Pathogenesis of autoimmune disease Flashcards
Rheumatoid arthritis
- Chronic joint inflammation potentially resulting in joint damage
- inflammation site is synovium
- autoantibody association=RHEUMATOID factor and anti-cyclic citrullinated peptide antibodies (CCP)
Anklyosing spondylitis
- Chronic spinal inflammation resulting in spinal fusion and deformity
- inflammation site is enthesis
- no auto-antibodies=’seronegative’
Types of seronegative spondylarthropathies
- ankylosing spondylitis
- reiter’s syndrome and reactive arthritis
- psoriatic arthritis (arthritis associated with psoriasis)
- enteropathic synovitis (arthritis associated with GI inflammation)
SLE
- Chronic tissue inflammation in the presence of self antigen antibodies
- multi-site inflammation=particularly joints, skin and kidneys
- autoantibody assocation=ANTINUCLEAR antibodies and anti-double stranded DNA antibodies
Types of connective tissue diseases
- SLE
- Systemic sclerosis
- Sjogren’s syndrome
- Inflammatory muscle disease=polymyositis, dermatomyositis
- overlap syndromes=mixture of above problems
HLA molecules
HUMAN LEUKOCYTE ANTIGEN
- major histocompatibility complex in humans
- genes within MHC class I and class II regions encode cell surface proteins
Association between MHC and disease:
- rheumatoid arthritis and HLA-DR4=class II
- SLE and HLA-DR3=class II
- Anklyosing spondylitis and HLA-B27=class I
HLA molecule function
- HLA molecules present antigens to T lymphocytes
- Class I on all nucleated cells=CD8+ T cells=cell killing
- Class II on antigen presenting cells=CD4+ T cells=antibody response
- peptide binding site made up of walls (alpha-helical structures) and floor (beta-pleated sheet)
- sequence in peptide-binding groove determines which antigens bind
- T cells only see antigen-bound MHC=MHC restriction
Pathogenesis of HLA-associated diseases/////
-due to peptide antigen (exogenous or self) that is able to bind to HLA molecule and trigger disease=arthritogenic antigen
Examples include:
-antigen and HLA-B27 tirggers CD8+ T cell response in ankylosing spondylitis
-antigen and HLA-DR4 triggers CD4+ T cell response in rheumatoid arthritis
Auto-antibodies in rheumatoid arthritis
- rheumatoid factor
- anti-cylic citrullinated peptide antibody
Auto-antibodies in SLE
- antinuclear antibodies=ALWAYS
- anti-double stranded DNA antibodies=SPECIFIC FOR SLE (serum level correlates with disease activity)
- anti-cardiolipin antibodies (association with risk of arterial and venous thrombosis)
Auto-antibodies in osteoarthritis, reactive arthritis, ankylosing spondylitis and gout
NONE
Auto-antibodies in systemic vasculitis
-Antinuclear cytoplasmic antibodies
Auto-antibodies in diffuse systemic sclerosis
-anti SCl-70 antibody
Auto-antibodies in limited systemic sclerosis
-anti-centromere antibodies
Auto-antibodies in dermato/polymyositis
-anti-tRNA transferase antibodies
Auto-antibodies in Sjogren’s syndrome
No unique antibodies but typically see antinuclear antibodies (anti-Ro and anti-La) and rheumatoid factor
Auto-antibodies in mixed connective tissue disease
-Anti-U1-RNP antibodies
Antinuclear antibodies
- directed against nucleus contents
- if positive for ANA in lab, further tests performed to determine ANA type (screening)
Disease activity in SLE
Sick lupus patient commonly has:
- low complement levels
- high serum levels of anti-ds-DNA antibodies
Current pathogenesis of SLE//////
1) Apoptosis of cells=translocation of nuclear antigens to membrane surface
2) Impaired clearance of apoptotic cells=enhanced presentation of nuclear antigens to immune cells
3) B cell autoimmunity
4) Tissue damage by antibody effector mechanisms=complement activation and Fc receptor engagement
Cytokines in rheumatology
TNFalpha=dominant pro-inflammatory cytokine in rheumatoid synovium and its many (pleotropic) actions are detrimental here:
- chemokine release
- endothelial cell activation
- leukocyte accumulation
- angiogenesis
- osteoclast activation
- PGE2 production
- pro-inflammatory cytokine release
KEY IN RHEUMATOID ARTHRITIS
RANKL
IMPORTANT IN BONE DESTRUCTION IN RHEUMATOID ARTHRITIS
- produced by T cells and synovial fluid fibroblasts in rheumatoid arthritis
- stimulates osteoclastogenesis (osteoclast formation=BREAKS DOWN)
- binds to ligand on osteoclast precursors (RANK)=production
- RANKL action antagonised by osteoprotegerin (decoy receptor)
Upregulated by:
- IL-1, TNFalpha
- IL-17 (potent action on osteoclastogenesis via RANKL-RANK pathway)
- PTH related peptide
Denosumab
- monoclonal antibody against RANKL
- indicated for treatment of osteoporosis, bone metastases, multiple myeloma and giant cell tumours (slowing bone turnover=aim of Tx)
B cell hyper-reactivity/////
- key feature of SLE=modern treatments targeting B cells have been developed (number or turnover)
- Rituximab=chimeric anti-CD20 antibody to deplete B cells
- Belimumab=monoclonal antibody against B cell survival factor BLYS
- shown to be effective in reducing SLE symptoms
Belimumab
- Recombinant fully human IgG1 monoclonal antibody against BLyS (B-lymphocyte stimulator)
- inhibits BAFF activity leading to impaired B cell survival and reduced B cell numbers
Treatment against cytokines
- complex network of pro-inflammatory cytokines in inflammatory cascade=TNFalpha is dominant
- IL-6 and IL-1 blockade available in clinic
- inhibition of TNFalpha
- can also deplete B cells in rheumatoid arthritis by I.V. administration of antibody against CD20 (B cell surface antigen) such as Rituximab
Primary anti-phospholipid antibody syndrome
Anti-cardiolipin antibodies in absence of SLE
Detecting presence of antinuclear antibodies
/
Ankylosing spondylitis and HLA molecules
- no arthritogenic peptide binding to HLA-B27 identified
- Ankylosing spondylitis independent of CD8+ T cells
- new theory suggests due to abnormalities in HLA-B27 and IL-23 pathway
- HLA-B27 has tendency to misfold which causes cellular stress=triggers IL-23 release and IL-17 production by adaptive immune cells (CD4+ Th17 cells) and innate immune cells (CD4-, CD8- T cells=double negative)
- double negative T cells detected in entheses=explanation for enthesopathy occurring in ankylosing spondylitis
Prostaglandins in rheumatology
-lipid mediators of inflammation act on platelets, endothelium, uterine tissue and mast cells
