Musculoskeletal 7 - Pathogenesis of Autoimmune Disease Flashcards
1
Q
What is ankylosing spondylitis?
A
- Chronic spinal inflammation that can result in spinal fusion and deformity
- Site of inflammation is the enthesis (enthesitis)
- No autoantibodies (‘seronegative’)
Spondylitis = inflammation of the spine Ankylosing = bone fusing together
2
Q
List the seronegative spondyloarthropathies
A
- Ankylosing spondylitis
- Reiters syndrome and reactive arthritis
- Arthritis associated with psoriasis (psoriatic arthritis)
- Arthritis associated with gastrointestinal inflammation (enteropathic synovitis)
3
Q
What are the associations between HLA and rheumatology?
A
- Rheumatoid arthritis and HLA-DR4
- SLE and HLA-DR3
- Ankylosing spondylitis and HLA-B27
4
Q
What are the functions of MHC class 1 and II?
A
- Class 1 present on all nucleated cells, bind to endogenous antigens (eg. viral peptides) and present to CD8 t cells (response is cell death)
- MHC II on APCs only, exogenous antigens binding to CD4 T cells resulting in antibody response
5
Q
Describe structure of HLA
A
- Peptide-binding site made up of walls (a-helical structures) and floor (beta-pleated sheet)
- Sequence in peptide-binding groove determines which antigens can bind
- T cells and only see antigen bound to MHC (MHC restriction)
6
Q
Describe pathogenesis of HLA-associated disease
A
- Due to 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 Ankylosing Spondylitis
- E.g. antigen and HLA-DR4 triggers CD4 +ve T cell response in Rheumatoid Arthritis
7
Q
Describe significance of HLA in ankylosing spondylitis
A
- No arthritogenic peptide that binds HLA-B27 identified
- If you express human HLA-B27 in rats (i.e. transgenic rats) you get a similar disease that develops in the absence of CD8 +ve T cells
- 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 and this causes cellular stress that triggers interleukin-23 release and 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
- Interestingly these ‘double negative’ T cells have been detected in entheses and this may explain why enthesopathy occurs in Ankylosing Spondylitis, they are very sensitive to cellular stress
8
Q
List key autoantibodies in rheumatology
A
- Rheumatoid arthritis: Rheumatoid factor and anti-cyclic citrullinated peptide antibody
- SLE: Antinuclear antibodies and anti double stranded DNA atibodies
- Diffuse systemic sclerosis: Anti-scl-70
- Limited systemic sclerosis: anti-centromere antibodies
- Dermato/polymyositis: anti-t-RNA transferase antibodies
- Mixed connective tissue disease: anti-U1-RNP antibodies
- None in osteoarthritis, reactive arthritis, gout, or ankylosing spondylitis
9
Q
List autoantibodies in SLE
A
- Antinuclear antibodies in all SLE cases but not specific for SLE
- Anti-dsDNA specific for SLE and the serum level correlates with disease activity. Can be used to monitor the disease progress, alongside complement (which is low in disease)
10
Q
What do antinuclear antibodies react to?
A
- Different types (a lab will perform further tests to determine ANA type)
- Anti-Ro, anti-la, anti-centromere, anti-RNP, andti-dsDNA, anti-Sm
- May be cytoplasmic eg. anti-tRNA synthetase antibodies and anti-ribosomal P antibodies
11
Q
Describe pathophysiology of SLE
A
- Autoantibodies trigger inflammatory cascades by binding via Fc region
- Apoptosis leads to translocation of nuclear antigens to membrane surface
- Impaired clearance of apoptotic cells results in enhanced presentation of nuclear antigens to immune cells
- B cell autoimmunity
- Tissue damage by antibody effector mechanisms (complement activation and Fc receptor engagement)
12
Q
How is RANKL important in rheumatoid arthritis?
A
- RANKL (receptor activator of nuclear factor kB ligand)
- Produced by T cells and synovial fibroblasts in rheumatoid arthritis
- Acts to stimulate osteoclast formation (osteoclastogenesis)
- Upregulated by:
Interleukin-1, TNF-a
Interleukin-17 – potent action on osteoclastogenesis via RANKL-RANK pathway
PTH-related peptide - Binds to ligand on osteoclast precursors (RANK)
13
Q
How are prostaglandins important in rheumatology?
A
- Phospholipase A2 to arachidonic acid, which can enter COX pathway to form prostaglandins or lipooxygenase pathway to form leukotrienes
- Prostaglandins mediate vasodilation, bronchodilation, inhibit platelet aggegation
- Leukotrienes stimulate leucocyte chemotaxis, smooth muscle contraction and bronchoconstrition and mucus secretion
- Mediators of inflammation
14
Q
How are prostaglandins manipulated by treatments?
A
- Glucocorticoids inhibit phospholipase A2
- NSAIDs inhibit COX (analgesia, anti-pyretic, anti-inflammatory and anti-platelet)
15
Q
What is the key cytokine in rheumatoid arthritis?
A
TNF-alpha is the dominant pro-inflammatory cytokine in the rheumatoid synovium
