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Y2 LCRS2 Musculoskeletal > Pathogenesis of Autoimmune Disease (Part 2) > Flashcards

Pathogenesis of Autoimmune Disease (Part 2) Flashcards

(42 cards)

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1
Q

What auto-antibody is associated with systemic vasculitis?

A

antinuclear cytoplasmic antibodies (ANCA)

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2
Q

What auto-antibody is associated with diffuse systemic sclerosis?

A

Anti-Scl-70 antibody (AKA antibodies to topoisomerase-1)

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3
Q

What auto-antibody is associated with limited systemic sclerosis?

A

Anti-centromere antibodies.

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4
Q

What auto-antibody is associated with dermato-/Polymiositis?

A

Anti-tRNA transferase antibodies e.g. histidyl transferase (also termed anti-Jo-1 antibodies)

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5
Q

What auto-antibodies are associated with Sjögren’s syndrome?

A

No unique antibodies but typically see

  • Antinuclear antibodies - Anti-Ro and anti-La antibodies
  • Rheumatoid factor
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6
Q

What auto-antibody is associated with mixed connective tissue disease?

A

Anti-U1-RNP antibodies

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7
Q

Which auto-antibody is epecific to lupus?

A

Anti-double stranded DNA antibodies (anti-dsDNA).

Specific for SLE and SERUM LEVEL of antibody correlates with disease activity.

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8
Q

What is the commonest auto-antibody found in lupus?

A

Atinuclear antibodies (ANA)

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9
Q

Describe the laboratory test used for testing for ANA in lupus. Is this diagnostic of SLE?

A
  1. Human cells are placed on a glass slide, immobilised and permeabilised so that anything can bind to them.
  2. Patient serum is then added and if it contains ANAs then these will bind the the cells.
  3. To tell whether ANAs have bound, you add a fluorescently labelled monoclonal antibody that binds to the ANA and you observe the pattern of attachment

ANAs are NOT diagnostic of SLE.

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11
Q

If the ANA test comes back as positive, what will the lab do further tests for?

A

If ANA is positive the clinical laboratory will perform further tests to determine which type of ANA it is – typically these include screening for:

  • Anti-Ro
  • Anti-La
  • Anti-centromere
  • Anti-Sm
  • Anti-RNP
  • Anti-ds-DNA antibodies
  • Anti-Scl-70

Cytoplasmic antibodies include:

  • Anti-tRNA synthetase antibodies
  • Anti-ribosomal P antibodies
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12
Q

Name the 4 patterns of ANA binding which can be seen iin different conditions.

A
  • Homogenous
  • Speckled
  • Nucleolar
  • Fine Speckled
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13
Q

Which auto-antibody level SPECIFIC for lupus does not correlate with disease activity?

A

Anti-Sm antibody (antigen is ribonucleoprotein)

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14
Q

What is the antigen of Anti-Ro and Anti-La antibodies in SLE?

A

ribonucleoprotein

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15
Q

What conditions other than SLE are ANti-Ro and Anti-La antobodies associated with?

A
  • Secondary Sjögren’s syndrome
  • Neonatal lupus syndrome (transient rash in neonate, permanent heart block)
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16
Q

What condition other than SLE are anti-ribosomal P antibodies associated with?

A

Cerebral lupus

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17
Q

What is the current theory for the pathogenesis of systemic lupus erythematosus?

A
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18
Q

Which cells secrete these cytokines? What is their function?

  1. γ-IFN
  2. IL-1
  3. IL-2
  4. IL-6
  5. TNF-α
19
Q

Describe the disease activity in SLE.

Study These Flashcards
A

Sick lupus patient commonly has

  • Low complement levels (complement is consmed by complexes when ill)
  • High serum levels of anti-ds-DNA antibodies
22
Q

What are the CD4+ T helper cell subsets?

Study These Flashcards
A

Th1, Th2, Th17

23
Q

What is TNF-a produced by and why is it called the dominant cytokine? Which inflammatory condition is it most associated with?

Study These Flashcards
A
  • It is produced by macrophages
  • Inhibition of TNF-a results in blockage of production of IL-1, IL-8, chemokine IL-8 and GM-CSF therefore TNF-a is a DOMINANT cytokine
  • It has pleotropic effects
  • Dominant pro-inflammatory cytokine is the rheumatoid synovium
24
Q

What is the function of Th1 cells?

Study These Flashcards
A

Secrete IL-2 and γ-IFN and response is important in CD8 +ve cytotoxicity and macrophage stimulation

25
Q

What is the fuction of Th2 cells?

Study These Flashcards
A

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

26
Q

What is the function of Th17 cells?

Study These Flashcards
A
  • Develop in response to IL-23
  • They 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, IBD and multiple sclerosis
28
Q

Which cytokine causes inflammation of the synovium in rheumatoid arthritis?

29
Which cytokine blockade can be used for the treatment of rheumatoid arthritis? What else can be blocked in the treatment?
IL-6 TNF-a (IL-1 blockade not recommended) B cell depletion can also be used
30
How can B cells be depleted in the treatment of rheumatoid arthritis?
Parenteral (intravenous) administration of an antibody against a B cell surface antigen, CD20. This is called **rituximab,** clinically.
31
What drug is used to treat SLE?
Belimumab
32
Wha drug is used to treat rheumatoid arthritis?
Tocilizumab
33
What is RANKL? How is it associated with rheumatoid arthritis?
* RANKL = receptor activator of nuclear factor kappa-B ligand * Produced by T cells and synovial fibroblasts in rheumatoid arthritis * It is important in bone destruction as it stimulates osteolast formation by **osteoclastogenesis.**
34
What can RANKL be upregulated by?
* Interleukin-1 * TNF-a * Interleukin-17 – potent action on osteoclastogenesis via RANKL-RANK pathway * PTH-related peptide
35
Describe belimumab and its use for the treatment of SLE.
* Belimumab = recombinant, fully human IgG1 monoclonal antibody, against BLYS/BAFF * Inhibits activity of BAFF resulting in **impaired B cell survival** and **reduced B cell numbers** **BAFF and APRIL receptor systems on B cells:** * APRIL and BAFF synthesisted as transmembrane proteins which can be released as cytokines * Produced by innate immune cells and activated T cells * Oligomers of BAFF and APRIL recgonise 3 receptors on B cells: BCMA, TACI, BAFFR. * They increase survival of transitional immature B-cells + long-lived bone marrow plasma cells + promote antigen-presenting function of B cells...ect = B cell survival increased.
36
How does RANKL stimulate osteoclast formation? How can it be antagonised?
Osteoclastogenesis - binds to ligands on osteoclast precursors (RANK) Antagonised by a decoy receptor - osteoprotegerin (OPG)
37
What is the monoconal antibody drug used against RANKL?
DENOSUMAB
38
Apart from downregulation of RANKL, what else can Denosumab be used for?
indicated for treatment of osteoporosis, bone metastases, multiple myeloma and Giant cell tumours
39
Which biological therapies targetting B cells are used to target B cells in treatment of SLE?
B cell hyper-reactivity drugs in SLE * RITUXIMAB - chimeric anti-CD20 antibody used to deplete B cells * BELIMUMAB - monoclonal antobody against a B cell surival factor called BLYS - licensed for use in autoantibody positive SLE patiens who have high degree of disease activity.
41
What are prostaglandins and what do they act on?
Lipid mediators of inflammation that act on platelets, endothelium, uterine tissues, mast cells.
42
Describe the sythesis of prostaglandins and which pathways they can enter.
* Synthesised from essential fatty acids * Phosholipase A2 generates arachnoidic acid from diacylglycerol in cell membranes Arachnoidic acid then enters 2 pathways: 1. Cyclooxygenase pathway - arachnoidic acid---\> prostaglandins 2. Lipoxygenase pathway - arachnoidic acid ---\> leukotrienes
43
What are the functions of prostaglandins (produced by the cyclooxygenase pathway)?
Prostaglandin functions (examples) * Vasodilation (PGI2 aka prostacyclin via the IP receptor) * Inhibit platelet aggreggation (PGI2) * Bornchodilatation (e.g. PGE2 acting via EP2 or PGI2 receptors) * Uterine contraction (PGF2alpha)
44
What is the function of leukotrienes (produced by the lipooxygenase pathway)?
Leukotriene function examples: * Leukocyte chemotaxis (LTB4) * Smooth muscle contraction * Bronchoconstriction * Mucus secretion (LTC4, LTD4, LTE4 via CysT1 receptors) Leuktriene receptor antagonists are used in asthma e.g. montelukast, zafirlukast.
45
What class of drugs inhibits phospholipase A2? what inhibits cyclooxygenase?
1. Glucocorticoids 2. COX inhibitors ie. NSAIDs
46
What are the benefits and side effects of inhibiting COX?
**Benefits**: analgesia, anti-pyretic, anti-inflammatory and anti-platelet (thromboxane A2) **Unwanted effects:** e.g. asthma exacerbation, gastro-intestinal ulcers, thrombosis, liver and renal problems
47
What are the two isoforms of COX? What was the aim when first creating these drugs and why was this not safe?
* COX 1 and COX 2 * It was hoped that with COX2 selective drugs there would be anti-inflammatory effects and no interference with "house-keeping" COX1 effects * However, COX2 selective drugs were associated with increased cardiovascular events. However risk also applies to some traditional non-selective NSAIDS such as diclofenac.

Y2 LCRS2 Musculoskeletal (13 decks)

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