Pathogenesis of Autoimmune Disease (12.02.2020) Flashcards
What is RA?
SYNOVITIS
- Chronic joint inflammation that can result in joint damage
- Site of inflammation is the synovium
- Associated with autoantibodies:
- Rheumatoid factor
- Anti-cyclic citrullinated peptide (CCP) antibodies
Ankylosing spondylitis
ENTHESITIS
- Chronic spinal inflammation that can result in spinal fusion and deformity
- Site of inflammation is the enthesis
- No autoantibodies (‘seronegative’)
Name seronegative spondyloarthropathies.
Ankylosing spondylitis
Reiters syndrome and reactive arthritis
Arthritis associated with psoriasis (psoriatic arthritis)
Arthritis associated with gastrointestinal inflammation (enteropathic synovitis)
What is SLE?
IMMUNE COMPLEXES
- Chronic tissue inflammation in the presence of antibodies directed against self antigens
- Multi-site inflammation but particularly the joints, skin and kidney
- Associated with autoantibodies:
- Antinuclear antibodies
- Anti-double stranded DNA antibodies
What diseases belong to the group of connective tissue diseases?
- Systemic lupus erythematosus
- Inflammatory muscle disease: polymyositis, dermatomyositis
- Systemic sclerosis
- Sjogren’s syndrome
- A mixture of the above: ‘Overlap syndromes’
HLA associated with RA
HLA-DR4
HLA associated with SLE
HLA-DR3
HLA associated with ankylosing spondylitis
HLA-B27
HLA molecules in AI disease
- if you have the HLA it does not mean you have or will have the disease
- if you have the disease you are likely to have the specific HLA associated with it.
- HLA molecules are important for recognition of antigens by T-cells
- HLA molecules were first recognised on human white cells – hence termed human leucocyte antigens (‘HLA’)
MHC I vs MHC II
MHCI
- HLA-A/B/C
- found on all nucleated cells
- endogenous/intracellular AG (viral peptides, tumour antigens, self-peptides)
- CD8 +ve T cell
- response: cell killing
MHCII
- HLA-DR/DQ/DP
- found on specific antigens presenting cells (B-cells, monocytes, dendritic cells)
- exogenous/extracellular AG (bacterial peptides, self peptides)
- CD4 +ve T cell
- response: AB response
What is the structure of the peptide binding sequence like?
- Peptide-binding site made up of walls (α-helical structures) and floor (β-pleated sheet)
- Sequence in peptide-binding groove determines which antigens can bind
- T cells only see antigen-bound to MHC (‘MHC restriction’)
Pathogenesis of HLA-associated disease
- ? 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
HLA molecules and pathogenesis in ankylosing spondylitis
- 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
- > So need new hypothesis!
- 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 Spondyliti
What are the autoantibodies in RA?
- RF
- Anti-cyclic citrullinated peptide antibody
also termed antibodies to citrullinated peptide antigens (ACPA)
What are the autoantibodies in SLE?
- ANA (antinuclear antibodies)
- anti-dsDNA
(- Anti-cardiolipin antibodies
also termed anti-phospholipid antibodies and associated with risk of arterial and venous thrombosis in SLE; may also occur in absence of SLE in what is termed the ‘primary anti-phospholipid antibody syndrome)
Which of the following diseases have autoantibodies and which ones don’t?
RA SLE OA rA AS Gout Systemic vasculitis Diffuse systemic sclerosis Limited systemic sclerosis Dermato-/Polymyositis Sjögren’s syndrome Mixed connective tissue disease
RA (RF, ACPA)
SLE (ANA, anti-dsDNA, anti-cardiolipin)
Systemic vasculitis (ANCA -> Antinuclear cytoplasmic antibodies)
Diffuse systemic sclerosis (Anti-Scl-70 antibody)
Limited systemic sclerosis (Anti-centromere antibodies)
Dermato-/Polymyositis (Anti-tRNA transferase antibodies)
Sjögren’s syndrome (No unique antibodies but typically see ANA: Anti-Ro and anti-La antibodies and RF)
Mixed connective tissue disease (Anti-U1-RNP antibodies)
OA, rA, AS and gout do not have autoantibodies.