Genome-wide association studies (GWAS) and functional genomic analyses have implicated several ITGAM (CD11b) single-nucleotide polymorphisms (SNPs) in the development of SLE and other disorders. ITGAM encodes the αM chain of the β2 integrin Mac-1, a receptor that plays important roles in myeloid cell functions. The ITGAM SNP rs1143679, which results in an arginine to histidine change at amino acid position 77 of the CD11b protein, has been shown to reduce binding to several ligands and to alter Mac-1-mediated cellular response in vitro. Importantly, however, the potential contribution of this SNP variant to the initiation and/or progression of immune and inflammatory processes in vivo remains unexplored. Herein, we describe for the first time the generation and characterization of a mouse line expressing the 77His variant of CD11b. Surprisingly, we found that 77His did not significantly affect Mac-1-mediated leukocyte migration and activation as assessed using thioglycollate-induced peritonitis and LPS/TNF-α-induced dermal inflammation models. In contrast, expression of this variant did alter T cell immunity, as evidenced by significantly reduced proliferation of ovalbumin (OVA)-specific transgenic T cells in 77His mice immunized with OVA. Reduced antigen-specific T cell proliferation was also observed when either 77His splenic dendritic cells (DCs) or bone marrow-derived DCs were used as antigen-presenting cells (APCs). Although more work is necessary to determine how this alteration might influence the development of SLE or other diseases, these in vivo findings suggest that the 77His variant of CD11b can compromise the ability of DCs to induce antigen-driven T cell proliferation.

中文翻译：

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表达ITGAM的rs1143679等位基因变体的小鼠（CD11b）显示受损的DC介导的T细胞增殖。

全基因组关联研究（GWAS）和功能基因组分析已在SLE和其他疾病的发生中牵涉到几种ITGAM（CD11b）单核苷酸多态性（SNP）。ITGAM编码β2整合素Mac-1的αM链，该受体在髓样细胞功能中起重要作用。ITGAM SNP rs1143679可导致CD11b蛋白第77位氨基酸处的精氨酸变为组氨酸，已显示可减少与几种配体的结合并在体外改变Mac-1介导的细胞反应。然而，重要的是，该SNP变体对体内免疫和炎性过程的开始和/或进展的潜在贡献尚待探索。在此，我们首次描述了表达CD11b 77His变体的小鼠品系的生成和表征。出奇，我们发现77His不会显着影响Mac-1介导的白细胞迁移和活化，如使用巯基乙酸盐诱导的腹膜炎和LPS /TNF-α诱导的皮肤炎症模型评估的那样。相反，该变体的表达确实改变了T细胞免疫，如卵白蛋白（OVA）特异性转基因T细胞在用OVA免疫的77His小鼠中的增殖明显减少所证明的。当将77His的脾树突状细胞（DC）或骨髓来源的DC用作抗原呈递细胞（APC）时，也观察到抗原特异性T细胞增殖减少。尽管需要更多的工作来确定这种改变如何影响SLE或其他疾病的发展，但这些体内发现表明CD11b的77His变体可以损害DC诱导抗原驱动的T细胞增殖的能力。