STAT4 Is Largely Dispensable for Systemic Lupus Erythematosus-like Autoimmune- and Foreign Antigen-Driven Antibody-Forming Cell, Germinal Center, and Follicular Th Cell Responses.
STAT4 Is Largely Dispensable for Systemic Lupus Erythematosus-like Autoimmune- and Foreign Antigen-Driven Antibody-Forming Cell, Germinal Center, and Follicular Th Cell Responses.
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DOI：
10.4049/immunohorizons.2000111
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发表时间：
2021-01-14
期刊：
影响因子：
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通讯作者：
Rahman, Ziaur S M
中科院分区：
文献类型：
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作者：
Fike, Adam J;Chodisetti, Sathi Babu;Rahman, Ziaur S M
全基因组关联研究确定了转录因子STAT4基因和STAT4信号通路中的其他几个基因（如IL12A，IL12B，JAK2和TYK2）的变体，这些基因与发生系统性红斑狼疮（SLE）和其他自身免疫性疾病的风险增加有关。与全基因组关联研究数据一致，STAT4显示在SLE小鼠模型中的自身免疫应答和自身免疫发展中起重要作用。尽管STAT4在小鼠和人类SLE发展中具有如此重要的作用，但很少有人知道STAT4是否以及如何调节滤泡外Ab形成细胞（AFC）和滤泡生发中心（GC）反应，这是自身反应性B细胞发育和自身抗体产生的两个主要途径。令我们惊讶的是，我们发现STAT4在各种自身免疫和SLE易感小鼠模型中在很大程度上促进自身免疫AFC和GC应答，这与自身抗体产生、免疫复合物沉积和免疫细胞浸润在肾脏中密切相关。我们进一步观察到，STAT4缺陷对蛋白Ag免疫或流感病毒感染期间的AFC、GC和Ag特异性Ab应答没有影响。此外，在自身免疫和SLE易感小鼠和蛋白Ag免疫和流感病毒感染的小鼠中，CD4+效应细胞和滤泡Th细胞应答在没有STAT4的情况下是完整的。总之，我们的数据表明STAT4在SLE小鼠模型中的AFC、GC和Ab应答以及某些外源Ag驱动的应答中起着重要作用。
Genome-wide association studies identified variants in the transcription factor STAT4 gene and several other genes in the STAT4 signaling pathway, such as IL12A, IL12B, JAK2, and TYK2, which are associated with an increased risk of developing systemic lupus erythematosus (SLE) and other autoimmune diseases. Consistent with the genome-wide association studies data, STAT4 was shown to play an important role in autoimmune responses and autoimmunity development in SLE mouse models. Despite such important role for STAT4 in SLE development in mice and humans, little is known whether and how STAT4 may regulate extrafollicular Ab-forming cell (AFC) and follicular germinal center (GC) responses, two major pathways of autoreactive B cell development and autoantibody production. To our surprise, we found STAT4 to be largely dispensable for promoting autoimmune AFC and GC responses in various autoimmune- and SLE-prone mouse models, which strongly correlated with autoantibody production, and immune complex deposition and immune cell infiltration in the kidney. We further observed that STAT4 deficiency had no effects on AFC, GC, and Ag-specific Ab responses during protein Ag immunization or influenza virus infection. Additionally, CD4+ effector and follicular Th cell responses in autoimmune- and SLE-prone mice and protein Ag-immunized and influenza virus-infected mice were intact in the absence of STAT4. Together, our data demonstrate a largely dispensable role for STAT4 in AFC, GC, and Ab responses in SLE mouse models and in certain foreign Ag-driven responses.