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LCRS Musculoskeletal > Pathogenesis of Autoimmune Disease > Flashcards

Pathogenesis of Autoimmune Disease Flashcards

1
Q

what is rheumatoid arthritis (RA)?

A

synovitis
chronic joint inflammation and therefore joint damage, pain and stiffness

SYMMETRICAL

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2
Q

what are the associated anti-antibodies in RA?

A

o Rheumatoid factor.

o Anti-cyclic citrullinated peptide (CCP) antibodies

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3
Q

what is ankylosing spondylitis?

A

enthesis

chronic spinal inflammation causing spinal fusion and deformity.

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4
Q

what are the associated auto-antibodies in anky.spond?

A

none

seronegative disease

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5
Q

what are some examples of seronegative spondyloarthropathies?

A

spondyloarthropathies are seronegative by definition (shown by the absence of rheumatoid factor)

o Ankylosing spondylitis.
o Reiter’s syndrome (reactive arthritis)
o Psoriatic arthritis
 – arthritis associated with psoriasis.
o Enteropathic synovitis – arthritis associated with GI inflammation.
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6
Q

what is systemic lupus erythematosus (SLE)?

A

immune complexes mediated
Chronic tissue inflammation from antibodies directed against self-antigens.

usually involves skin, joints, kidneys and other organs

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7
Q

which site does SLE commonly inflame?

A

joints
skin
kidneys

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8
Q

what are the associated auto-antibodies in SLE?

A

o Anti-nuclear antibodies.

o Anti-double-stranded DNA antibodies.

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9
Q

what are some examples of connective tissue disorders?

A
  • SLE
  • Inflammatory muscle disease (polymyositis, dermatomyositis)
  • Systemic sclerosis
  • Sjogren’s syndrome
  • “Overlap” syndromes (mixtures)
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10
Q

what HLA is associated with RA?

A

HLA-DR4

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11
Q

what HLA is associated with SLE?

A

HLA-DR3

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12
Q

what HLA is associated with anky.spond?

A

HLA-B27

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13
Q

what do HLA encode for?

A

MHC class I and II

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14
Q

which chromosome do HLA class I and II come from?

A

Chr 6

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15
Q

which chromosome does the beta 2 microglobulin of HLA class I come from?

A

Chr 15

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16
Q

what do HLA molecules do?

A

present to T cells
o Class 1 –> CD8+ T-cells (cell killing).
o Class 2 –>CD4+ T-cells (helper T-cells).

T cells are MHC restricted i.e. only method of seeing an antigen

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17
Q

describe the structure of the peptide binding site for HLA molecule to T cells?

A

o Walls - alpha-helical structures.

o Floor - beta-pleated sheet.

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18
Q

what are peptide antigens bind to HLA molecules to trigger disease?

A 
Arthritogenic antigens (these can be exogenous or self)
o E.G. Antigen-HLA-B27 --> (MHC class 1)--> triggers CD8+ T-cell response in Ankylosing Spondylitis.

o E.G. Antigen-HLA-DR4–> (MHC class 2)–> triggers CD4+ T-cell response in RA (therefore involves antibodies)

19
Q

what class HLA is associated with RA?

A

MCH Class 2

HLA DR4

20
Q

what class HLA is associated with SLE?

A

MHC Class 2

HLA DR3

21
Q

what class HLA is associated with anky.spond?

A

Class 1

however studies in rats show that anky.spond can be triggered independent of T cells (CD8+) when they express HLA-B27 and T cells were removed

22
Q

what does the updated theory on anky.spond describe is the genetic abnormality?

A

abnormalities in both HLA-B27 AND IL-23 pathway

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

23
Q

how is IL-17 product triggered by the IL-23 pathway?

A

• 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.

24
Q

what are anti-nuclear ABs directed against in SLE?

A

the nucleus
there are auto antigens in the nucleus but <100 react to ANAs
of those, only a few react in SLE

25
Q

name some sernonegative disorders

A

OA
ReA
Anky.spond

26
Q

how can ANAs be detected?

A

Anti-nuclear antibodies (ANA)

detected by immunofluorscence

27
Q

what is the significance of ANA in terms of SLE?

A

seen in all SLE cases (but not specific to it)
determine a positive case for SLE
further tests will be done from there to determine what the autoABs are reacting to

28
Q

what is the significance of anti-dsDNA ABs in SLE?

A

these autoABs are specific to SLE and can be used to determine disease activity as serum levels correlate with activity

29
Q

what are the 2 important biochemical measurements seen in a sick SLE Pt?

A
  1. Low complement levels (consumed)

2. High serum levels of anti-ds-DNA antibodies due to immune complexes

30
Q

what is the hypothesised pathogenesis of SLE?

A

failure to regulate apoptosis and impaired clearance of immune complexes

  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.
  3. B-Cell autoimmunity.
  4. Tissue damage by antibody effector mechanisms
    – e.g. complement activation and Fc-receptor engagement.
31
Q

what is the key cytokine involved in RA?

A

TNF-alpha

pro-inflammatory

32
Q

what is the biological therapy used to manipulate cytokine levels?

A

monoclonal antibodies

33
Q

what are the effects of TNF-alpha that are detrimental to synovium?

A 
o	Chemokine release.
o	Endothelial cell activation.
o	Leukocyte accumulation.
o	Angiogenesis.
o	Osteoclast activation.
o	PGE2 production.
o	Pro-inflammatory cytokine release.
34
Q

what are the biological therapies available for RA?[3]

A
  • TNF-alpha antagonists e.g. infliximab
  • IL-6 and IL-1 blockage
  • depletion of B cells using anti CD20 ABs e.g. rituximab

IL-6 and TNF-alpha blockage has higher efficacy than IL-1

35
Q

what produces RANKL in RA and what does it lead to?

A

by T-cells and synovial fibroblasts in RA

leads to bone destruction

36
Q

what cytokines upregulate RANKL?

A

o IL-1, TNF-a.

o IL-17 – potent action on oesteoclastogenesis via RANKL-RANK pathway.

o PTH-rp

37
Q

what antagonises RANKL?

A

Osteoprotegerin (OPG)

38
Q

what is the treatment available against RANKL?

A

Denosumab
– monoclonal antibody against RANK (RANKL analogue)

involved in osteoporosis, bone metastasis, multiple myeloma & giant cell tumours

39
Q

what is B cell activity like in SLE?

A

hyper-reactive and therefore can be depleted as part of treatment to reduce their effects

40
Q

what are the treatments for B cell hyper-reactivity?

A

o Rituximab
– chimeric anti-CD20 antibody.

o Belimumab
– monoclonal human IgG1 antibody against B-cell survival factor (BLYS) which inhibits BAFF

41
Q

what is used to treat prostaglandin type inflammation pain?

A 
NSAIDs (just remove pain but not the natural history) 
analgesia
anti-pyretic
anti-inflam
anto-platelet
42
Q

what pathway do NSAIDs affect?

A

arachidonic acid –> prostaglandin pathway by inhibiting COX

43
Q

what is produced in the cyclo-oxygenase pathway?

A

AA to prostaglandins

44
Q

what is produced in the lipooxygenase pathway?

A

arachidonic acid to leukotrienes

LCRS Musculoskeletal (11 decks)

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