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. 2022 Jul 25:13:936707.
doi: 10.3389/fimmu.2022.936707. eCollection 2022.

Identification of immune hub genes participating in the pathogenesis and progression of Vogt-Koyanagi-Harada disease

Yiqi Wang  1   2 , Yahan Ju  1   2 , Jiajing Wang  1   2 , Na Sun  3 , Zhimin Tang  1   2 , Huiqin Gao  1   2 , Ping Gu  1   2 , Jing Ji  1   2
Affiliations

Identification of immune hub genes participating in the pathogenesis and progression of Vogt-Koyanagi-Harada disease

Yiqi Wang et al. Front Immunol. .

Abstract

Background: Vogt-Koyanagi-Harada (VKH) disease is an autoimmune inflammatory disorder characterized by bilateral granulomatous uveitis. The objective of this study was to identify immune hub genes involved in the pathogenesis and progression of VKH disease.

Methods: High throughput sequencing data were downloaded from the Gene Expression Omnibus (GEO) and an immune dataset was downloaded from ImmPort. Immune differentially expressed genes (DEGs) were obtained from their intersection in the GEO and ImmPort datasets. Immune hub genes for VKH disease were selected through differential expression analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Disease Ontology (DO), protein-protein interaction (PPI) network, and clustering analyses. Confidence in the immune hub genes was subsequently validated using box plots and receiver operating characteristic (ROC) curves.

Results: A total of 254 DEGs were screened and after the intersection with ImmPort, 20 genes were obtained as immune DEGs. Functional enrichment analysis indicated that the key genes were mainly involved in several types of immune pathways (such as the lymphocyte mediated and leukocyte mediated immune responses, natural killer cell mediated cytotoxicity, and antigen binding) and immunodeficiency diseases. Following PPI network analysis, the top seven genes in cluster 1 were selected as potential immune hub genes in VKH. After evaluating the accuracy of the hub genes, one gene (GNLY) was excluded because its expression level was statistically similar in VKH patients and healthy controls. Finally, six immune hub genes, namely KLRC2, KLRC3 SH2D1B, GZMB, KIR2DL3, and KIR3DL2 were identified as playing important roles in the occurrence and development of VKH disease.

Conclusion: Six immune hub genes (KLRC2, KLRC3 SH2D1B, GZMB, KIR2DL3, and KIR3DL2) identified by our bioinformatics analyses may provide new diagnostic and therapeutic targets for VKH disease.

Keywords: Vogt-Koyanagi-Harada disease; functional enrichment analyses; immune hub genes; protein-protein interaction network analysis; receiver operating characteristic curves.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
In total, 254 differentially expressed genes (DEGs) were identified in Vogt-Koyanagi-Harada (VKH) patients and healthy controls (HC) and the top 50 DEGs are shown in (A) the heatmap, with significantly up-regulated genes marked in red and significantly down-regulated genes marked in blue. (B) Venn diagram of immune DEGs. Clinical dataset of VKH disease (GSE166663) and immune dataset (ImmPort) were intersected to identify immune DEGs.
Figure 2
Figure 2
Bubble plot of gene ontology (GO) functional analysis included the respective top 10 terms in (A) biological process, (B) cellular component, and (C) molecular function, indicating that the immune differentially expressed genes (DEGs) were mainly involved in humoral immune response, lymphocyte mediated immunity, leukocyte mediated immunity, and antigen binding (P<0.05).
Figure 3
Figure 3
(A) Bar plot of results from Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analysis indicating that antigen processing and presentation, natural killer cell mediated cytotoxicity, and graft-versus-host disease were most significantly activated in the gene sets (P<0.05). (B) Bar plot of disease ontology (DO) functional analysis showed the top 10 diseases, with the immune differentially expressed genes (DEGs) primarily participating in the pathogenesis of human immunodeficiency virus infectious disease (P<0.05).
Figure 4
Figure 4
(A) Protein-protein interaction (PPI) network for 12 immune differentially expressed genes (DEGs) with the upregulated genes marked in red and the downregulated genes marked in blue. (B) Cluster 1 consisting of seven genes was constructed using MCODE.
Figure 5
Figure 5
Validation of immune potential hub genes in the gene expression level. The expressions of KLRC2, KLRC3, SH2D1B, GZMB, KIR2DL3, and KIR3DL2 were significantly lower in Vogt-Koyanagi-Harada patients (VKH) than in healthy controls (HC). The expression level of GNLY was not statistically significantly different between the two groups.
Figure 6
Figure 6
Validation of the diagnostic value of immune potential hub genes. Receiver operating characteristic values and area under the curve (AUC) statistics indicated that all seven potential hub genes had diagnostic value for Vogt-Koyanagi-Harada disease.
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