Describe the causes for auto-immunity?
- Immune responses to self antigens
- Represents a breakdown of immunological tolerance
- Immune reactions to self antigens can occur as part of the controlled inflammatory reaction
Describe the role of cytokines in RA?
Acute- removal of pathogen/tissue repair
-Chronic- Tissue destruction
What is the consequence of chronic inflammation?
- Chronic inflammation causes tissue damage
- Inflammation associated with auto-immunity are chronic, unregulated and persistent
Describe the clinically observed long term complications in patients with RA?
-Liver: Acute phase response Iron redistribution -Fat: free fatty acids, adipocytes -Muscle: Insulin resistance -Blood vessels: Atherogenesis, Myocardial infraction Stroke -Brain: Low stress tolerance -Depression Bone: Low bone mineral density -Fracture
Describe the joint damage in RA?
1) Usually multiple joints in symmetrical fashion
- Morning stiffness
- Swelling, heat, redness and pain
- Loss of function
2) Destructive process
- Bone erosion
- Synovial and cartilage damage
What are the clinical markers of RA?
-Elevated ESR
-Elevated CRP
-Presence of auto-antibodies:
Rheumatoid factor (RF)
Cyclic citrullinated peptide (CCP) antiboides
Describe the role of Rheumatoid factor in RA?
RF are antibodies directed against the FC portion of another antibody leading to immune complex formation
-Presents in 6060-70% of the patients with RA
What are the limitations of RF in diagnosing RA?
- Not specific for RA (also present in other auto-immune diseases , infectious diseases and healthy individuals
- Some RA patients are seronegative
- Levels do not correlate with disease activity
- RF +ve patients have a more severe disease
What is the role of anti-cyclic citrullinated peptide (CCP) antibody in diagnosis of RA?
- Antibodies directed against CCP are found in 60-70% of the patients with RA
- Very rarely found in healthy people who do not go on to develop RA
- Detectable in blood many years before the disease onset
- Anti CCP +ve has more aggressive clinical course of disease
Describe the role of citrullination in RA?
- Process of replacing protein arginnine residues with citrulline residue
- Occurs normally in the body but if occurs on an unusual part of the protein, they may be recognised as foreign leading to antibody response
What is the etiology of RA?
Genes- autoimmune disease
- Immune dysfunction
- Environment
Describe the genetics of RA?
- Relatively low gene penetrance
- no particular gene
- susceptibility and severity is determined by a combination of genes
- Must be other factors in addition to genetics that have a role in the susceptibility and severity of autoimmune disease
Name the genes associated with RA?
- HLA-DRB1 SE: Human leukocyte antigen accounts for 30-50% the overall genetic risk
- PTPN22 - Negative regulator of antigen receptor signalling in T and B cells (protein tyrosine phosphatsase 22)
- CTLA4: co-stimulation supressor that regulates interactions between T cells and antigen presenting cells (down regulated in RA)
- TFAAIP3: inhibitor of NF-kB and TNF a mediated apoptosis (down regulated in RA)
what are the roles of hormones in R diagnosis?
- Men have low testosterone
- RA patients experience remission during pregnancy with less disease activity and increased T regulatory cells
- Risk of RA is elevated after giving birth
- Early menopause has been associated with both an increased of risk of RA
- Use of oral contraceptives modestly decreases risk of ACPA+RA
- Mixed data on HRT
What is the role of smoking in RA?
- Heavy smoking of both sexes increases the of RA
- Smoking and HLA-DRB1 alleles increase the risk of being anti- CCP+ve
Describe the molecular mechanism of joint destruction?
- Swelling over extensor tendons, writs and MCP joints
- Synovium hyperplasia ( an increase in cell numbers)
- Synovial fibroblasts have reduced apoptosis, enhanced anchorage, up regulated adhesion molecules and increased proliferation
Describe the joint pathology in RA?
- Pannus- inflamed synovial membrane
- Synovial fluid: rich in neutrophils
- Synovitis
- Cartilage erosion
- Bone erosion
Describe the composition of synovial tissue?
- Macrophages (40%)
- T lymphocytes (40%)
- B lymphocytes and plasma cells (5%)
- Fibroblasts and endothelial cells (10-15%)
Describe osteoblast bone erosion?
- Cytokines including IL-17, RANKL, TNF -alpha, IL-1 and IL-6 promote osteoclast differentiation and activation
- Little repair as cytokines inhibit the differentiation of osteoblast
- Deep bone resorption pits develop, which become filled with inflammatory tissue
- Worse at mechanically vulnerable sites, such as the 2nd and 3rd metacarpal
- 80% of the RA patients within 1 year of diagnosis
Describe mechanism if cartliage erosion?
- Fibroblasts make matrix metalloproteases MMO which break down the collagen network in the cartilage
- Chondrocytes undergo apoptosis
- Fibroblasts adhere to an invade the cartilage
- Leads to bio- mechanical dysfunction and joint space narrowing
What are the role of T cells in RA?
- Human Leukocyte antigen (HLA) association suggest T cell role
- RA synovium is rich in activated T cells (Th17 cells and Th1 cells predominate)
- Increasingly Th17 cells have been suggested as a major pathogenic subset
What is the role of IL17 is known to?
- Activate synovial fibroblast and osteoclast
- Favour cartliage resorption
- T regulatory cells are enriched in RA joint but appear to be a defect that can be reversed by blocking TNF
What are the roles of B cells in RA?
- Auto-antibodies associated with disease are usually present before the onset of symptoms
- B cells form diffuse or follicular infiltrates in the RA synovium
- B cells depletion using monoclonal anti-CD20 is effective treatment
- B Cells also produce cytokines and are important for antigen presentation
What are the roles of innate immune cells in RA?
- Infiltrating macrophages, mast cells and NK cells in the synovium
- Macrophages appear to be key effectors:
1) phagocytosis
2) Antigen presentation
3) TNF, IL-1 and IL-6
