title: Collagen induced arthritis (CIA) in mice features regulatory transcriptional network connecting major histocompatibility complex (MHC H2) with autoantigen genes in the thymus.
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.
authors.affiliation: Molecular Immunogenetics Group, Department of Genetics, Faculty of Medicine of Ribeirão Preto, University of São Paulo, 14040-900 Ribeirão Preto, SP, Brazil.
authors.forename: Paula B
authors.initials: PB
authors.lastname: Donate
authors.forename: Thaís A
authors.initials: TA
authors.lastname: Fornari
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Junta
authors.forename: Danielle A
authors.initials: DA
authors.lastname: Magalhães
authors.forename: Cláudia
authors.initials: C
authors.lastname: Macedo
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.forename: Catherine
authors.initials: C
authors.lastname: Nguyen
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: Geraldo A
authors.initials: GA
authors.lastname: Passos
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D001324:Autoantigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D019295:Computational Biology; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000276:immunology; D006649:Histocompatibility Antigens / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D046228:Microarray Analysis; D017634:Self Tolerance; D013045:Species Specificity; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000096927:AIRE Protein
chemical_list: D001324:Autoantigens; D006649:Histocompatibility Antigens; D014157:Transcription Factors; D000096927:AIRE Protein