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Open Access Research article

The gene expression profile of preclinical autoimmune arthritis and its modulation by a tolerogenic disease-protective antigenic challenge

Hua Yu1, Changwan Lu23, Ming T Tan3 and Kamal D Moudgil14*

Author Affiliations

1 Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 West Baltimore Street, HSF-1, Suite 380, Baltimore, MD 21201, USA

2 Department of Medicine, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF-314, Baltimore, MD 21201, USA

3 Division of Biostatistics and Bioinformatics, Department of Epidemiology and Public Health, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF-261, Baltimore, MD 21201, USA

4 Division of Rheumatology, Department of Medicine, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA

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Arthritis Research & Therapy 2011, 13:R143  doi:10.1186/ar3457

Published: 13 September 2011

Abstract

Introduction

Autoimmune inflammation is a characteristic feature of rheumatoid arthritis (RA) and other autoimmune diseases. In the natural course of human autoimmune diseases, it is rather difficult to pinpoint the precise timing of the initial event that triggers the cascade of pathogenic events that later culminate into clinically overt disease. Therefore, it is a challenge to examine the early preclinical events in these disorders. Animal models are an invaluable resource in this regard. Furthermore, considering the complex nature of the pathogenic immune events in arthritis, microarray analysis offers a versatile tool to define the dynamic patterns of gene expression during the disease course.

Methods

In this study, we defined the profiles of gene expression at different phases of adjuvant arthritis (AA) in Lewis rats and compared them with those of antigen mycobacterial heat shock protein 65 (Bhsp65)-tolerized syngeneic rats. Purified total RNA (100 ng) extracted from the draining lymph node cells was used to generate biotin-labeled fragment cRNA, which was then hybridized with an oligonucleotide-based DNA microarray chip. Significance analysis of microarrays was used to compare gene expression levels between the two different groups by limiting the false discovery rate to < 5%. Some of the data were further analyzed using a fold change ≥2.0 as the cutoff. The gene expression of select genes was validated by quantitative real-time PCR.

Results

Intriguingly, the most dramatic changes in gene expression in the draining lymphoid tissue ex vivo were observed at the preclinical (incubation) phase of the disease. The affected genes represented many of the known proteins that participate in the cellular immune response. Interestingly, the preclinical gene expression profile was significantly altered by a disease-modulating, antigen-based tolerogenic regimen. The changes mostly included upregulation of several genes, suggesting that immune tolerance suppressed disease by activating disease-regulating pathways. We identified a molecular signature comprising at least 12 arthritis-related genes altered by Bhsp65-induced tolerance.

Conclusions

This is the first report of microarray analysis in the rat AA model. The results of this study not only advance our understanding of the early phase events in autoimmune arthritis but also help in identifying potential targets for the immunomodulation of RA.

Keywords:
adjuvant arthritis; gene expression; heat shock proteins; immune tolerance; microarray analysis