Rhuem - Pathogenesis of AI Disease

Question 1

3 AI disorders?

Answer 1

RA - rheumatoid arthritis

Ankylosing spondylitis

SLE - systemic lupus erythematosus

Question 2

Explain RA

Answer 2

Caused by: SYNOVITIS

• Chronic inflammation –> joint damage
• Inflammation site is in the synovium

Associated with autoantibodies:
• Rheumatoid factor
• Anti-cyclic citrullinated peptide (CCP) Abs

Question 3

Explain Ankylosing Spondylitis

Answer 3

Caused by: ENTHESIS

• Chronic spinal inflammation –> spinal fusion and deformity
• Inflammation site is in the enthesis (where a ligament inserts into bone)

NO autoantibodies
• described as “seronegative”

Question 4

What are the different types of ‘seronegative spondyloarthropathies’?

Answer 4

Types of “Seronegative Spondyloarthropathies”:

• Ankylosing spondylitis
• Reiter’s syndrome and reactive arthritis
• Psoriatic arthritis – arthritis associated with psoriasis
• Enteropathic synovitis – arthritis associated with GI inflammation.

Question 5

Explain SLE

Answer 5

Caused by: IMMUNE COMPLEXES

• Chronic tissue inflammation from antibodies directed against self-antigens.
• Multi-site inflammation – particularly in joints, the skin and the kidneys

Associated with autoantibodies:
• Anti-nuclear antibodies
• Anti-double-stranded DNA antibodies

(Abs active complement via the classical route)

Question 6

Type of ‘Connective tissue diseases’?

Answer 6

• SLE
• Inflammatory muscle disease (polymyositis, dermatomyositis)
• Systemic sclerosis
• Sjogren’s syndrome
• ‘Overlap syndromes’ (mixtures of above)

Question 7

Link between HLA molecules and rheumatology?

Answer 7

There is association between HLA & diseases:
• RA = HLA-DR4
• SLE = HLA-DR3
• Ak.S = HLA-B27

The genes within the MHC class 1 & 2 encode cell-surface proteins

Question 8

Which HLA classes are the rheumatological diseases associated with?

Answer 8

Ak.S = Class 1 HLA

RA, SLE = Class 2 HLA

Question 9

What is the function of the MHC classes?

Answer 9

To present antigens to T-cells:
• Class 1 –> CD8+ T-cells (cell killing)
• Class 2 –> CD4+ T-cells (helper T-cells)

(onenote table!!)

Question 10

Therefore, explain the pathogenesis of HLA molecules

Answer 10

Arthritogenic antigen

• due to peptide antigen (exogenous OR self) that is able to bind to HLA molecule and trigger disease

Question 11

Explain the pathogenesis of Ak.S in terms of HLA molecules

Answer 11

NO arthritogenic peptide that binds HLA-B27 identified

New theory:
• Ak.S is due to abnormalities in BOTH HLA-B27 & IL-23 pathway

Question 12

Explain the theory of pathogenesis of Ak.S

Answer 12

HLA-B27 has a propensity to miss-fold to cause cellular stress  triggers IL-23 pathway to trigger IL-17 production by:

• Adaptive immune cells – CD4+ Th17 Cells
• Innate immune cells – CD4-, CD8- (‘double negative’) T-cells

The “double negative” T-cells have been detected in enthesis and could be the reason for enthesopathy in AS.

Question 13

Key autoantibodies of RA?

Answer 13

• Rheumatoid Factor

* Anti-cyclic citrullinated peptide antibody

Question 14

Key auto-Abs of SLE?

Answer 14

• Antinuclear Abs
• Anti-double stranded DNA Abs (anti-dsDNA)
• Anti-cardiolipin Abs

The no. of auto-Abs in the serum can be used to assess the severity of the disease

Question 15

ANAbs & lupus - and how can they be detected?

Answer 15

There are many autoantigens in the nucleus
• BUT in lupus, <100 are reported to react to ANAbs (so lupus reacts with few)

Detection of autoAbs:
• Permeabilising cells on glass slide (to allow entry of autoAbs)
• Patient serum places over = if any ANAbs present, will bind = immunofluorescence

Question 16

What does a patient with SLE generally have?

Answer 16

1. Low complement levels

2. High serum levels of anti-dsDNA Abs

Question 17

What is the current understanding of the pathogenesis of SLE?

Answer 17

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

• in Lupus, there is impaired clearance so the immune system can react with nuclear antigens

3. B-Cell autoimmunity
4. Tissue damage by antibody effector mechanisms
   • e.g. complement activation and Fc-receptor engagement.

Question 18

Cytokines in rheumatology?

Answer 18

TNF-a is the dominant pro-inflammatory cytokine in the rheumatoid synovium and its pleotropic (many) actions are detrimental here:

o Chemokine release
o Endothelial cell activation
o Leukocyte accumulation
o Angiogenesis
o Osteoclast activation
o PGE2 production
o Pro-inflammatory cytokine release

TNF-a is released by macrophages

Question 19

What are some treatments agaisnt cytokines?

Answer 19

Against TNF-a (due to its wide-range of detrimental effects)

BUT also IL-6 & IL-1 blockage

Can also deplete B-cell in RA by IV administration of anti-B-cell Abs
• Rituximab - anti-CD20 Ab

Question 20

RANKL?

Answer 20

Produced by T-cells and synovial fibroblasts in RA

• leads to bone destruction (via. oestoclastogenesis)

Question 21

What is RANKL both unpregulated & antagonised by?

Answer 21

Upregulated by:
• IL-1, TNF-a
• IL-17 (potent action via. RANKL-RANK pathway)
• PTH-rp

Antagonised by:
• OPG (osteoprotegerin)

Question 22

Treatment aimed at RANKL?

Answer 22

Denosumab
• monoclonal Ab against RANKL

Treats - osteoporosis, bone metastasis, multiple myeloma & giant cell tumours

Question 23

Cytokines associated with SLE?

Answer 23

B-cell hypersensitivity is a key feature of SLE

SO treatments targeted against B-cells

Question 24

Treatment for SLE?

Answer 24

Against B-cells, treatments include:

• Rituximab - chimeric anti-CD20 Ab
• Belimumab - monoclonal human IgG1 Ab against B-cell survival factor (BLYS)

This inhibits BAFF (B-cell activating factor of TNF family) = reduced B-cell survival

Question 25

Prostaglandins in Rhuematology?

Answer 25

NSAIDs are used to deal with the prostaglandin-type inflammation pain
• they just remove the pain, do NOT deal with the natural history of the disease
• it just limits the arachidonic acid prostaglandin pathway