻度SLE表型。白介素17A(IL-17A)参与了这两种表型。由于IL-17受体A是许多IL-17家族成员信号通路的一部分，我们研究了IL-17受体信号在具有B6/LPR背景的小鼠疾病发展中的作用。B6/LPR小鼠与IL-17受体A缺陷(IL-17RA KO)小鼠杂交，并随着时间的推移而跟踪疾病的发展。与B6/LPR小鼠相比，IL-17RA KO/LPR小鼠表现出显著的淋巴增殖，表现为淋巴/脾肿大，淋巴细胞数量增加，双阴性T细胞扩增和浆细胞形成增加。然而，由于抗核抗体(ANA)效价和肾小球肾炎的诱导没有差异，SLE的表型并没有增强。相反，IL-17RA KO/LPR小鼠的高迁移率族蛋白1(HMGB1)和抗HMGB1自身抗体水平显著高于B6/LPR小鼠。这些数据表明，缺乏IL-17RA信号加剧了B6/LPR小鼠的淋巴增殖表型，但不影响SLE表型。
Defects in Fas function correlate with susceptibility to systemic autoimmune diseases like autoimmune lymphoproliferative syndrome (ALPS) and systemic lupus erythematosus (SLE). C57BL/6 lpr (B6/lpr) mice are used as an animal model of ALPS and develop a mild SLE phenotype. Involvement of interleukin-17A (IL-17A) has been suggested in both phenotypes. Since IL-17 receptor A is part of the signaling pathway of many IL-17 family members we investigated the role of IL-17 receptor signaling in disease development in mice with a B6/lpr background. B6/lpr mice were crossed with IL-17 receptor A deficient (IL-17RA KO) mice and followed over time for disease development. IL-17RA KO/lpr mice presented with significantly enhanced lymphoproliferation compared with B6/lpr mice, which was characterized by dramatic lymphadenomegaly/splenomegaly and increased lymphocyte numbers, expansion of double-negative (DN) T-cells and enhanced plasma cell formation. However, the SLE phenotype was not enhanced, as anti-nuclear antibody (ANA) titers and induction of glomerulonephritis were not different. In contrast, levels of High Mobility Group Box 1 (HMGB1) and anti-HMGB1 autoantibodies were significantly increased in IL-17RA KO/lpr mice compared to B6/lpr mice. These data show that lack of IL-17RA signaling aggravates the lymphoproliferative phenotype in B6/lpr mice but does not affect the SLE phenotype.