Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Immunobiology (1979), 2011-05, Vol.216 (5), p.591-603

Ort / Verlag

Netherlands: Elsevier GmbH

Erscheinungsjahr

2011

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• 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.