抗中性粒细胞胞质抗体相关性血管炎伴肾损伤中铁死亡亚型和免疫特征的综合分析

陶密; 耿明慧; 黎煜研; 何一晴; 廖文文; 吴小燕; 高苹

doi:10.3969/j.issn.1671-2390.2023.11.007

抗中性粒细胞胞质抗体相关性血管炎伴肾损伤中铁死亡亚型和免疫特征的综合分析

Comprehensive analysis of ferroptosis patterns and immunologic characteristics in antineutrophil cytoplasmic antibody-associated vasculitis

摘要

摘要:
目的探究抗中性粒细胞胞质抗体（anti-neutrophil cytoplasmic antibodies, ANCA）相关性血管炎（anca-associated vasculitis, AAV）伴肾损伤中铁死亡亚型及在免疫微环境的作用,为开发新的免疫治疗提供基础。
方法从GEO数据库下载关于AAV的肾脏数据集。基于差异表达的结果上，共识聚类算法用于铁死亡亚型的鉴定。采用单样本基因集富集分析和基因集变异分析算法来评估亚型的免疫浸润和信号通路。进一步由LASSO、SVM-RFE算法筛选关键的铁死亡特征基因（ferroptosis related genes, FRGs），并由独立数据集进行验证。CIBERSORT用于评估FRGs的浸润免疫细胞的丰度。最后，由rsm包构建FRGs的临床诊断性模型，使用 Nephroseq V5 数据库分析FRGs与肾功能之间的相关性。
结果 24个铁死亡相关基因在AAV伴肾损伤中显著差异表达，无监督聚类分析确定了两种不同铁死亡亚型，其在基因表达、免疫浸润、生物功能通路上存在显著差异。进一步筛选了一个由 ALOX5、CD44、CRYAB、TP53和FTH1组成的FRGs集，其可有效地区分AAV伴肾损伤和正常对照组。趋化因子受体、巨噬细胞和HLA等与FRGs呈显著正相关。由FRGs构建的临床诊断模型的受试者工作特征曲线的曲线下面积为0.961，而且其与肾小球滤过率均呈负相关；除了CRYAB、FTH1外，其他FRGs与血肌酐均呈正相关，表明它们可能与AAV的肾损伤密切相关，是预后生物标志物。
结论本研究发现AAV伴肾损伤中铁死亡与免疫微环境密切相关，为更好地了解铁死亡模式而开发新的AAV 伴肾损伤的治疗方案奠定了基础。

Abstract:
Objective To lay the groundwork for formulating novel immunotherapies through understanding the regulatory role of ferroptosis and its function in immune microenvironment in ANCA-associated vasculitis (AAV) with renal injury.
Methods Kidney data sets on AAV were downloaded from the database of Gene Expression Omnibus (GEO). Based upon the results of differential expression, consensus clustering algorithm was employed for identifying the subtypes of iron mortality. Single sample gene set enrichment analysis (ssGSEA) and gene set variation analysis (GSVA) were performed for evaluating the immune invasion and signaling pathways of subtypes. Key ferroptosis-related genes (FRGs) were further screened by LASSO and SVM-RFE algorithms and verified by independent data sets. CIBERSORT was utilized for assessing the abundance of infiltrating immune cells for FRGs. Finally a clinical diagnostic model of FRGs was constructed by rsm package. And the correlation between FRGs and renal function was examined by Nephroseq V5 database.
Results Twenty-four ferroptosis related genes were significantly differentially expressed in AAV with kidney injury. Unsupervised cluster analysis revealed the regulatory patterns of two different ferroptosis subtypes with significant differences in gene expression, immune infiltration and biological functional pathways. A set of FRGs composed of ALOX5, CD44, CRYAB, TP53, and FTH1 was selected by two machine learning algorithms. It could effectively distinguish AAV with kidney injury from normal control group. CCR, macrophage and HLA were correlated positively with FRGs. Area under ROC curve of clinical diagnostic model constructed by FRGs was 0. 961. FRGs were correlated negatively with glomerular filtration rate (GFR). However, except for CRYAB and FTH1, other FRGs were correlated positively with serum creatinine (Scr). It implicated their potential relevance to renal injury in ANCA-associated vasculitis (AAV) and their potential as prognostic biomarkers.
Conclusions Ferroptosis in AAV with kidney injury is correlated closely with immune microenvironment. It provides rationales for devising new treatments for AAV with kidney injury through a better understanding the pattern of ferroptosis.

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