Targeting the epigenetic modifications of synovial cells

Rheumatoid arthritis (RA) is a systemic inflammatory disease that mainly affects the synovial tissues of joints. Like in other autoimmune-related disorders, both the etiology as well as the pathogenesis of RA has not yet been completely unravelled. It is generally accepted, though, that autoimmune disorders develop through a combination of the individual genetic susceptibility, environmental factors, and dysregulated immune responses. Genetic predisposition has been described in RA, in particular as “shared epitope”, a distinct sequence of amino acids within the antigen presenting peptide groove of the major histocompatibility complex (MHC). Imbalanced immunity is reflected by the production of autoantibodies and the accumulation of reactive helper T cells within the rheumatoid synovium. In addition, environmental factors have been postulated as disease modulating agents, including smoking, nutrition and infectious agents. So far, these factors have been studied almost exclusively as separate agents. However, the way genes are transcribed can be affected by environment, nutrition, and ageing – without changes in the nucleotide sequence of the underlying DNA. These patterns of alterations in the gene expression profiles are called epigenetics. The term epigenetics is used to refer to molecular processes that regulate gene expression patterns, however without changing the DNA nucleotide sequence. These epigenetic changes comprise the postsynthetical methylation of DNA and posttranscriptional modifications of histones, including methylation, phosphorylation, ubiquitination, sumoylation, biotinlyation and, most importantly, deacetylation and acetylation. With respect to the complex pathogenesis of rheumatic diseases, the epigenome is an emerging concept that integrates different etiologies and, thus, offers the opportunity for novel therapeutic strategies. Based on the fact that current therapies have not resulted in an ACR 70 above 60% and have never been targeting the activated synovial fibroblast, novel therapeutic strategies should target the epigenetic pathways of synovial activation in RA

Pattern recognition by pentraxins

Pentraxins are a family of evolutionarily conserved pattern-recognition proteins that are made up of five identical subunits. Based on the primary structure of the subunit, the pentraxins are divided into two groups: short pentraxins and long pentraxins. C-reactive protein (CRP) and serum amyloid P-component (SAP) are the two short pentraxins. The prototype protein of the long pentraxin group is pentraxin 3 (PTX3). CRP and SAP are produced primarily in the liver while PTX3 is produced in a variery oftissues during inflammation. The main functions of short pentraxins are to recognize a variery of pathogenic agents and then to either eliminate them or neutralize their harmful effects by utilizing the complement pathways and macrophages in the host. CRP binds to modified low-densiry lipoproteins, bacterial polysaccharides, apoptotic cells, and nuclear materials. By virtue of these recognition functions, CRP participates in the resolution ofcardiovascular, infectious, and autoimmune diseases. SAP recognizes carbohydrates, nuclear substances, and amyloid fibrils and thus participates in the resolution of infectious diseases, autoimmuniry, and amyloidosis. PTX3 interacts with several ligands, including growth factors, extracellular matrix component and selected pathogens, playing a role in complement activation and facilitating pathogen recognition by phagoeytes. In addition, data in gene-targeted mice show that PTX3 is essential in female fertiliry, participating in the assembly of the cumulus oophorus extracellular matrix. PTX3 is therefore a nonredundant component ofthe humoral arm of innate immuniry as well as a tuner of inflammation. Thus, in conjunction with the other components ofinnate immuniry, the pentraxins use their pattern-recognition properry for the benefit of the host