Collagen induced arthritis (CIA) in mice features regulatory transcriptional network connecting major histocompatibility complex (MHC H2 ) with autoantigen genes in the thymus

• Published in: Immunobiology (1979) Vol. 216; no. 5; pp. 591 - 603
• Main Authors: Donate, Paula B, Fornari, Thaís A, Junta, Cristina M, Magalhães, Danielle A, Macedo, Cláudia, Cunha, Thiago M, Nguyen, Catherine, Cunha, Fernando Q, Passos, Geraldo A
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier GmbH 01.05.2011
• Subjects: Advanced Basic Science; Aire; AIRE Protein; Allergy and Immunology; Animals; Arthritis, Experimental - genetics; Arthritis, Experimental - immunology; Arthritis, Experimental - metabolism; Autoantigens - genetics; Autoantigens - immunology; Autoantigens - metabolism; Cells, Cultured; Collagen induced arthritis; Computational Biology; Gene Expression Profiling; Gene Regulatory Networks - immunology; Histocompatibility Antigens - metabolism; MHC; Mice; Mice, Inbred DBA; Microarray Analysis; Promiscuous gene expression; Self Tolerance; Species Specificity; Thymus; Thymus Gland - immunology; Thymus Gland - metabolism; Thymus Gland - pathology; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional network; cTEC; promiscuous gene expression; MHC; major histocompatibility complex; phosphate-buffered saline; Thymus; type II collagen; mTEC; CIA; thymic epithelial cell; peripheral tissue autoantigens; PBS; cortical thymic epithelial cell; CII; Aire; human leukocyte antigen; Transcriptional network; significance analysis of microarrays; rheumatoid arthritis; PGE; RA; TEC; medullary thymic epithelial cell; complete Freud's adjuvant; collagen induced arthritis; HLA; PTA; SAM; CFA; Promiscuous gene expression; Collagen induced arthritis
• ISSN: 0171-2985; 1878-3279
• DOI: 10.1016/j.imbio.2010.09.007

Abstract Considering that imbalance of central tolerance in the thymus contributes to aggressive autoimmunity, we compared the expression of peripheral tissue autoantigens (PTA) genes, which are involved in self-representation in the thymic stroma, of two mouse strains; DBA-1/J (MHC- H2 q ) susceptible and DBA-2/J (MHC- H2 d ) resistant to collagen induced arthritis (CIA). We evaluate whether these strains differ in their thymic gene expression, allowing identification of genes that might play a role in susceptibility/resistance to CIA. Microarray profiling showed that 1093 PTA genes were differentially modulated between collagen immunized DBA-1/J and DBA-2/J mice. These genes were assigned to 17 different tissues/organs, including joints/bone, characterizing the promiscuous gene expression (PGE), which is implicated in self-representation. Hierarchical clustering of microarray data and quantitative RT-PCR analysis showed that Aire (autoimmune regulator), an important regulator of the PGE process, Aire-dependent (insulin), Aire-independent ( Col2A1 and Gad67 ), and other 22 joint/bone autoantigen genes were down-regulated in DBA-1/J compared with DBA-2/J in the thymus. Considering the importance of MHC- H2 in peptide-self presentation and autoimmunity susceptibility, we reconstructed transcriptional networks of both strains based on actual microarray data. The networks clearly demonstrated different MHC-H2 transcriptional interactions with PTAs genes. DBA-1/J strain featured MHC- H2 as a node influencing downstream genes. Differently, in DBA-2/J strain network MHC- H2 was exclusively self-regulated and does not control other genes. These findings provide evidence that CIA susceptibility in mice may be a reflex of a cascade-like transcriptional control connecting different genes to MHC- H2 in the thymus.