1 Rheumatoid: Pathogenesis of autoimmune disease Flashcards
(30 cards)
Define Rheumatoid arthritis
Chronic joint inflammation that can result in joint damage
Where is the site of inflammation in rheumatoid arthritis?
synovium (synovitis)
What 2 autoantibodies is Rheumatoid arthritis associated with?
Associated with autoantibodies:
- Rheumatoid factor
- Anti-cyclic citrullinated peptide (anti -CCP) antibodies
Define Ankylosing spondylitis
Where is its site of inflammation?
Chronic spinal inflammation that can result in spinal fusion and deformity (e.g exaggerated kyphosis, loss of normal lumbar lordosis)
- site of inflammation: enthesis (enthesitis)
Note: no autoantibodies
Ankylosing spondylitis is associated/not associated with autoantibodies
Ankylosing spondylitis is not associated with autoantibodies
Define SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
Where is its site of inflammation?
Chronic tissue inflammation in the presence of antibodies directed against self antigens
- excess immune complex formation
- subset/part of connective tissue disease
- site of inflammation: Multi-site (but particularly joints/skin/kidney)
What 2 autoantibodies is SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) associated with?
- Antinuclear antibodies (ANA)
- Anti-double stranded DNA antibodies (anti-dsDNA)
what is the HLA Molecule associated with:
Rheumatoid Arthritis=
Systemic Lupus Erythematosus =
Ankylosing Spondylitis =
Rheumatoid Arthritis = HLA-DR4
Systemic Lupus Erythematosus = HLA-DR3
Ankylosing Spondylitis = HLA-B27
–> important in antigen recognition by T cells
What is the main function of MHC Class I & II molecules?
- presents antigens to T cells
What is the general pathogenesis of HLA associated diseases?
A peptide antigen (exogenous or self) that is able to bind to HLA molecule and trigger disease (‘arthritogenic antigen’)
E.g. antigen and HLA-B27 triggers CD8 +ve T cell response in ___________
E.g. antigen and HLA-DR4 triggers CD4 +ve T cell response in ___________
E.g. antigen and HLA-B27 triggers CD8 +ve T cell response in Ankylosing Spondylitis
E.g. antigen and HLA-DR4 triggers CD4 +ve T cell response in Rheumatoid Arthritis
Describe the possible pathogenesis of Ankylosing Spondylitis
don’t really need to know this - because studies still going on
Currently thought that the disease is due to abnormalities in both HLA-B27 and the interleukin-23 pathway:
HLA-B27 has a propensity to misfold –> causes cellular stress –> triggers interleukin-23 release + triggers interleukin-17 production by:
- Adaptive immune cells i.e. CD4 +ve Th17 cells
- Innate immune cells e.g. CD4 –ve, CD8 –ve (‘double-negative’) T cells
note: double -ve T cell = detected in enthuses –> may explain enthesopathy
which rheumatoid disease are not associated with auto antibodies ?
Osteoarthritis, reactive arthritis, gout, ankylosing spondylitis = all NONE
Note: Autoantibodies in rheumatology
Systemic vasculitis = antinuclear cytoplasmic antibodies (ANCA)
- Diffuse systemic sclerosis: Anti-Scl-70 antibody (aka antibodies to topoisomerase-1)
- Limited systemic sclerosis: Anti-centromere antibodies
- Dermato/polymyositis: Anti-tRNA transferase antibodies E.g. histidyl transferase (anti-Jo-1 antibodies)
- Sjögren’s syndrome: no unique antibodies but typically see:
o ANAs - Anti-Ro + anti-La antibodies
o Rheumatoid factor
- Mixed connective tissue disease: Anti-U1-RNP antibodies
-
If ANA (antinuclear antibodies) are tested positive –> what further tests might you screen for?
Anti-Ro Anti-La Anti-centromere Anti-Sm Anti-RNP Anti-ds-DNA antibodies Anti-Scl-70
Cytoplasmic antibodies include:
- Anti-tRNA synthetase antibodies
- Anti-ribosomal P antibodies
Patients with SYSTEMIC LUPUS ERYTHEMATOSUS commonly has:
- high / low complement levels
- high / low serum anti-dsDNA Antibodies
Patients with SYSTEMIC LUPUS ERYTHEMATOSUS commonly has:
- low complement levels
complement gets consumed –> complement levels go down - high serum anti-dsDNA Antibodies (high immune complex levels)
Describe the general pathogenesis for SYSTEMIC LUPUS ERYTHEMATOSUS
in SLE –> antigen = inside the nucleus
a) Apoptosis –> causes translocation of nuclear antigens to membrane surface
b) Impaired clearance of apoptotic cells –> results in enhanced presentation of nuclear antigens to immune cells
c) causes B cell autoimmunity
d) Tissue damage by antibody effector mechanisms e.g. complement activation and Fc receptor engagement
What are main cytokines involved in rheumatology ?
IL-1 IL-2 IL-6 TNF-a y-IFN
Th1: secrete____ + ____, important in CD8+ cytotoxicity + macrophage stimulation
- Th2: secrete ____(IgE responses), _____ (eosinophils), ____ (B cells–> plasma cells) and ____ (inhibit macrophage response)
- Th17 cells develop in response to ____ + secrete ____ –> which triggers IL-6, IL-8, TNFα, MMPs and RANKL in target cells. –> Important in mucosal immunity but also in arthritis, psoriasis, inflammatory bowel disease, MS
Th1: secrete IL-2 + γ-IFN, important in CD8 +ve cytotoxicity + macrophage stimulation
- Th2: secrete IL-4 (IgE responses), IL-5 (eosinophils), IL-6 (B cells –> plasma cells) and IL-10 (inhibit macrophage response)
- Th17 cells develop in response to IL-23 + secrete IL-17 à triggers IL-6, IL-8, TNFα, MMPs and RANKL in target cells. Important in mucosal immunity but also in arthritis, psoriasis, inflammatory bowel disease, MS
what cytokine is a dominant pro-inflammatory cytokine in rheumatoid synovium?
TNF-a
In rheumatoid arthritis, what cells produce RANKL?
T cells
+
Synovial Fibroblasts
What does RANKL DO?
stimulates osteoclast formation
What is RANKL unregulated by?
- Interleukin-1,
- TNF-a
- Interleukin-17
- -> has potent action on osteoclastogenesis via RANKL-RANK pathway
- PTH-related peptide
How does RANKL Work?
- RANKL Binds to ligand on osteoclast precursors (RANK)
- Action antagonized by decoy receptor – osteoprotegerin (OPG)
