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,
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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.