Abstract
Human uveitis is a type of T cell-mediated autoimmune disease that often shows relapse–remitting courses affecting multiple biological processes. As a cytoplasmic process, autophagy has been seen as an adaptive response to cell death and survival, yet the link between autophagy and T cell-mediated autoimmunity is not certain. In this study, based on the differentially expressed genes (GSE19652) between the recurrent versus monophasic T cell lines, whose adoptive transfer to susceptible animals may result in respective recurrent or monophasic uveitis, we proposed grouping annotations on a subcellular layered interactome framework to analyze the specific bioprocesses that are linked to the recurrence of T cell autoimmunity. That is, the subcellular layered interactome was established by the Cytoscape and Cerebral plugin based on differential expression, global interactome, and subcellular localization information. Then, the layered interactomes were grouping annotated by the ClueGO plugin based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. The analysis showed that significant bioprocesses with autophagy were orchestrated in the cytoplasmic layered interactome and that mTOR may have a regulatory role in it. Furthermore, by setting up recurrent and monophasic uveitis in Lewis rats, we confirmed by transmission electron microscopy that, in comparison to the monophasic disease, recurrent uveitis in vivo showed significantly increased autophagy activity and extended lymphocyte infiltration to the affected retina. In summary, our framework methodology is a useful tool to disclose specific bioprocesses and molecular targets that can be attributed to a certain disease. Our results indicated that targeted inhibition of autophagy pathways may perturb the recurrence of uveitis.
Highlights
It is estimated that approximately 10% of the blindness cases in the United States have been caused by uveitis[1,2]
Our analyses indicated that the recurrent T cell line showed significantly increased autophagy activity compared to the monophasic line, and these results were testified in vivo by transmission electron microscopy (TEM)
The framework we proposed here, grouped annotations on the subcellular layered interactome, can decipher the most relevant biological process, which may point to a novel way to enhance the understanding of regulatory mechanisms behind a gene expression experiment
Summary
It is estimated that approximately 10% of the blindness cases in the United States have been caused by uveitis[1,2]. (PDSAg from S-Ag and R16 from IRBP) specific T cell lines induce a monophasic disease course, whereas R14- (a peptide derived from IRBP) specific T cell lines mediate a typical recurrent disease process when adoptively transferred to a susceptible animal [3]. The mechanisms that underlie recurrent human uveitis remain unclear,Regulatory T cells (Tregs) that selectively restrain the PDSAg-specific T cells and protect from recurrent disease have not been identified and the underlying cause for the relapsing phase of the disease appears to originate in large part in subtle differences in the specific effector phenotype of T cells generated [3]. The different antigen-specific T cell lines may allow a direct comparison between the recurrent and monophasic phenotypes of the disease to elicit the initiation element to induce the recurrence of uveitis
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