The Role of Secondary Lymphoid Tissues’ Peptidyl Arginine Deiminase Type 4 and Myeloperoxidase in the Pathogenesis of Autoimmune Arthritis

Abstract

Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease characterized by extensive synovitis resulting in cartilage and bone erosions. RA has a high prevalence among the global population. RA is associated with a dysregulated immune response and citrullination, a post-translational modification of proteins catalyzed by peptidylarginine deiminases (PADs). PADs, in particular PAD4, are involved in the formation of neutrophil extracellular traps (NETs) and may play a role both in generating potential auto-antigens and in host defense against bacterial infections. RA onset is preceded by a breach of self-tolerance and the presence of anti-citrullinated protein antibodies (ACPAs). This project aimed to determine the role of PAD4 in the pathogenesis and progression of RA patients, Behçet's disease patients (BD), which was used as a disease control compared to healthy control. We hypothesized that PAD4 and MPO are expressed in secondary lymphoid tissues (SLT) and their expression correlates with ACPA production in RA. Using Collageninduced arthritis (CIA) mice model and wild type control, PAD4 was confirmed to be expressed in arthritis prone (DBA/1) and resistant (BALB/c) mice using Real-Time Polymerase Chain Reaction (RT-PCR) and Western Blotting (WB). Further investigation was done to investigate the distribution and cellular source of expression of PAD4 and MPO in the SLT of (DBA/1 Vs. BALB/c) by Immunohistochemistry (IHC). Additionally, PAD4 and ACPA concentrations were assessed by running an Enzyme-Linked Immunosorbent Assay (ELISA), it was found that PAD4 and ACPA were positively correlated in RA serum compared to BD. In conclusion, the data suggest that PAD4 may show modulatory effects on the inflammatory response, iii which in turn may impact on the outcome of such processes. A better understanding of these mechanisms will hopefully assist in designing newer therapeutic interventions aimed at re-establishing immunological tolerance. In the future, Pharmacological inhibition of PAD4 has been proposed and trialed as an RA therapy.