Pathogenesis of autoimmune disease Flashcards
List 3 key autoimmune disorders
Rheumatoid arthritis
Ankylosing spondylitis
Systemic Lupus Erythematosus (SLE)
What is rheumatoid arthritis
Is it associated with autoantibodies? If so, which
Chronic joint inflammation that can result in joint damage
Site of inflammation is the synovium (chronic synovitis)
Associated with autoantibodies:
- Rheumatoid factor
- Anti-cyclic citrullinated peptide (CCP) antibodies
What is ankylosing spondylitis.
Is it associated with autoantibodies? If so, which
Chronic spinal inflammation that can result in spinal fusion and deformity
Site of inflammation is the enthesis (area where ligaments or tendons insert into bone e.g. intervertbral disks and the achilles tendon)
No autoantibodies (‘seronegative’)
Ankylosing spondylitis is an example of which type of disease? List other types of this disease
SERONEGATIVE SPONDYLOARTHROPATHIES
- Ankylosing spondylitis
- Reiters syndrome and reactive arthritis
- Arthritis associated with psoriasis (psoriatic arthritis)
- Arthritis associated with gastrointestinal inflammation (enteropathic synovitis)
What is systemic lupus erythematosus (SLE)?
Is it associated with autoantodies?
Chronic tissue inflammation in the presence of antibodies directed against self antigens (creating of IMMUNE COMPLEXES)
Multi-site inflammation
Multi-site inflammationociated with autoantibodies:
Antinuclear antibodies
Anti-double stranded DNA antibodies
SLE is multi-site inflammation but particularly affects which tissues
Multi-site inflammation but particularly the joints, skin and kidney
SLE comes under which kind of disease. Give other examples
CONNECTIVE TISSUE DISEASES
Systemic lupus erythematosus
Inflammatory muscle disease: polymyositis, dermatomyositis
Systemic sclerosis
Sjogren’s syndrome
A mixture of the above: ‘Overlap syndromes’
Outline the HLA types associated with
Rheumatoid arthritis, SLE and ankylosing spondylitis
Rheumatoid Arthritis HLA-DR4
Systemic Lupus Erythematosus HLA-DR3
Ankylosing Spondylitis HLA-B27
Why are certain HLA associated with autoimmune disease
The MHC molecule is responsible for antigen presentation
There is a certain type of MHC that is associated with these autoimmune diseases - some MHC molecules can present the antigen in such a way that you get more of an immune response being generated
What determines whether a T cell will see an antigen
Sequence in peptide-binding groove determines which antigens can bind
T cells only see antigen-bound to MHC (‘MHC restriction’)
Outline where class I MHC is present and the function
Class 1 on all nucleated cells present endogenous antigens….
CD8 +VE T cell
Response it cell killing
Outline where class II MHC is present and the function
On APCs presenting exogenous antigens….. CD4+VE T cell
Leads to antibody response
Where are HLA molecules encoded
encoded in a gene locus called the major histocompatibility complex. They encode surface proteins. There are various serotypes.
Outline the HLA types associated with each MHC class
The HLA gene locus codes for which part of the MHC molecule
MHC Class I: HLA A, B or C
MHC Class II: DR molecules
HLA codes for the alpha chains in the MHC molecule
The beta-2 microglobulin of MHC comes from a different gene locus
Which MHC class is RA, SLE and AS associated with
Rheumatoid arthritis and SLE are associated with MHC class II molecules
*Ankylosing spondylitis is associated with MHC class I molecules
What is the strucutre of MHC
Peptide-binding site made up of walls (α-helical structures) and floor (β-pleated sheet
Outline the concept of MHC restriction
T-cells can recognise antigen when it is complexed In HLA molecules
This is referred to as MHC restriction
T/F ankylosing spondylitis is CD8 cell dependent
So
HLA-B27 binds antigens, and this triggers CD8+ T cells
This was thought to be the basis of ankylosing spondylitis
However, in mice, the CD8+ T cells were removed, and the rats still showed disease, so this theory cannot be correct
Outline the proposed theory for ankylosing spondylitis
HLA-B27 has a propensity to MISFOLD, which causes cellular stress that triggers IL-23 release and triggers IL-17 production by:
Adaptive immune cells e.g. CD4+ cells, Th17 cells
Innate immune cells e.g. CD4- + CD8- (double negative) T cells
This release of chemical mediators leads to inflammation
What is the proposed reason for akylosing spondylitis occurring in enthesis
The innate cells which release IL-23 and IL-17 due to HLA-B27 misfolding (causing cellular stress)
are present in the entheses and this may explain why enthesopathy occurs in ankylosing spondylitis
Outline the overall 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 (although no arthritogenic peptide for HLA-B27 has been identified)
E.g. antigen and HLA-DR4 triggers CD4 +ve T cell response in Rheumatoid Arthritis (an example is citrullinated peptides)
What are the important autoantibodies in:
- Rheumatoid arthritis
- SLE
- Osteoarthritis
- Reactive arthritis
- Gout
- Ankylosing spondylitis
- Rheumatoid factor, ACPA
- Antinuclear antibodies, anti-double stranded DNA antibodies, anti-cariolipin antibodies
- None
- None
- None
- None
The anti-Scl-70 autoantibody is key for which disease
The anti-centromere antibody is key in which disease
Which autoantibody is key for dermato-polymyositis
Which autoantibody is key for mixed connective tissue disease
Diffuse systemic sclerosis
Limited systemic sclerosis
Anti-tRNA transferase antibodies
Anti-U1-RNP antibodies
State the significance of antinuclear antibodies (ANA)
Seen in all SLE cases
Not specific for SLE
State the significance of anti-dsDNA autoantibody
Specific for SLE
Serum level of antibody correlates with disease activity
State the significance of the anti-cardiolipin autoantibody
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
What can help to differentiate between connective tissue diseases such as lupus, systemic sclerosis, inflammatory muscle disease (polymyositis, dermatomyositis ) etc.
ANAs could signal the body to begin attacking itself which can lead to autoimmune diseases, including lupus, scleroderma, Sjögren’s syndrome, polymyositis/dermatomyositis, mix.
It is important to then get the more specific tests such as anti-centromere (+ve in Limited systemic sclerosis) or anti-dsDNA (+ve in SLE) to determine the exact disease
Most of these autoantibodies are affecting inside the nucleus but some affecting the cytoplasm (e.g. Anti-tRNA synthetase antibodies
Anti-ribosomal P antibodies… obvious as these appear in the cytoplasm)
What will happen to complement levels and anti-ds-DNA levels in a SLE patient who is currently sick
Low complement levels (as the complement is ‘consumed’ by the immune complexes)
High serum levels of anti-ds-DNA antibodies
Outline the current pathogenesis model in SLE
How can autoantibodies be made against antigens within the nucleus
Physioogically, apoptosis leads to translocationof nuclear antigens to membrane surface
In SLE there is then impaired clearance of apoptotic cells resulting in enhanced presentation of nuclear antigens to immune cells
There is B cell autoimmunity
There is tissue damage by antibody effector mechanisms e.g. complement activation and Fc receptor engagement
Subsets of CD4+ T helper clels
Th1, Th2 and Th17
Function of Th1
Th1 cells secrete IL-2 and γ-IFN and response is important in CD8 +ve cytotoxicity and macrophage stimulation
Function of Th2
Th2 cells secrete IL-4 (IgE responses), IL-5 (eosinophils), IL-6 (B cells to plasma cells) and IL-10 (inhibit macrophage response)
Function of Th17
develop in response to IL-23 and secrete IL-17, a potent cytokine which triggers IL-6, IL-8, TNFα, matrix metalloproteinases and RANKL in target cells. Important in mucosal immunity but also in disease including arthritis, psoriasis, inflammatory bowel disease and multiple sclerosis
Which cells are the following cytokines predominately released by and to what effect:
γ-IFN IL-1 IL-2 IL-6 TNF-a
γ-IFN- T cells. Activates macrophages
IL-1 - Macrophage. Activates T cells, fever, pro-inflame.
IL-2- T cell. Activates T and B cells
IL-6- T cell. Activates B cells and the acute phase response
TNF-a- Macrophage. Like IL-1, more destructive
How is TNFa relevant to rheumatology
The cytokine tumour necrosis factor-alpha (TNFα) is the main cause of rheumatoid synovitis. Downregulation of it is disease modifying
Produced by activated macrophages in rheumatoid synovium.
PLEITROPIC: Bone erosion, pain/swelling, joint space narrowing due to effects on osteoclasts, synovioctes and chondrocytes.
Which are the key inflammatory cytokines
IL-1, IL-2, IL-6 and TNF-a
Which cytokines can be targeted in practice
IL1, IL6 and TNF-a
Why might chronic inflammation have its own vascular supply
Due to TNFa allowing angiogenesis.
It also causes endothelial cell, osteoclast activation
In addition to cytokine blockade, what other modulation can we do in rheumatoid arthritis
In addition to cytokine blockade, we can also deplete B cells in rheumatoid arthritis by parenteral (intravenous) administration of an antibody against a B cell surface antigen, CD20
Similar to this is denosumab (antibody against RANKL) used in osteoporosis treamtnet
I.e
Outline the importance of RANKL in rheumatoid arthritis
RANKL is important in bone destruction in rheumatoid arthritis
Produced by T cells and synovial fibroblasts in rheumatoid arthritis
OsteoClastogenesis
Upregulated by IL-1, TNFa, IL17 and PTH related peptide
What is the indication for denosumab
DENOSUMAB – monoclonal antibody against RANKL
indicated for treatment of osteoporosis, bone metastases, multiple myeloma and Giant cell tumours
i.e not used in rheumatoid
How has SLE been therapeutically targeted
B cell hyper-reactivity is key feature of SLE
Hence biological therapies targeting B cells have been used in the treatment of SLE
(it is immune complex mediated and b cells are important!)
Give examples of drugs used in SLE treamtnet
Rituximab – a chimeric anti-CD20 antibody used to deplete B cells
Belimumab - a monoclonal antibody against a B cell survival factor call BLYS
Explain what happens with the spine in ankylosing spondylitis
exaggeration of thoracic kyphosis, loss of lumbar lordosis
What types of compounds are prostaglandins, and what are they made from
LIPIDS, and they are made from fatty acids
Which two substances can be made from arachidonic acid, and how
Common: phospholipase A2 generates AA from DAG.
Then, AA can become:
- Prostaglandins, via AA using COX pathway
- Leukotrienes, via AA using LOX pathway
What are the functions of the following prostaglandins:
PGI2
PGE2
PGF2a
PGI2: vasodilation, inhibit platelets, bronchodilation
PGE2: bronchodilation
PGF2a: uterine contractions
What is the function of leukotrienes, produced using LOX
Leukotrienes mediate:
- Leukocyte chemotaxis
- Smooth muscle contraction, bronchoconstriction and mucus secretion
Which leukotriene mediates leucocyte chemotaxis
LTB4
Which drugs can be used to target prostaglandins/leukotrienes
- GC inhibits phospholipase A2
2. NSAIDs inhibit COX
Benefits and unwanted effects of NSAIDs
Benefit:
- antipyretic
- analgesic
- anti-inflammaotry
- anti-platelet
Unwanted:
- peptic ulcer
- asthma exacerbation
- thrombosis
- liver and renal problems
What are the agonist and antagonist of the RANK recepetor
RANKL is agonist
Action antagonized by decoy receptor – osteoprotegerin (OPG)
