Post-translational and therapy-induced modifications in rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial proliferation and excessive mononuclear infiltration leading to destruction of bone and cartilage, with subsequent joint deformities and physical disability. Even though RA etiology is still unknown, autoantibody driven pathogenic mechanisms are considered to be important, with strong evidence for the pathogenic potentials of antibodies directed against citrullinated antigens. Several drugs are used for RA treatment such as non-steroidal anti-inflammatory drugs, glucocorticoids, disease modifying anti-rheumatic drugs and biological agents. Intra-articular glucocorticoids, potent anti-inflammatory compounds, are successfully used by clinicians as an adjuvant therapy for RA, but there is limited information regarding their molecular mechanisms of action. This thesis work investigates the relevance of the post-translational modification citrullination in RA pathogenesis and inflammation and the effect of intra-articular glucocorticoids in RA inflammation and associated bone destruction.
Approximately 60% of RA patients are characterized by presence of anti-citrullinated protein antibodies (ACPAs), associated with worse disease prognosis. ACPA development can be a result of a gene-environment interaction between HLA-shared epitope and smoking. We demonstrated that both citrullinated proteins and peptidylarginine deiminase 2 enzyme expression is increased in bronchoalveolar lavage cells of smokers in comparison to non-smokers, which could be an early step in the pathogenesis of ACPA positive RA. In RA inflamed synovial tissue citrullinated proteins - potential targets of ACPAs - are present. We demonstrated the presence of citrullinated proteins in a wide range of inflammatory tissues, which suggests that citrullination is not specific for synovial inflammation but more generally associated with inflammation. Our findings suggest that additional factors than presence of citrullinated proteins determine the association between presence of ACPAs and synovial inflammation. Decreased apoptosis is linked to RA synovial inflammation. We demonstrated that intra-articular glucocorticoids modify RA synovial inflammation by decreasing T cell numbers and we investigated if this was linked to T cell apoptosis. We found RA synovial T cells resistant to glucocorticoid induced apoptosis both at the synovial tissue and fluid level, a specific feature for RA attributed to interactions with monocytes in the inflammatory synovial environment. Synovial inflammation in RA is linked to bone destruction, a dynamic process balancing bone matrix synthesis by osteoblasts and bone resorption by osteoclasts, mediated through the receptor activator of NFκB ligand (RANKL)-osteoprotegerin (OPG) system. We demonstrated that intra-articular glucocorticoid treatment decreased synovial RANKL expression without changes in OPG expression. The synovial RANKL/OPG ratio thus decreased following treatment, suggesting a bone protective effect of intra-articular glucocorticoids in the rheumatoid joint.
In conclusion, we have demonstrated that citrullination might be a relevant mechanism for RA pathogenesis in the context of gene-environment interactions, while it is not an exclusive characteristic of RA inflammation. RA synovial inflammation and associated bone destruction is modified by intra-articular glucocorticoids, while RA synovial monocytes render T cells glucocorticoid induced apoptosis resistant, suggesting that combination treatment with monocyte targeted therapies could be beneficial.
List of scientific papers
I. Makrygiannakis D, Hermansson M, Ulfgren AK, Nicholas AP, Zendman AJ, Eklund A, Grunewald J, Skold CM, Klareskog L, Catrina AI (2008). Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann Rheum Dis. Apr 15: Epub ahead of print
https://pubmed.ncbi.nlm.nih.gov/18413445
II. Makrygiannakis D, af Klint E, Lundberg IE, Löfberg R, Ulfgren AK, Klareskog L, Catrina AI (2006). Citrullination is an inflammation-dependent process. Ann Rheum Dis. 65(9): 1219-22. Epub 2006 Mar 15
https://pubmed.ncbi.nlm.nih.gov/16540548
III. Makrygiannakis D, af Klint E, Catrina SB, Botusan IR, Klareskog E, Klareskog L, Ulfgren AK, Catrina AI (2006). Intraarticular corticosteroids decrease synovial RANKL expression in inflammatory arthritis. Arthritis Rheum. 54(5): 1463-72
https://pubmed.ncbi.nlm.nih.gov/16646024
IV. Makrygiannakis D, Neregård P, af Klint E, Snir O, Grundtman C, Catrina AI (2008). Interactions between monocytes and T cells are essential for inhibition of synovial T cell glucocorticoid mediated apoptosis in rheumatoid arthritis. [Submitted]
History
Defence date
2008-05-30Department
- Department of Medicine, Solna
Publication year
2008Thesis type
- Doctoral thesis
ISBN
978-91-7357-539-3Number of supporting papers
4Language
- eng