Pluto Bioinformatics

GSE102728: IgG immunocomplexes sensitize human monocytes for inflammatory hyperactivity via transcriptomic and epigenetic reprogramming in autoimmune disease

Bulk RNA sequencing

Prevalence of circulating immunocomplexes (ICs) strongly correlates with systemic autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis (RA) in humans. In the case of RA, deposits of IgG ICs are abundant in affected joints of patients, yet molecular mechanisms for the pathogenic roles of such ICs are not fully understood. We present here evidence that IgG ICs precipitated from RA sera sensitized human monocytes for a long-lasting inflammatory functional state characterized by a strong TNF response to cellular proteins representing damage-associated molecular patterns (DAMPs) and microbe-derived pathogen-associated molecular patterns (PAMPs). Importantly, plate-coated human IgG (cIgG, a mimic of deposited IC without antigen restriction) exhibited similarly robust ability of monocyte sensitization in vitro. The cIgG-induced functional programming is through FcRIIa/Syk signaling and accompanied by characteristic phenotypic changes, readjustment of autocrine feed-forward and feedback regulatory loops with dynamic shift in the transcription factor repertoire and epigenetic modification of various inflammatory cytokine genes. Moreover, macrophages freshly isolated from synovia of patients with RA, but not sera-negative arthropathy, displayed signature gene expression profile highly similar to that of IC-sensitized human monocytes, indicative of historical priming events by IgG ICs in vivo. Thus, the ability of IgG ICs to drive sustainable functional sensitization/reprogramming of monocytes and macrophages towards inflammation may render them key players in the development of chronic inflammatory autoimmune diseases. SOURCE: Xiao-Ming Gao (xmgao@suda.edu.cn) - Soochow University