Pathogenesis of Autoimmune Disease

Question 1

Give examples of autoimmune musculoskeletal disorders

Answer 1

Rheumatoid arthritis
Ankylosing spondylitis
Systemic Lupus Erythematosus (SLE)

Question 2

What are HLA molecules

Answer 2

Human leukocyte antigens
The first regions of the MHC to be sequenced
genes within the MHC class I and class II regions encode cell surface proteins

Question 3

Which MHC gene is associated with Rheumatoid arthritis

Answer 3

HLA-DR-4

Question 4

Which MHC gene is associated with systemic lupus erythematosus

Answer 4

HLA-DR3

Question 5

Which MHC gene is associated with Ankylosing spondylitis

Answer 5

HLA-B27

Question 6

Describe MHC class I (expression, antigen, recognition and response)

Answer 6

Found in all nucleated cells
Endogenous antigen
CD8 +ve T cells
Cell killing

Question 7

Describe MHC class II (expression, antigen, recognition and response)

Answer 7

Found in antigen presenting cells
Exogenous antigens
CD4 +ve T cells
Antibody response

Question 8

Give examples of APCs

Answer 8

Dendritic Cells
B cells
Macrophages

Question 9

Give examples of endogenous and exogenous antigens

Answer 9

Endogenous - viral peptide, tumour antigen, self-peptides

Exogenous - Bacterial peptides, self peptides

Question 10

What are the key auto-antibodies in rheumatoid arthritis

Answer 10

Rheumatoid factor

Anti-cyclic citrullinated peptide antibody

Question 11

What are the key auto-antibodies in systemic lupus erythematosus

Answer 11

Antinuclear antibodies (ANA)
Anti-double stranded DNA antibodies (anti-dsDNA)

Question 12

Describe the disease activity in systemic lupus erythematosus

Answer 12

Low complement levels

High serum levels of anti-ds-DNA antibodies

Question 13

Describe the pathogenesis of systemic lupus erythematosus

Answer 13

1. Apoptosis leads to translocation of nuclear antigens to membrane surface
2. Impaired clearance of apoptotic cells results in enhanced presentation of nuclear antigens to immune cells
3. B cell autoimmunity
4. Tissue damage by antibody effector mechanisms e.g. complement activation and Fc receptor engagement

Question 14

What cytokines are release by T cells and what are their effects

Answer 14

γ-IFN - Activated macrophages
IL-2 - Activates T and B cells
IL-6 - Activates B cells, acute phase response

Question 15

What cytokines are release by macrophages and what are their effects

Answer 15

IL-1 - Activates T cells, fever, pro-inflammatory

TNF-alpha - similar to IL-1, more destructive

Question 16

What cytokines do Th1 cells release and what are they involved in

Answer 16

IL-2 and γ-IFN

Response is important in CD8 +ve cytotoxicity and macrophage stimulation

Question 17

What cytokines do Th2 cells release and what are they involved in

Answer 17

IL-4 (IgE responses)
IL-5 (eosinophils)
IL-6 (B cells to plasma cells)
IL-10 (inhibit macrophage response)

Question 18

What cytokines do Th17 cells release and what are they involved in

Answer 18

develop in response to IL-23 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

Question 19

What is RANKL and what is it produced by

Answer 19

RANKL (receptor activator of nuclear factor kappa-B ligand)

Produced by T cells and synovial fibroblasts in rheumatoid arthritis

Question 20

What is the action of RANKL

Answer 20

Stimulates osteoclast formation

Question 21

What is RANKL unregulated by

Answer 21

Interleukin-1, TNF-alpha

Interleukin-17 – potent action on osteoclastogenesis via RANKL-RANK pathway

PTH-related peptide

Question 22

Give an example of a drug used that targets RANKL

Answer 22

Denosumab – monoclonal antibody against RANKL

indicated for treatment of osteoporosis, bone metastases, multiple myeloma and Giant cell tumours

Question 23

Give examples of therapies use for SLE therapy

Answer 23

Rituximab - chimeric anti-CD20 used to deplete B cells

Belimumab - monoclonal antibody against B cell survival factor BLYS

Question 24

What are prostaglandins

Answer 24

lipid mediators of inflammation that act on platelets, endothelium, uterine tissue and mast cells

Question 25

How are prostaglandins synthesised

Answer 25

Phospholipase A2 generates arachidonic acid from diacylglycerol in cell membranes. Arachidonic acid enters two pathways: cyclooxygenase (prostaglandins) or lipooxygenase (leukotrienes)

Question 26

What are the actions of prostaglandins

Answer 26

Prostaglandins mediate vasodilatation (PGI2), inhibit platelet aggregation (PGI2), bronchodilatation (e.g. PGE2 acting via receptor called EP2, PGI2), uterine contraction (PGF2alpha)

Question 27

What is ankylosing spondylitis and describe the immunology

Answer 27

Chronic spinal inflammation that can result in spinal fusion and deformity
Site of inflammation is the enthesis
No autoantibodies (‘seronegative’)

Question 28

Which musculoskeletal diseases are not associated with any auto-antibodies

Answer 28

Osteoarthritis
Reactive arthritis
Gout
Ankylosing spondylitis

Question 29

Describe the use of antinuclear antibodies (ANA) in SLE

Answer 29

Seen in all SLE cases

Not specific for SLE

Question 30

Describe the use of anti-double stranded DNA antibodies

Answer 30

Specific for SLE

Serum level of antibody correlates with disease activity

Question 31

Give examples of treatments that target B cells in SLE

Answer 31

rituximab - chimeric anti-CD20 antibody used to deplete B cells

belimumab - monoclonal antibody against a B cell survival factor call BLYS