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eLCRS - 머크 > 1 Rheumatoid: Pathogenesis of autoimmune disease > Flashcards

1 Rheumatoid: Pathogenesis of autoimmune disease Flashcards

1
Q

Define Rheumatoid arthritis

A

Chronic joint inflammation that can result in joint damage

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2
Q

Where is the site of inflammation in rheumatoid arthritis?

A

synovium (synovitis)

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3
Q

What 2 autoantibodies is Rheumatoid arthritis associated with?

A

Associated with autoantibodies:

  • Rheumatoid factor
  • Anti-cyclic citrullinated peptide (anti -CCP) antibodies
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4
Q

Define Ankylosing spondylitis

Where is its site of inflammation?

A

Chronic spinal inflammation that can result in spinal fusion and deformity (e.g exaggerated kyphosis, loss of normal lumbar lordosis)

  • site of inflammation: enthesis (enthesitis)

Note: no autoantibodies

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5
Q

Ankylosing spondylitis is associated/not associated with autoantibodies

A

Ankylosing spondylitis is not associated with autoantibodies

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6
Q

Define SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

Where is its site of inflammation?

A

Chronic tissue inflammation in the presence of antibodies directed against self antigens

  • excess immune complex formation
  • subset/part of connective tissue disease
  • site of inflammation: Multi-site (but particularly joints/skin/kidney)
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7
Q

What 2 autoantibodies is SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) associated with?

A
  • Antinuclear antibodies (ANA)

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

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8
Q

what is the HLA Molecule associated with:

Rheumatoid Arthritis=

Systemic Lupus Erythematosus =

Ankylosing Spondylitis =

A

Rheumatoid Arthritis = HLA-DR4

Systemic Lupus Erythematosus = HLA-DR3

Ankylosing Spondylitis = HLA-B27

–> important in antigen recognition by T cells

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9
Q

What is the main function of MHC Class I & II molecules?

A
  • presents antigens to T cells
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10
Q

What is the general pathogenesis of HLA associated diseases?

A

A peptide antigen (exogenous or self) that is able to bind to HLA molecule and trigger disease (‘arthritogenic antigen’)

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11
Q

E.g. antigen and HLA-B27 triggers CD8 +ve T cell response in ___________

E.g. antigen and HLA-DR4 triggers CD4 +ve T cell response in ___________

A

E.g. antigen and HLA-B27 triggers CD8 +ve T cell response in Ankylosing Spondylitis

E.g. antigen and HLA-DR4 triggers CD4 +ve T cell response in Rheumatoid Arthritis

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12
Q

Describe the possible pathogenesis of Ankylosing Spondylitis

don’t really need to know this - because studies still going on

A

Currently thought that the disease is due to abnormalities in both HLA-B27 and the interleukin-23 pathway:

HLA-B27 has a propensity to misfold –> causes cellular stress –> triggers interleukin-23 release + triggers interleukin-17 production by:

  • Adaptive immune cells i.e. CD4 +ve Th17 cells
  • Innate immune cells e.g. CD4 –ve, CD8 –ve (‘double-negative’) T cells
    note: double -ve T cell = detected in enthuses –> may explain enthesopathy
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13
Q

which rheumatoid disease are not associated with auto antibodies ?

A

Osteoarthritis, reactive arthritis, gout, ankylosing spondylitis = all NONE

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14
Q

Note: Autoantibodies in rheumatology

Systemic vasculitis = antinuclear cytoplasmic antibodies (ANCA)

  • Diffuse systemic sclerosis: Anti-Scl-70 antibody (aka antibodies to topoisomerase-1)
  • Limited systemic sclerosis: Anti-centromere antibodies
  • Dermato/polymyositis: Anti-tRNA transferase antibodies E.g. histidyl transferase (anti-Jo-1 antibodies)
  • Sjögren’s syndrome: no unique antibodies but typically see:

o ANAs - Anti-Ro + anti-La antibodies

o Rheumatoid factor

  • Mixed connective tissue disease: Anti-U1-RNP antibodies
A

-

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15
Q

If ANA (antinuclear antibodies) are tested positive –> what further tests might you screen for?

A 
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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16
Q

Patients with SYSTEMIC LUPUS ERYTHEMATOSUS commonly has:

  • high / low complement levels
  • high / low serum anti-dsDNA Antibodies
A

Patients with SYSTEMIC LUPUS ERYTHEMATOSUS commonly has:

  • low complement levels
    complement gets consumed –> complement levels go down
  • high serum anti-dsDNA Antibodies (high immune complex levels)
17
Q

Describe the general pathogenesis for SYSTEMIC LUPUS ERYTHEMATOSUS

A

in SLE –> antigen = inside the nucleus

a) Apoptosis –> causes translocation of nuclear antigens to membrane surface
b) Impaired clearance of apoptotic cells –> results in enhanced presentation of nuclear antigens to immune cells
c) causes B cell autoimmunity
d) Tissue damage by antibody effector mechanisms e.g. complement activation and Fc receptor engagement

18
Q

What are main cytokines involved in rheumatology ?

A 
IL-1 
IL-2 
IL-6 
TNF-a
y-IFN
19
Q

Th1: secrete____ + ____, important in CD8+ cytotoxicity + macrophage stimulation

  • Th2: secrete ____(IgE responses), _____ (eosinophils), ____ (B cells–> plasma cells) and ____ (inhibit macrophage response)
  • Th17 cells develop in response to ____ + secrete ____ –> which triggers IL-6, IL-8, TNFα, MMPs and RANKL in target cells. –> Important in mucosal immunity but also in arthritis, psoriasis, inflammatory bowel disease, MS
A

Th1: secrete IL-2 + γ-IFN, important in CD8 +ve cytotoxicity + macrophage stimulation

  • Th2: secrete IL-4 (IgE responses), IL-5 (eosinophils), IL-6 (B cells –> plasma cells) and IL-10 (inhibit macrophage response)
  • Th17 cells develop in response to IL-23 + secrete IL-17 à triggers IL-6, IL-8, TNFα, MMPs and RANKL in target cells. Important in mucosal immunity but also in arthritis, psoriasis, inflammatory bowel disease, MS
20
Q

what cytokine is a dominant pro-inflammatory cytokine in rheumatoid synovium?

A

TNF-a

21
Q

In rheumatoid arthritis, what cells produce RANKL?

A

T cells
+
Synovial Fibroblasts

22
Q

What does RANKL DO?

A

stimulates osteoclast formation

23
Q

What is RANKL unregulated by?

A
  • Interleukin-1,
  • TNF-a
  • Interleukin-17
  • -> has potent action on osteoclastogenesis via RANKL-RANK pathway
  • PTH-related peptide
24
Q

How does RANKL Work?

A
  • RANKL Binds to ligand on osteoclast precursors (RANK)

- Action antagonized by decoy receptor – osteoprotegerin (OPG)

25
Q

What is denosumab?

what is it used for?

A

denosumab = monoclonal antibody against RANKL

clinical use:
- use for osteoporosis, bone metastases, multiple myeloma and Giant cell tumours

26
Q

What is a key feature of SYSTEMIC LUPUS ERYTHEMATOSUS?

A

B cell hyper-reactivity

27
Q

What drugs target B cells to treat SLE ? (2 examples)

and how do they work?

A

Rituximab (IV) – chimeric anti-CD20 antibody = used to deplete B cells

Belimumab - monoclonal antibody against B cell survival factor BLYS

–> by decreasing B cells –> decreases antibodies

28
Q

PROSTAGLANDINS IN RHEUMATOLOGY

i.e what is the effect of NSAIDS on rheumatology

A
  • NSAID –> used to control joint pain/ swelling

- -> but doesn’t reduce joint damage

29
Q

Note:
MHC Class I = HLA A B C
MHC CLASS II = HLA DR DQ DP

A

-

30
Q

TNF -a is a pleotrophic cytokine
what are some of its effects ?

where is is mainly produced ?

A

pleotrophic cytokine that can cause:

  • leukocyte accumulation
  • angiogenesis
  • osteoclast activation
  • chondrocyte activation

note: mainly produced by activated macrophages in rheumatoid synovium

eLCRS - 머크 (9 decks)

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