Pathogenesis of Autoimmune Disease Flashcards Preview

Y2 LCRS 2 - Musculoskeletal - Laz COPY > Pathogenesis of Autoimmune Disease > Flashcards

Flashcards in Pathogenesis of Autoimmune Disease Deck (41)
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1
Q

Define Rheumatoid Arthritis

A
  • Chronic autoimmune disease characterised by pain, stiffness and symmetrical synovitis of synovial joints
2
Q

What is the site of inflammation in rheumatoid arthritis?

A
  • Synovium
3
Q

What are the two main autoantibodies that are associated with rheumatoid arthritis?

A
  • Rheumatoid factor
  • Anti-cyclic citrullinated peptide antibody
4
Q

Other than at joints, where else is synovium found?

A
  • Around tendons (tendosynovium)
5
Q

Define Ankylosing Spondylitis

A
  • Chronic spinal inflammation that can result in fusion and deformity
6
Q

What is the site of inflammation in ankylosing spondylitis?

A
  • Entheses – where a ligament or a tendon inserts into bone
7
Q

What family of diseases is ankylosing spondylitis a part of?

A
  • Seronegative spondyloarthropathies
8
Q

Which other diseases fall into the family of diseases known as seronegative spondyloarthropathies?

A
  • Reiter’s syndrome
  • Reactive arthritis
  • Psoriatic arthritis
  • Enteropathic synovitis
9
Q

Apart from the site of inflammation and disease, how does the pathophysiology of ankylosing spondylitis differ from that of rheumatoid arthritis?

A
  • Ankylosing sponylitis is seronegative
  • Whereas rheumatoid arthritis is seropositive as it involves autoimmunity with the rheumatoid factor and anti-cyclic citrullinated peptide autoantibodies
10
Q

Describe how ankylosing spondylitis may present in patients and why

A
  • Patients may have exaggerated thoracic kyphosis
  • Due to fusion of vertebrae as a result of chronic spinal inflammation
  • Also pain in the back
11
Q

Define Systemic Lupus Erythematosus (SLE)

A
  • Chronic tissue inflammation in the presence of antibodies directed at self-antigens NOTE: it is inflammation of sterile tissue
  • It involves anti nuclear antibodies and immune complexes attacking the DNA, it can even involve anti-double stranded DNA antibodies
  • It causes systemic inflammation due to the ubiquitous nature of immune complexes
12
Q

Lupus causes multi-site inflammation but state some sites that are particularly badly affected.

A
  • Joints
  • Skin
  • Kidneys
13
Q

What are the two autoantibodies that are associated with lupus?

A
  1. Anti-nuclear antibodies
  2. Anti-double stranded DNA antibodies
14
Q

1) What family of diseases is lupus a part of?
2) What other diseases are part of this family?

A

1)

  • Connective tissue diseases

2)

  • Systemic sclerosis (diffuse and localised)
  • Polymyositis/Dermatomyositis
  • Sjogren’s syndrome
  • Mixed connective tissue disease
15
Q

What is Sjogren’s syndrome?

A
  • An autoimmune disease that targets the exocrine glands (e.g. lacrimal glands)
16
Q

What are the MHC associations of rheumatoid arthritis, ankylosing spondylitis and SLE?

A
  • SLE – HLA-DR3 therefore MHIC II
  • Rheumatoid arthritis – HLA-DR4 - therefore MHC II
  • Ankylosing spondylitis – HLA-B27 - therefore MHC I
17
Q

On which chromosome is HLA encoded?

A
  • Chromosome 6
18
Q

A change in which class of MHC is associated with rheumatoid arthritis, ankylosing spondylitis and SLE?

A
  • Ankylosing spondylitis = Class 1
  • Rheumatoid Arthritis + SLE = Class 2
19
Q

Which cells express class I MHC and which cells recognise this class of MHC?

A
  • All nucleated cells (they display endogenous antigens)
  • They are recognised by CD8+ T cells
20
Q

Which cells express class II MHC and which cells recognise this class of MHC?

A
  • Antigen presenting cells e.g. macrophages, dendritic cells (they display exogenous antigens)
  • Recognised by CD4+ T cells
21
Q

How does HLA-B27 cause ankylosing spondylitis?

A
  • Ankylosing spondylitis is independent of CD8+ T cells
  • HLA-B27 has a propensity to misfold, which causes cellular stress and triggers the release of IL-23 and IL-17 by adaptive immune cells (CD4+ Th17 cells) and innate immune cells (CD4- and CD8- double negative innate immune cells)
  • The release of chemical mediators leads to inflammation
  • The cellular stress is most likely to occur in innate immune cells (the double negative CD4- and CD8- ) and these are present in the entheses – hence why ankylosing spondylitis causes enthesitis
22
Q

What is the key autoantibody in:

1) Diffuse systemic sclerosis
2) Limited systemic sclerosis
3) Dermatomyositis/Polymyositis
4) Mixed connective tissue damage

A

1) Diffuse systemic sclerosis - Anti-Scl-70 antibody
2) Limited systemic sclerosis - Anti-centromere antibody
3) Dermatomyositis/Polymyositis - Anti-tRNA transferase antibody
4) Mixed connective tissue disease - Anti-U1-RNP antibody

23
Q

What is the difference in the specificity of the autoantibodies in SLE?

A
  • Anti-nuclear antibodies are found in all cases of SLE but isn’t specific to SLE
  • Anti-dsDNA antibodies are specific to SLE – serum level of this antibody correlates with disease activity
24
Q

How is the presence of anti-nuclear antibodies detected?

A

Some cells are permeabilised so the antibodies can enter the cell and then the patient’s serum is washed over the cells If there are anti-nuclear antibodies, they will bind to the nuclear antigens

25
Q

What are the features of a sick lupus patient in terms of complement levels and serum levels of anti-dsDNA antibodies?

A
  • Low complement levels
  • High serum levels of anti-dsDNA antibodies
26
Q

Outline the pathophysiology of SLE

A
  • Apoptosis leads to the translocation of nuclear antigens onto the surface of the cell so that they are accessible to the immune system
  • In lupus, apoptotic cells are not cleared normally
  • This impaired clearance enables abnormal presentation to the immune system
  • The immune response is amplified through B cells, which upon recognition of these nuclear antigens, begiin producing anti-nuclear antibodies
  • Tissue damage by antibody effector mechanisms e.g. complement activation and Fc receptor engagement
  • These effects are widepspread due to circulation of the immune complexes
27
Q

In SLE (systemic lupus erythomatus), there are < 100 posssible ANA-nuclear antigen interactions

Give 2 examples of cytoplasmic antibodies hwhich are anti-nuclear antibodies

A
  1. Anti-tRNA synthetase antibodies
  2. Anti-ribosomal P antibodies
28
Q

State 5 important cytokines in rheumatology, and for each, mention where they are produced and their functions

A
  • IL-1 – produced by macrophages - activates T cells, fever + pro-inflammatory
  • IL-2 – produced by T cells – activates T + B cells
  • IL-6 – produced by T cells – activates B cells + acute phase response
  • TNF-alpha – produced by macrophages – similar to IL-1 but more destructive
  • Gamma-IFN – produced by T cells – activates macrophages
29
Q

TNF-alpha is highly involved in rheumatoid arthritis, it has pleiotropic (many different) effects which may be detrimental and contribute to the pathogenesis in rheumatoid arthritis, give 3 of its effects that contribute to its role in Rheumatoid Arthritis

A
  1. Activates osteoclasts - erodes the bone
  2. Activate synoviocytes - joint inflammation and swelling (due to increased production of synovial fluid)
  3. Activate chondrocytes - cartilage degradation
30
Q

Blockage of which cytokine with biological therapy has proven to be very effective in reducing some of the negative effects of rheumatoid arthritis and what does biological therapy mean - i.e. what is involved?

A
  • TNF-alpha
  • Biological therapy - monoclonal antibodies that neutralise the effects of TNF-alpha
31
Q

What is RANKL produced by and what does it do?

A
  • RANKL is produced by T-cells and synovial fibroblasts It stimulates osteoclast formation
32
Q

What can upregulate RANKL production?

A
  • IL-17
  • IL-1
  • TNF-alpha
  • PTH-related peptide
33
Q

What decoy receptor antagonises the action of RANKL?

A
  • Osteoprotegrin (OPG)
34
Q

Name a monoclonal antibody that targets RANKL

A
  • Denusomab
35
Q

Other than cytokine blockade, what else can be targeted to improve symptoms in rheumatoid arthritis?

A
  • B-cell depletion (B cell hyperactivity is a key feature of SLE)
36
Q

State two drugs that deplete B cells and specify what they target

A
  1. Rituximab – anti-CD20 monoclonal antibody
  2. Belimumab – anti-BLYS monoclonal antibody (BLYS is a B cell survival factor)
37
Q

What are the effects of prostaglandins produced by COX?

A
  • Vasodilation
  • Inhibit platelet aggregation
  • Bronchodilation
  • Uterine contraction
38
Q

What are the effects of leukotrienes produced by lipooxygenase?

A
  • Leukocyte chemotaxis
  • Smooth muscle contraction
  • Bronchoconstriction
  • Mucous secretion
39
Q

Starting from the starting molecule Phospholipase A2 and what molecules are needed for formation of phospholipase A2, detail how you get to and then detail both divergent pathways that can occur to form 2 different types of molecules and mention what these are

A
  1. Phosholipase A2 requires essential fatty acids
  2. Phospholipase A2 forms Arachidonic acid from diacylglycerol from cell membranes. Arachidonic acid is the immediate precursor to 2 divergent pathways
  3. You can go down the prostaglandin pathway through cyclooxygenase (COX 1 + 2) enzymes
  4. Or you can go down the leukotriene pathway through lipooxygenase enzymes
40
Q

What do glucocorticoids inhibit?

A
  • Phospholipase A2
41
Q

Why might you use NSAIDs as part of the management of rheumatoid arthritis?

A
  • Because they are analgaesic so relieve some pain
  • Because they are anti-inflammatory so reduce the inflammation