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Both adaptive and innate immune mechanisms are involved in the pathophysiology of RA

Pathophysiology

The pathophysiology of RA is complex and appears to involve multiple mechanisms1–4

  • The pathophysiology of RA involves aspects of both innate and adaptive immunity, which may occur in a parallel fashion.1
  • Activation of the innate immune response with ubiquitously expressed autologous antigens probably occurs early in RA and may serve as a key pathogenic mechanism that initiates synovial inflammation.1,5
  • Several autoantibody systems are implicated, including:
    • Rheumatoid factor (RF) – produced by synovial B-cells1,2
    • Anti-cyclic citrunillated peptide (CCP) antibodies; potentially a more specific indicator of RA than RF3
  • Activation of the innate immune response is likely to activate the adaptive immune system, through the presentation of autoantigens via MHC molecules to T cells.
  • Activated T cells in the synovium stimulate monocytes, macrophages and synovial fibroblasts to produce pro-inflammatory cytokines, for example, interleukin (IL)-1, IL-6, IL-15, IL-18, tumor necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor4–6
  • These inflammatory responses are implicated in:
    • Driving continued immune cell recruitment to the joint and synovium1
    • Stimulating B cells to produce immunoglobulins, including RF1,4
    • Inducing expression of adhesion molecules, which further promote recruitment of activated immune cells1
    • Driving expression of degradative enzymes, thereby initiating joint destruction1,4

References:

  1. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature 2003; 423:356–361.
  2. Ates A, et al. Effects of rheumatoid factor isotypes on disease activity and severity in patients with rheumatoid arthritis: a comparative study. Clin Rheumatol 2007; 26:538–545.
  3. Silveira IG, et al. Anti-CCP antibodies have more diagnostic impact than rheumatoid factor (RF) in a population tested for RF. Clin Rheumatol 2007; 26:1883–1889.
  4. Choy EH & Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001; 344:907–916.
  5. Smolen JS, et al. New therapies for treatment of rheumatoid arthritis. Lancet 2007; 370:1861–1874.
  6. Heinrich PC, et al. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 1998; 334 (Pt 2):297–314.