Pathogenesis of autoimmune disease

Question 1

What is rheumatoid arthitis?

Answer 1

• Caused by synovitis (inflammation of synovial membrane)
• Chronic joint inflammation -> joint damage
• Inflammation site is in the synovium

Question 2

Which antibodies are involved in rheumatoid arthritis?

Answer 2

• Rheumatoid factor

- Anti-cyclic citrullinated peptide (anti-CCP)

Question 3

What are seronegative spondyloarthropathies?

Answer 3

Group of inflammatory rheumatic diseases with common clinical and aetiological features, including axial and peripheral inflammatory arthritis, enthesitis, extra-articular manifestations and a link to HLA-B27 epitope

Question 4

What are some examples of seronegative spondyloarthropathies?

Answer 4

Ankylosing spondylitis

Reiter’s syndrome and reactive arthritis

Psoriatic arthritis –arthritis associated with psoriasis

Enteropathic synovitis –arthritis associated with GI inflammation

Question 5

What is ankylosing spondylitis?

Answer 5

• Chronic spinal inflammation -> spinal fusion and deformity
• Inflammation site is in the enthesis (where a ligament inserts into bone)
• No autoantibodies hence seronegative

Question 6

What is systemic lupus erythematosus?

Answer 6

• 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
• Antibodies active complement via the classical route

Question 7

What are the autoantibodies associated with SLE?

Answer 7

• Anti nuclear antibodies

- Anti double stranded DNA antibodies

Question 8

What are the types of connective tissue diseases?

Answer 8

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

Question 9

What are the HLAs associated with RA, SLE and anklyosing spondylitis?

Answer 9

RA: HLA-DR4
SLE: HLA-DR3
AS: HLA-B27

Question 10

Where is MHC class 1 found?

Answer 10

All nucleated cells

Question 11

Where is MHC class 2 found?

Answer 11

Antigen presenting cells e.g. dendritic cells, B cells

Question 12

Which chromosomes do HLA come from?

Answer 12

HLA class 1 and 2 comes from Chr6 and the beta 2-microglobulin part of class 1 HLA comes from Chr15

Question 13

What are the HLA classes are associated with RA, SLE and anklyosing spondylitis?

Answer 13

AS: Class 1 HLA.

RA, SLE: Class 2 HLA

Question 14

Which T cell recognises HLA class 1 and 2?

Answer 14

Class 1 -> CD8+ T-cells (cell killing)

Class 2 -> CD4+ T-cells (helper T-cells)

Question 15

What is the peptide binding site of HLA made of?

Answer 15

Walls: alpha-helical structures
Floor: beta-pleated sheet

Question 16

What does MHC restriction mean?

Answer 16

T-cells only see antigen bound MHC

Question 17

Do osteoarthritis, reactive arthritis, gout and akylosing spondylitis have autoantibodies?

Answer 17

no

Question 18

What are arthitogenic antigens?

Answer 18

Peptide antigens (exogenous or self) that can bind to HLA molecules to trigger joint disease

e.g. antigen HLA-DR4 -> triggers CD4+ repsonse in RA

Question 19

What is the pathogenesis of alkylosing spondylitis?

Answer 19

• It was shown experimentally that ankylosing spondylitis is independent of the CD8+ T-cells as when rats were made to express human HLA-B27 and CD8+ T-cells were removed, they still developed AS
• New theory: AS is due to abnormalities in both HLA-B27 and IL-23 pathway
• HLA-B27 has a tendency to miss-fold to cause cellular stress -> triggers IL-23 pathway to trigger IL-17 production by: adaptive immune cells (CD4+ Th17 cells) and innate immune cells (CD4-, CD8-)

Question 20

What are anti-nuclear antibodies targeting in SLE?

Answer 20

Nucleus - number of antibodies in serum used to assess severity

Question 21

Are antinuclear antibodies specific to SLE and are they found in all SLE cases?

Answer 21

• seen in all cases
• not specific for SLE

(There are loads of autoantigens in the nucleus but in lupus <100 are reported to react to anti-nuclear antibodies)

Question 22

How are the anti-nuclear antibodies detected?

Answer 22

• Permeabilising cells on a glass slide to allow entry of autoantibodies
• Patients’ serum is placed over the cells and if any ANA are present, they will bind to the nucleus and be detected by immunofluorescence

Question 23

What does a sick lupus patient normally have?

Answer 23

1. Low complement levels

2. High serum levels of anti-ds-DNA antibodies

Question 24

What is the pathogenesis of lupus?

Answer 24

1. During apoptosis of cells there is 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 25

What are some cytokines, which cells are they released from and what do they do?

Answer 25

y-IFN -> T cells -> activate macrophages IL-1 -> macrophages -> activate T cells, fever, pro-inflammatory IL-2 -> T cells -> activate B/T cells IL-6 -> T cells -> activate B cells, acute phase repsonse TNF-alpha -> macrophages -> similar to IL-1, more destructive

Question 26

How can cytokines be switched off?

Answer 26

Biological therapy -> monoclonal ABs

Question 27

What are the types of T helper cells and what do they do?

Answer 27

Th1 cells secrete IL2 and y-IFN and response is important in C8+ response and macrophage stimulation Th2 cells secrete IL-4 (IgE response), IL-5 (eosinophils), IL-6 (B cell to plasma cells) and IL-10 (inhibit macrophages) Th17 cells develop in repsonse to IL-23 and secrete IL-17 a potent cytokine that triggers other cytokines. Affect matrix metalloproteinases and RANKL in target cells. Important in mucosal immunity, arthritis, psoriasis, IBD and multiple sclerosis

Question 28

What is TNF-alpha? What release it?

Answer 28

- TNF-a is released by macrophages | - TNF-a is the dominant pro-inflammatory cytokine in the rheumatoid synovium and it has many detrimental effects

Question 29

What are the effects of TNF-a?

Answer 29

- Chemokine release - Endothelial cell activation - Leukocyte accumulation - Angiogenesis - Osteoclast activation - PGE2production - Pro-inflammatory cytokine release

Question 30

What are some treatments against cytokines?

Answer 30

- Treatment can be aimed at TNF-alpha due to its wide ranged detrimental effects - IL-6 and IL-1 blockage is available - IL-6 and TNF-a blockage is much more efficacious than IL-1 blockade - We can also deplete B-cells in RA by IV administration of anti-B-cell antibodies (against CD20) e.g. rituximab

Question 31

What produced RANKL and what does it result in and how?

Answer 31

RANKL is produced by T-cells and synovial fibroblasts in RA -> leads to bone destruction (via oesteoclastogenesis)

Question 32

What upregulates RANK-L?

Answer 32

IL-1, TNF-alpha IL-17 –potent action on oesteoclastogenesis via RANKL-RANK pathway PTH-rp

Question 33

What are some treatments aimed at RANKL?

Answer 33

Denosumab –monoclonal antibody against RANKL Treats –osteoporosis, bone metastasis, multiple myeloma & giant cell tumours

Question 34

What are some treatments for SLE against cytokines?

Answer 34

Rituximab –chimeric anti-CD20 antibody Belimumab –monoclonal human IgG1 antibody against B-cell survival factor (BLYS).This inhibits BAFF (B cell activating factor of the TNF family) -> reduced B cell survival and numbers

Question 35

What are prostaglandins? What are they made from?

Answer 35

Lipid mediators of inflammation that act on platelets, endothelium, uterine tissue and mast cells. Synthesised from essential fatty acids: phospholipase A2 generates arachidonic acid from diacylglycerol in cell membranes. This enter two pathways: cyclooxygenase (prostaglandins made) and lipooxygenase

Question 36

What inhibits phospholipase 2?

Answer 36

glucocorticoids

Question 37

What inhibits COX?

Answer 37

NSAIDs

Question 38

What are the benefits of NSAIDs? Unwanted effects?

Answer 38

analgesia. anti-pyretic, anti-inflammatory, anti-platelet | unwanted: asthma exacerbation. gastrointestinal ulcers, thrombosis, liver and renal problems

Question 39

What are the 2 isoforms of COX?

Answer 39

COX 1/2 - only 2 selective would achieve anti-inflammatory effects and not interfere with COX-1 housekeeping role but they have more CVS problems

Question 40

What are NSAIDs used for?

Answer 40

NSAIDs are used to deal with the prostaglandin-type inflammation pain. NSAIDs just remove the pain, it doesn’t deal with the natural history of the disease.