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Rheumatoid Arthritis
Prof. Mohammed K. Senna
Abbreviations
M Macrophages
FBLs Fibroblasts
RA Rheumatoid arthritis
PMNLs Polymorphonuclear leukocytes
DC Dendritic cells
The etiology and pathogenesis of RA
Q K R A A
glutamine leucine arginine alanine alanine
Role of Genes
Smoking
Smoking
Proposed Mechanisms
Infection
Early RA
Early RA
Early RA T cell activation Inflammation/destruction
Early RA
Early RA
The earliest lesions in rheumatoid synovitis are
A) Micro-vascular injury
Advanced RA
Synovial Immunologic Processes and Inflammation of Advanced Synovium
Rheumatoid Synovium
Rheumatoid Synovium
Hyperplasia and
hypertrophy of the
synovial lining cells
Edema
Synovial Immunologic Processes and Inflammation of advanced synovium
Cells
Cells T cells
Partial amelioration of
A decline in serum RF
signs and symptoms of
titers
inflammation
Cells Mast Cells
FBLS play a critical part in many pathogenic events in the RA synovium. They can contribute to
pathology through a reduced ability to undergo apoptosis (forming pannus), the production of
proteases that degrade the extracellular matrix, and invasion into cartilage. In addition, FBLS
produce a variety of molecules that modulate growth, inflammation, angiogenesis, and cell
recruitment, and induce activation of and cytokine production by immune cells.
Cells Osteoclasts
Cytokines
Cytokines Pro-inflammatory Cytokines
Within the rheumatoid synovium, CD4+ T cells differentiate into TH1- cells
producing the pro-inflammatory IFN-γ and appear to be deficient in differentiation
into TH2-like cells capable of producing the anti-inflammatory cytokine IL-4:
Synovial Fluid
Synovial Fluid
The exudative synovial fluid contains more PMNLs than mononuclear cells.
• Vasoactive mediators (e.g. histamine produced by the mast cells) facilitate the
Once in the synovial fluid, the PMNLs ingest immune complexes, with the resultant:
• Production of large amounts of COX and LOX pathway products by cells in the
synovial fluid and tissue further accentuates the signs and symptoms of
inflammation.
Synovial Immunologic Processes and Inflammation of advanced synovium
Inflamed Synovium
PANNUS
Small blood
Proliferating Inflammatory
vessels
FBLs cells
(angiogenesis)
Systemic Manifestations
Synovial Fluid
Macrophages
• Central effectors of synovitis.
• Clinically effective biologic agents consistently reduce
macrophage infiltration in the synovium.
• Act through release of cytokines (e.g., TNF-α and IL-1, 6,
12, 15, 18, and 23), ROS, nitrogen intermediates,
production of prostanoids and matrix-degrading enzymes,
phagocytosis, and antigen presentation.
Synovial Immunologic Processes
and Inflammation
Innate immune pathway
Neutrophils
• Contribute to synovitis by synthesizing prostaglandins,
proteases, and ROS.
Mast cells
• Produce high levels of vasoactive amines, cytokines,
chemokines, and proteases.
Synovial Immunologic Processes
and Inflammation
Cytokines and Intracellular Signaling Pathways
TNF-α
• Plays a fundamental role through activation of cytokine
and chemokine expression, expression of endothelial-cell
AM, protection of synovial fibroblasts, promotion of
angiogenesis, suppression of regulatory T cells, and
induction of pain
Synovial Immunologic Processes
and Inflammation
Cytokines and Intracellular Signaling Pathways
IL-6
• Local leukocyte activation
• Autoantibody production
• Promote acute phase responses
• Anemia
• Cognitive dysfunction
• Lipid-metabolism dysregulation.
Synovial Immunologic Processes
and Inflammation
Cytokines and Intracellular Signaling Pathways
IL-1 family
• IL-1α, 1β, 18, and 33
• Abundantly expressed in RA
• They promote activation of leukocytes, endothelial cells,
chondrocytes, and osteoclasts.
Synovial Immunologic Processes
and Inflammation
Mesenchymal Tissue Responses
Synovial hyperplasia
Due to altered resistance to apoptosis, which is mediated by
diverse pathways, including:
• Mutations of the tumor-suppressor gene p5363;
• Expression of stress proteins (e.g., heat-shock protein 70),
which foster the survival of FLSs
• Modulation of the function of the endoplasmatic
reticulum by synoviolin, that regulates the balance of cell
proliferation and apoptosis.
Structural Damage
Structur al Damage
Cartilage Damage
RANKL
receptor activator of TNF-α
NF-κB ligand
MC-SF IL-1,6,17