3 major immunologic features of RA
Rheumatoid factors:
- Autoantibodies against Fc IgG
Infiltration of lymphocytes and activated macrophages into synovium.
Local production of TNF and pro-inflammatory cytokines in synovium
Epidemiology of RA
More common women than men
3:1
Worldwide prevalence
- 1%
Age diagnosed: 40-50
Long term complications of RA
Atherogenesis [complement complexes, IL-6, TNF]
- MI
- Stroke
Fatigue, depression
Decreased bone mineral density/ Susceptibility to fractures
Insulin resistance/ impaired glucose tolerance
Joint damage pattern in RA
Symmetrical, polyarthritic
- Morning stiffness
- Inflammation: swelling, hear, red, pain, loss of function
Bone erosion
Synovitis
Cartilage erosion
Synovitis
Inflammation of the synovium
- The cardinal feature of RA
Features:
- Swelling over extensor tendons, wrists, MCP joints
- Synovium hyperplasia
Synovium fibroblast:
- reduced apoptosis
- enhanced anchorage
- Upregulated adhesion molecules
- Increased proliferation
Composition of synovial tissue
Mainly macrophages and T cells
Fibroblasts
Endothelial cells
B cells + plasma cells
Main pro inflammatory cytokines involved in RA
IL-1
TNF-a
IL-6
IL-17
Role of innate immune cells in RA
Macrophages, mast cells and NK cells invade synovium
- Macrophages: phagocytosis, Ag-presentation, release of TNF, IL-1, IL-6
Neutrophils invade fluid with and undergo enhanced NETosis
Role of T cells in RA
Th17= release of Il-17
- activates synovial fibroblasts and osteoclast= cartilage reabsorption
Th1 cells= release of inflammation cytokines
T reg cells
- Defective (can be reversed by blocking TNF)
Role of B cells in RA
Auto-antibodies are present before onset of symptoms
B cells form follicular and diffuse infiltrates in synovium
Also produce cytokines, and antigen present
Cartilage erosion
- Fibroblasts
- Chondrocytes
Fibroblasts
- Make metalloproteases= break down collagen
- Adhere to and invade cartilage
Chondrocytes
- Undergo apoptosis
All leads to joint space narrowing, biomechanics dysfunction
Bone erosion
Osteoclast differentiation and activation= bone resorption
- IL-17, RANKL, TNF, IL-1, IL-6
- Cytokines inhibit the differentiation of osteoblasts
Pits develop and fill with inflammatory tissue
Sites worse- 2nd and 3rd metacarpal
Rheumatoid factor
- Description
- Prevalence
- Limitations
Antibodies against Fc portion of Ab form immune complex
Present in 60-70%
Limitations
- Not specific (86%), also in other AI disease, Healthy individuals
- Not all RA patients have it
- Levels do not correlate with disease activity
- Positive patients= more severe disease
CCP
Cyclic citrullinated peptide antibody
Found in 60-70% of RA patients
98% specificity:
- Rarely found in healthy people who do not develop RA
Detected in blood many years before onset
Positive= more aggressive clinical course of disease
Citrullination
Process of replacing arginine with citrulline in proteins
If it changes a protein significantly enough, protein can be recognised as foreign and Ab response can occur
Cirullinated self proteins in RA
Ab are made against these proteins in RA:
- Alpha-enolase
- Keratine
- Fibronogen
- Fibronectin
- Collegen
- Vimentin
CCP antibodies role in pathogenesis
Can enhance the development and severity of inflammation when mild synovitis is present (in mice)
Possible mechanisms
- Activation of inflammatory cells by anti-CCP complexes
- Anti-CCP neutrophil cell death= NETs
- Anti-CCPs drive osteoclastogenesis
Genetics and RA
Polygenic: no single gene is necessary or sufficient
Polymorphisms
- HLA etc
Some hereditary factors (monozygotic have higher inheritance than dizygotic)
Hormones and RA
Testosterone are protective
Pregnancy:
- Risk increase after given birth and breastfeeding after first pregnancy
- Remission during pregnancy (increased of Treg cells)
Risk after menopause not affected by HRT
Smoking and RA
Increases risk with HLA-DR4
alleles
Effect of smoking is greater in genetically susceptible individuals (esp. HLA DRB1)
- Increases anti-CCP positive risk
Environmental influences on RA
Smoking
Infections
Periodontitis
Hormones
Rituximab
Partially humanised anti-CD20 monoclonal Ab.
Mechanism
- Opsonised B cells and forms complex which are attacked
Mechanisms of attack
- Complement mediated cytotoxicity
- Ab-dependent Cytotoxicity
- CR mediated opsonic phagocytosis
- Apoptosis
Infliximab
Partially humanised mAb
- Against TNF
- Combined with methotrexate
Mechanism
- Neutralises TNF and stimulates ADCC
Administration
- IV
- 3mg per kg of body weight
- Repeat 2, then 6 weeks, then every 8 weeks
Methotrexate
- Drug type
- Mechanism (4)
- Administration
Synthetic disease modifying anti-rheumatic drug (DMARD)
Mechanism
- Inhibits cell proliferation
- Increases adenosine level (anti-inflammatory)
- Reduces production of damaging polyamine
- Induces apoptosis of activated CD4, CD8
Administration:
- 7.5 and 25mg weekly
- Subcutaneous/ orally
Outcomes
- Reduces inflammation and controls it
- Reduces CVD death in RA
- Anchor drug in combination with other therapies
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Overview24
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Innate immunity 128
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Innate immunity 222
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Adaptive immunity 111
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Adaptive immunity 2+317
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Vaccines41
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Chemokines and cytokines39
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Immunological tolerance25
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Immunological disease classifications19
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Mucosal immunology27
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Autoimmune disease 120
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Autoimmune disease 216
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HIV and AIDS23
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Pharmacology18
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Immunodeficiency17
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Atopy and allergy 117
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Atopy, allergy and delayed type hypersensitivity 221
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Psychoimmunotherapy11
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transplantation immunology19
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RA25
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MT 11
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Hereditary angioedema12
