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Musculoskeletal > Pathogenesis of Autoimmune Disease > Flashcards

Pathogenesis of Autoimmune Disease Flashcards

1
Q

Define Rheumatoid Arthritis.

A

Chronic autoimmune disease characterised by pain, stiffness and symmetrical synovitis of synovial joints

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2
Q

What is the site of inflammation in rheumatoid arthritis?

A

Synovium

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3
Q

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

A
  1. Rheumatoid factor

2. Anti-cyclic citrullinated peptide (CCP) antibody

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4
Q

Other than at joints, where else is synovium (synovial membrane) found?

A

Around tendons (tenosynovium)

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5
Q

Define Ankylosing Spondylitis.

A

Chronic spinal inflammation that can result in fusion and deformity

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6
Q

What is the site of inflammation in ankylosing spondylitis?

A

Entheses – where a ligament or a tendon inserts into bone

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7
Q

What family of diseases is ankylosing spondylitis a part of?

A 
Seronegative spondyloarthropathies 
No autoantibodies (‘seronegative)
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8
Q

Which other diseases fall into this seronegative spondyloarthropathies family of diseases?

A
  1. Reiter’s syndrome and reactive arthritis
  2. Psoriatic arthritis
  3. Enteropathic synovitis
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9
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

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10
Q

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

A

Joints, Skin and Kidneys

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11
Q

What are the two autoantibodies that are associated with lupus?

A

Anti-nuclear antibodies

Anti-double stranded DNA antibodies

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12
Q

What family of diseases is lupus a part of?

A

Connective tissue diseases

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13
Q

What other diseases are part of this Connective tissue diseases family?

A
  1. Systemic sclerosis (diffuse and localised)
  2. Polymyositis/Dermatomyositis
  3. Sjogren’s syndrome
  4. Mixed connective tissue disease
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14
Q

What is Sjogren’s syndrome?

A

An autoimmune disease that targets the exocrine glands (e.g. lacrimal glands)

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15
Q

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

A

Rheumatoid arthritis – HLA-DR4
SLE –HLA-DR3
Ankylosing spondylitis – HLA-B27

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16
Q

On which chromosome is HLA encoded?

A

Chromosome 6

17
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

18
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 (cytotoxic)
-intracellular antigens are recognised and repose is to kill them

19
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
-response is antibody response

20
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 and innate immune cells

-release of chemical mediators leads to inflammation

The cellular stress is most likely to occur in innate immune cells and these are present in the entheses ( connective tissue between tendon or ligament and bone)
– hence why ankylosing spondylitis causes enthesitis

21
Q

What is the key autoantibody in:

a. Diffuse systemic sclerosis
b. Limited systemic sclerosis
c. Dermatomyositis/Polymyositis
d. Mixed connective tissue damage

A

a. Diffuse systemic sclerosis
Anti-Scl-70 antibody

b. Limited systemic sclerosis
Anti-centromere antibody

c. Dermatomyositis/Polymyositis
Anti-tRNA transferase antibody

d. Mixed connective tissue disease
Anti-U1-RNP antibody

22
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

23
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

24
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

25
Q

How do antinuclear antibodies react with nuclear antigens, which are found within the nucleus?

A
  1. Apoptosis leads to the translocation of nuclear antigens onto the surface of the cell so that they are accessible to the immune system
  2. In lupus, apoptotic cells are not cleared normally
  3. This impaired clearance enables abnormal presentation to the immune system
  4. The immune response is amplified through B cells
  5. Tissue damage by antibody effector mechanisms e/g complement activation and Fc receptor engagement
26
Q

State some important cytokines in rheumatology.

A

IL-1 – produced by macrophages and 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

27
Q

Blockage of which cytokine with biological therapy has proven to be very effective in reducing some of the negative effects of rheumatoid arthritis?

28
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)

29
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

30
Q

What can upregulate RANKL production?

A

IL-17
IL-1
TNF-alpha
PTH-related peptide

31
Q

What decoy receptor antagonises the action of RANKL?

A

Osteoprotegrin

32
Q

Name a monoclonal antibody that targets RANKL.

33
Q

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

A
  1. Rituximab – anti-CD20 monoclonal antibody used to deplete B cells
  2. Belimumab
    – anti-BLYS monoclonal antibody (BLYS is a B cell survival factor)
    - this inhibits BAFF (B cell activating factor of TNF family) hence reduces B cell survival and numbers
34
Q

What are the effects of prostaglandins produced by COX?

A

Prostaglandins

Vasodilation, inhibit platelet aggregation, bronchodilation, uterine contraction

35
Q

What are the effects of leukotrienes produced by lipooxygenase?

A

Leukotrienes

Leukocyte chemotaxis, smooth muscle contraction, bronchoconstriction, mucous secretion

36
Q

What do glucocorticoids inhibit?

A

Phospholipase A2

37
Q

Describe TNFa role in the rheumatoid synovial and list some of its other action

A

-dominant pro-inflammatory cytokine in the rheumatoid synovial

actions:

  1. chemokine release
  2. angiogenesis
  3. endothelial cell activation
  4. osteoclast activation
  5. PGE2 production
  6. leukocyte accumulation

Musculoskeletal (10 decks)

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