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Identification of gp96 as a novel target for treatment of autoimmune disease in mice.

ABSTRACT: Heat shock proteins have been implicated as endogenous activators for dendritic cells (DCs). Chronic expression of heat shock protein gp96 on cell surfaces induces significant DC activations and systemic lupus erythematosus (SLE)-like phenotypes in mice. However, its potential as a therapeutic target against SLE remains to be evaluated. In this work, we conducted chemical approach to determine whether SLE-like phenotypes can be compromised by controlling surface translocation of gp96. From screening of chemical library, we identified a compound that binds and suppresses surface presentation of gp96 by facilitating its oligomerization and retrograde transport to endoplasmic reticulum. In vivo administration of this compound reduced maturation of DCs, populations of antigen presenting cells, and activated B and T cells. The chemical treatment also alleviated the SLE-associated symptoms such as glomerulonephritis, proteinuria, and accumulation of anti-nuclear and -DNA antibodies in the SLE model mice resulting from chronic surface exposure of gp96. These results suggest that surface translocation of gp96 can be chemically controlled and gp96 as a potential therapeutic target to treat autoimmune disease like SLE.

SUBMITTER: Han JM

PROVIDER: S-EPMC2843739 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Identification of gp96 as a novel target for treatment of autoimmune disease in mice.

Han Jung Min JM Kwon Nam Hoon NH Lee Jin Young JY Jeong Seung Jae SJ Jung Hee Jung HJ Kim Hyeong Rae HR Li Zihai Z Kim Sunghoon S

PloS one 20100323 3

Heat shock proteins have been implicated as endogenous activators for dendritic cells (DCs). Chronic expression of heat shock protein gp96 on cell surfaces induces significant DC activations and systemic lupus erythematosus (SLE)-like phenotypes in mice. However, its potential as a therapeutic target against SLE remains to be evaluated. In this work, we conducted chemical approach to determine whether SLE-like phenotypes can be compromised by controlling surface translocation of gp96. From scree ...[more]

PMID: 20352117

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Project description:BackgroundAutoimmune thyroid disease (AITD) is induced by various factors, including inheritability, which regulates gene expression. Multiple loci correlated with AITD have been discovered utilizing genome-wide association studies (GWASs). Nevertheless, demonstrating the biological relevance and function of these genetic loci is difficult.MethodsThe FUSION software was utilized to define genes that were expressed differentially in AITD using a transcriptome-wide association study (TWAS) method in accordance with GWAS summary statistics from the largest genome-wide association study of 755,406 AITD individuals (30,234 cases and 725,172 controls) and levels of gene expression from two tissue datasets (blood and thyroid). Further analyses were performed such as colocalization, conditional, and fine-mapping analyses to extensively characterize the identified associations, using functional mapping and annotation (FUMA) to conduct functional annotation of the summary statistics of 23329 significant risk SNPs (P < 5 × 10-8) recognized by GWAS, together with summary-data-based mendelian randomization (SMR) for identifying functionally related genes at the loci in GWAS.ResultsThere were 330 genes with transcriptome-wide significant differences between cases and controls, and the majority of these genes were new. 9 of the 94 unique significant genes had strong, colocalized, and potentially causal correlations with AITD. Such strong associations included CD247, TPO, KIAA1524, PDE8B, BACH2, FYN, FOXK1, NKX2-3, and SPATA13. Subsequently, applying the FUMA approach, novel putative AITD susceptibility genes and involved gene sets were detected. Furthermore, we detected 95 probes that showed strong pleiotropic association with AITD through SMR analysis, such as CYP21A2, TPO, BRD7, and FCRL3. Lastly, we selected 26 genes by integrating the result of TWAS, FUMA, and SMR analysis. A phenome-wide association study (pheWAS) was then carried out to determine the risk of other related or co-morbid phenotypes for AITD-related genes.ConclusionsThe current work provides further insight into widespread changes in AITD at the transcriptomic level, as well as characterized the genetic component of gene expression in AITD by validating identified genes, establishing new correlations, and uncovering novel susceptibility genes. Our findings indicate that the genetic component of gene expression plays a significant part in AITD.

Dataset Information

Identification of gp96 as a novel target for treatment of autoimmune disease in mice.

Publications

Identification of gp96 as a novel target for treatment of autoimmune disease in mice.

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