Rheumatoid arthritis (RA) originates from dysregulated immune responses primarily involving the synovial tissues of joints. The abnormal immune responses in the synovial tissues are believed to be triggered by complex interactions between genetic background and environmental factors. Thereby, rheumatoid synovitis is the result of the chronic inflammation elicited by the interactions among innate immune cells including monocytes/macrophages, dendritic cells (DCs), mast cells, natural killer (NK) cells and polymorphonuclear neutrophils (PMNs), and adaptive immune cells including B and T lymphocytes, and fibroblast-like synoviocytes (FLSs). Arbitrarily, the chronic synovial inflammation in RA can be defined as an imbalance between proinflammatory and anti-inflammatory cytokines with preponderance in proinflammatory ones including interleukins (ILs) IL-1β, IL-6, IL-8, IL-17, and tumor necrosis factor (TNF) TNF-α
[1]. In addition, the activation, proliferation, and differentiation of B cells to plasma cells lead to the production of a variety of autoantibodies. Among them, the characteristic ones such as rheumatoid factors (RFs) (anti-denatured IgG antibodies) and anti-citrullinated protein antibodies (ACPAs) are highly associated with the pathogenesis and disease activity of RA
[2][3]. Well-documented upstream genetic factors implicated in RA pathogenesis include both human histocompatibility antigens (i.e., human leukocyte antigen, HLA, such as
HLA-DR4,
HLA-DRB1) and non-HLA genes (
PTPN22, CTLA-4, TRAF1-C5, STAT4, PADI4)
[3]. In addition, a setting of environmental factors such as infections (Epstein–Barr virus), chemicals (pesticides), heavy metals (organic mercury and cadmium), cigarette smoking, and lifestyle factors (socio-economic status and psychological factors) are all established risk elements in triggering RA
[4]. However, the most important discovery regarding its pathogenetic factors has been the epigenetic regulation of gene expression which mainly involves non-coding RNAs (ncRNAs). These non-translated small nucleotide sequences can be arbitrarily classified as microRNAs (miRs) with 20–24 nt. in size, and long non-coding RNAs (lncRNAs) with <300 nt. in size. These ncRNAs are not housekeeping molecules but can act as post-transcriptional regulators for mRNA expression by binding to 3′-untranslated regions (3′-UTR) of protein-coding genes
[5]. Such binding can be further modulated through a ribonucleoprotein complex called “RNA induced silencing complex (RISC)”
[6] where argonaute (Ago) proteins become the major catalytic component. The ncRNAs bound to Ago can guide RISC to the consequent complementary target sites
[7]. For further understanding of the immunopathological mechanisms of RA, it is worthwhile looking into the immunopathological roles of the two characteristic autoantibodies, RFs and ACPAs, relevant to the development of RA before going into the detailed discussion of aberrant ncRNA expression in patients with RA.