4. Pathogenesis of autoimmune disease

Question 1

What is rheumatoid arthritis?

Answer 1

• Chronic joint inflammation
• Pain, discomfort and destruction if untreated
• Synovium is inflamed - chronic synovitis
• Associated with autoantibodies:
- rheumatoid factor
- anti-cyclic citrullinated peptide (CCP) antibodies

Question 2

What is ankylosing spondylitis?

Answer 2

• Chronic spinal inflammation that can result in spinal fusion and deformity
• Pain and inflammation of the spine and bony fusion of the vertebrae if untreated
• Causes exaggerated thoracic kyphosis
• Enthesis (joins vertebrae) is inflamed - enthesitis => calcium deposition and bony fusion (spine becomes rigid)
• No autoantibodies

Question 3

What is arthritis associated with gastrointestinal inflammation called?

Answer 3

Enteropathic synovitis

Question 4

What drives pathogenesis in SLE?

Answer 4

• Autoantibodies and immune complexes

* Antibodies are referred to anti-nuclear antibodies + anti-double stranded DNA antibodies

Question 5

What is MHC restriction?

Answer 5

T cells only recognise antigens bound to MHC (HLA)

Question 6

What has the pathogenesis of HLA-associated disease hypothesised to be due to?

Answer 6

(Exogenous or self) antigen that is able to bind to the HLA molecule and trigger disease

(a new hypothesis is needed as this has kind of been disproven)

Question 7

What causes ankylosing spondylitis?

Answer 7

• Antigen and HLA-B27 triggers CD8+ response
• Thought to be due to abnormalities in HLA-B27 and IL-23 pathway
- HLA-B27 has propensity to misfold
- causes cellular stress
- triggers IL-23 release and IL-17 production by adaptive immune cells (CD4+ Th17) and innate immune cells (CD4- and CD8- ‘double-negative’ T cells)

Question 8

What are anti-nuclear antibodies?

Answer 8

• Antibodies react to an antigen within the nucleus (deep in the cell)
• Include anti-tRNA synthetase antibodies and anti-ribosomal P antibodies

Question 9

How many nuclear antigens have been reported to react with anti-nuclear antibodies in lupus?

Answer 9

<100

Question 10

What are the complement levels and serum levels of anti-ds-DNA antibodies commonly like in SLE?

Answer 10

• Low complement levels

* High serum levels of anti-ds-DNA antibodies

Question 11

How are nuclear antigens abnormally presented to the immune system in SLE and what response does it cause?

Answer 11

• Apoptosis normally translocates certain nuclear antigens to the surface of the cell
• Apoptotic cells are not cleared normally in lupus, which enables abnormal presentation
• Immune response is amplified through the B cells
• Tissue damage by antibody effector mechanisms (complement activation, Fc receptor engagement)

Question 12

When are autoantibodies normally detectable in SLE patients before symptoms?

Answer 12

About 10 years

Question 13

What do the CD4+ T helper cell subsets include?

Answer 13

• Th1
• Th2
• Th17

Question 14

What do Th1 cells secrete and what is their response important in?

Answer 14

• Secrete IL-2 and γ-IFN

* Response important in CD8+ cytotoxicity and macrophage stimulation

Question 15

Which 5 ILs does Th2 cells secrete and what is their response important in?

Answer 15

• IL-4 = plasma cells secreting IgE
• IL-5 = eosinophils
• IL-6 = B cells to plasma cells
• IL-10 = inhibit macrophage response
• IL-13 = plasma cells secreting IgE

Question 16

What do Th17 cells develop in response to, and what do they secrete + its action?

Answer 16

• Develop in response to IL-23
• Secrete IL-17 = potent cytokine which triggers the following in target cells:
- IL-6
- IL-8
- TNF-α
- Matrix metalloproteinases
- RANKL

Question 17

What can the cytokines secreted by T cells be manipulated and switched off by (biological therapy)?

Answer 17

Monoclonal antibodies

Question 18

What is the dominant pro-inflammatory cytokine in the rheumatoid synovium?

Answer 18

TNF-α

Question 19

What can TNF-α do to the bone/joints?

Answer 19

• Activate osteoclasts - bone erosion
• Activate synoviocytes - joint inflammation
• Activate chondrocytes - cartilage degradation

Question 20

Which cells producing TNF-α cause many of the negative effects?

Answer 20

Activated macrophages

Question 21

What cytokine blockade is now available in clinics for autoimmune inflammatory disorders?

Answer 21

IL-1 and IL-6 blockade

Question 22

How is RANKL significant in bone destruction in rheumatoid arthritis?

Answer 22

• Produced by T cells and synovial fibroblasts in rheumatoid arthritis
• Acts to stimulate osteoclast formation - breakdown of bown
• Up-regulated by IL-1, TNF-α, IL-17 and PTH-related peptide

Question 23

Which decoy receptor antagonises the binding of RANK to RANKL on osteoclast precursors?

Answer 23

Osteoprotegrin (OPG) - reducing osteoclast activity

Question 24

What is denosumab?

Answer 24

• Monoclonal antibody against RANKL (not used in rheumatoid arthritis)
• Indicated for osteoporosis, bone metastases etc.

Question 25

Which biological therapies are used for treating SLE?

Answer 25

• Rituximab - anti-CD20 to deplete B cells (clinical trials unsuccessful)
• Belimumab - antibody against B cell survival factor BLYS (B-lymophocyte stimulator) (licensed)
• Add on therapy with active autoantibody-positive SLE

Question 26

What 2 pathways does arachidonic acid enter?

Answer 26

• Cyclooxygenase pathway (arachidonic acid => prostaglandins)
• Lipooxygenase pathway (arachidonic acid => leukotrienes)

Question 27

What do prostaglandins mediate?

Answer 27

• Vasodilation
• Inhibit platelet aggregation
• Bronchodilation
• Uterine contraction

Question 28

What do leukotrienes mediate?

Answer 28

• Leucocyte chemotaxis
• Smooth muscle contraction
• Bronchoconstriction
• Mucus secretion

Question 29

What can be used to inhibit phospholipase A2?

Answer 29

Glucocorticoids

Question 30

Are NSAIDs effective at preventing joint damage long term?

Answer 30

No (deals more with symptoms rather than the history of the disease)