Musc 4 & 5 - Pathogenesis of Autoimmune disease and Rheumatoid Arthritis (RA) Flashcards
What is RA?
RA = Chronic joint inflammation that can result in joint damage
Site of inflammation is the synovium (often referred to as chronic synovitis)
Associated with 2 autoantibodies (Rhematoid factor and CCP antibodies)
Name 4 seronegative spondyloarthropathies
- Ankylosing spondylitis
- Reactive arthritis and Reiters syndrome
- Psoriatic arthritis
- Enteropathic synovitis
What is ankylosing spondylitis
Chronic spinal inflammation that can lead to spinal fusion and deformity
Site of inflammation = enthesis (connective tissue between tendon/ligament and bone - for spinal problems it occurs in vertebral bodies) = ENTHESITIS
It is seronegative (no antibodies)
What is Systemic Lupus Erythematosus (SLE) and what group of diseases does it belong to
SLE = chronic tissue inflammation in the presence of auto-antibodies
Inflammation occurs at various sites - particularly joints, skin and kidney
Associated with 2 antibodies - antinuclear antibodies, anti-double stranded DNA antibodies
SLE is part of the connective tissue diseases - associated w immune complexes and triggering complement system
Which 2 antibodies are involved in lupus
- Antinuclear antibodies
2. Anti-double stranded DNA antibodies
RA is associated with which HLA?
HLA-DR4 (MHC class 2) - i.e. exogenous, CD8
SLE is associated with which HLA?
HLA-DR3 (MHC class 2) - i.e. exogenous, CD8
Ankylosing spondylitis is associated with which HLA?
HLA-B27 (MHC class 1) - i.e. endogenous, CD4
Describe MHC class 1 molecules
HLA -A/B/C
Present on all nucleated cells
Responsible for endogenous (intracellular) antigen presentation
Recognised by CD8+ T cell
Response is cell killing
Describe MHC class 2 molecules
HLA - DR/DQ/DP
Present on antigen presenting cells
Responsible for exogenous (extracellular) antigen presentation
Recognised by CD4+ T cells
Causes antibody response
It is currently thought that Ankylosing Spondylitis is caused by abnormalities in HLA-B27 and IL-23. Explain
- HLA-B27 has a propensity to misfold - which causes cellular stress - which then causes IL-23 release and IL-17 cell production (inflammation) by:
- adaptive immune cells (i.e. CD4+ Th17 cells)
- innate immune cells (i.e. CD4 -ve, CD8 -ve, double negative T cells)
What are the 2 key antibodies in RA?
- Rheumatoid factor
2. Anti-cyclic citrullinated peptide antibody
What are the 2 key antibodies in SLE?
- Antinuclear antibodies (ANA)
2. Anti-double stranded DNA antibodies (anti-dsDNA)
Which autoimmune disorders have no antibodies involved (i.e. seronegative)
- Osteoarthritis
- Reactive arthritis
- Gout
- Ankylosing spondylitis
Which antibodies are involved in systemic vasculitis?
Antinuclear cytoplasmic antibodies (ANCA)
What is sclerosis
Skin thickening
What is the key antibody in diffuse systemic sclerosis?
Anti-Scl-70 antibody
What is the key antibody in limited systemic sclerosis
Anti-centromere antibodies
What is the antibody in dermato-/polymyositis
Anti-tRNA transferase inhibitors
What is the antibody in mixed connective tissue disease
Anti-u1-RNP antibodies
Name 4 connective tissue diseases
- SLE
- Inflammatory muscle disease
- Systemic sclerosis
- Sjogrens syndrome
What is the current paradigm for SLE understanding
Apoptosis = translocation of nuclear antigens to membrane surface
Impaired clearance of apoptotic cells = enhanced presentation of nuclear antigens to immune cells
B cell autoimmunity
Tissue damage by Ab effector mechanisms
What is the key signs of a sick SLE patient
- Low complement levels
2. High serum levels (o anti-dsDNA antibodies)
Which cytokine is one of the major contributors of synovitis
TNF-a
What are the CD4 +ve T helper subsets
Th1, Th2, Th17
What do Th1 cells secrete
IL-2 and y-IFN - important response in CD8+ve cytotoxicity and macrophage stimulation
What do Th2 cells secrete
IL-4 (IgE responses), IL-5 (eosinophils), IL-6 (B cell to plasma cell) and IL-10 (inhibit macrophage response)
What do Th17 cells develop in response to? And what do they secrete
Th17 cells develop in response to IL-23
They secrete IL-17 - potent cytokine which triggers IL-6, IL-6, TNF-a, MMPs and RANKL in target cells
Important in mucosal immunity - also in disease such as arthritis, psoriasis, IBD and MS
Describe y-IFN
Secreted by T-cells, activates macrophages
Describe IL-1
Secreted by macrophages
Activates T cells, fever, pro-inflammatory
Describe IL-2
Secreted by T-cells
Activates T and B cells
Describe IL-6
Secreted by T cells
Activates B cells, acute phase response
Describe TNF-a (dominant cytokine)
Secreted by macrophages
Similar to IL-1
What does TNF-a do in rheumatoid synovium?
Activates synovium, increased synovial fluid production
Where is TNF-a mainly produced?
In rheumatoid synovium by activated macrophages
Some cytokine treatments inhibit TNF-a. What effects does this have
Block of production of IL-1/6, chemokine, IL-8, GM-CSF
Il-1 inhibition is more or less effective than IL-6/TNF-a inhibition?
Less effective, not recommended for RA
In RA, explain the importance of RANKL in bone destruction
- Made by T-cell and synovial fibroblasts –> stimulate osteoclast formation
- Binds to receptor on osteoclast precursors
What is RANKL unregulated by
IL-1, TNF-a, IL-17 (potent)
Also by PTH-related peptide
RANKL action is antagonised by what?
Action of osteoprotegerin (decoy receptor)
Name a monoclonal antibody against RANKL
Denosumab - used for osteoporosis, bone metastases, multiple myeloma and Giant cell tumours
B-cell hyper-reactivity is a key feature of?
SLE
Name 2 biological therapies used to target B cells
- Rituximab - chimeric anti-CD20 Ab which depletes B cells
- Belimumab - monoclonal Ab against B cell survival factor (“BLYS”) - used as add-on therapy - not recommended for severe CNS lupus/lupus nephritis
What type of monoclonal antibody is belimumab
Recombinant fully human IgG1 monoclonal antibody against BLYS(/BAFF)
- works by inhibiting BLYS/BAFF - causes impaired B cell survival and reduced B cell numbers
NSAIDS are used in rheumatology. What are prostaglandins
Prostaglandins = lipid mediators of inflammation that act on platelets, endothelium, uterine tissue and mast cells
How is arachidonic acid synthesises
Phospholipase A2 generated arachidonic acid from diacylglycerol (DAG) in cell membranes
Which 2 pathways does arachidonic acid enter?
- COX pathway - arachidonic acid becomes prostaglandins
2. Lipooxygenase pathway - arachidonic acid becomes leukotrienes
What do prostaglandins do
Mediate vasodilation, inhibit platelet aggregation, bronchodilation, uterine contraction
What do leukotrienes do?
Mediate leukocyte chemotaxis and SM contraction, bronchoconstriction and mucus secretion
Which enzyme do glucocorticoids inhibit?
Phospholipase A2 - hence used in rheumatology (as well as NSAIDS)
What are the unwanted effects of glucocorticoids
Asthma exacerbation, GI ulcers, thrombosis, liver and renal problems
Define RA
Chronic autoimmune disease characterised by pain, stiffness and SYMMETRICAL synovitis of synovial joints
Spinal RA doesn’t mean the lumbar spine, it refers to?
The Atlanta-axial joint
What are the key features of RA
- Chronic arthritis
- Polyarthritis - swelling of many small joints of the hand/wrist
- symmetrical
- early morning stiffness
- joint erosions on radiographs - Extra-articular disease
- Rheumatoid nodules - Rheumatoid factor may be detected in blood
What is rheumatoid factor?
IgM autoantibody against IgG
Which gender is RA more common in?
F
What are the genetic and environmental components of RA?
Genetic: HLA-DRB gene variants which map the DRB-chains associated with RA
Environmental: smoking correlated with RA
What are the most commonly affected joints in RA?
- MTP
- MCP
- PIP
- Wrists
- Knees
- Ankles
Name 2 deformities in the hands that show RA
- Swan neck deformity - hyperextension at PIP, hyperflexion at DIP
- Boutonniere deformity - hyperflexion at PIP
Look at pictures of these to remembr
In RA, where is the primary site of pathology
Synovium
What does tenosynovium wrap around?
Tendon sheaths
Tenosynovitis = damages tendon and impairs function
RA may present with subcutaneous nodules.
T
Occurs in 30% of patient
It is a central area of fibrinoid necrosis surrounded by histiocytes and peripheral layer of connective tissue
Rheumatoid factor antibodies, describe them
- Typically IgM antibodies
- Recognise the Fc portion of IgG as their target antigen
i.e. IgM anti-IgG antibody
This causes RA nodules, etc
However, testing for Rheumatoid factor isn’t diagnostic as 30% of RA is RF negative
In RA, there are antibodies to citrullinated protein antigens (ACPAs/anti-CCPs). What do these do
- They are highly specific for RA (anti-CCP antibody)
- They cause citrullination of peptides, through enzymes called PADs (Peptidyl arginine deiminases). They convert Arginine —-> Citrulline.
ACPA is strongly linked with smoking
Where are PADs (Peptidyl arginine deiminases) found?
In high concentrations in neutrophils and monocytes –> common in inflamed sites (e.g. synovium)
In terms of HLA, when is an individual susceptible?
If they carry a conserved AA sequence in their HLA-DR4 antigen binding groove
Name some extra-articular features of RA
Common: subcutaneous nodules, fever and weight loss
Uncommon: vasculitis, etc
Caused by abnormal cytokine response - usually rapid improvement of symptoms after treating cytokine response
What radiographic abnormalities are present due to RA
Early - juxta-articular osteopenia
Later on - joint erosions at margins of the joint, followed by joint deformity and destruction after that
Describe the composition of synovium
1-3 cell deep
Contains macrophage like phagocytic cells (Type A synoviocyte)
Contains fibroblast-like cells - produce Hyaluronic acid (type B synoviocyte)
Also contains type 1 collagen
Why is synovial fluid viscous
Due to lots of Hyaluronic acid
What are the 2 major constituents of articular cartilage
Type 2 collagen and aggrecan
The pathogenesis of RA is still unclear but, what are some reasons for it?
Synovium becomes a proliferated mass of tissue (Pannus) due to:
- Neovascularisation
- Lymphangiogenesis
- Cytokine imbalance
In the management of RA, what is the treatment goal?
To prevent joint damage
Which 2 medications are given for management of RA
- DMARDS - Disease Modifying Anti-Rheumatic Drugs.
Started early in disease because risk of joint damage worsens with time - “steroid sparing”, safer and better for long term use - Glucocorticoid therapy - used short term, not Long term as too many SEs
There are new biological therapies being developed - Janus kinase inhibitors
What do DMARDs do and name some commonly used DMARDs
DMARDS have complex and slow onset of action
They induce remission (not cure) and prevent joint damage
- they reduce inflammation in synovium
- slow/prevent structural joint damage
EG: Methotrexate, sulphasalazine, hydroxychloroquine, Janus kinase inhibitors
Methotrexate is a DMARD, and has a lot of SEs. Therefore, what must happen?
Requires regular blood test monitoring.
Describe the biological therapies for RA
- Infliximab - anti TNF-a antibody
- Rituximab - B-cell antibody against CD20 antigen (causes B cell depletion)
- Abatacept - modulation of T-cell costimulation
- Tocilizumab or Sarilumab
What is the downside of biological therapy
- Increased infection risk
- Expensive
- TNF-a inhibition = increased susceptibility to mycobacterial infection
- B cell depletion therapy = Hep B reactivation
- B cell depletion therapy - JC virus infection and progressive multifocal leukoencephalopathy
