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Musculoskeletal > Pathogenesis of autoimmune disease > Flashcards

Pathogenesis of autoimmune disease Flashcards

1
Q

Rheumatoid arthritis

A
  • Chronic joint inflammation potentially resulting in joint damage
  • inflammation site is synovium
  • autoantibody association=RHEUMATOID factor and anti-cyclic citrullinated peptide antibodies (CCP)
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2
Q

Anklyosing spondylitis

A
  • Chronic spinal inflammation resulting in spinal fusion and deformity
  • inflammation site is enthesis
  • no auto-antibodies=’seronegative’
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3
Q

Types of seronegative spondylarthropathies

A
  • ankylosing spondylitis
  • reiter’s syndrome and reactive arthritis
  • psoriatic arthritis (arthritis associated with psoriasis)
  • enteropathic synovitis (arthritis associated with GI inflammation)
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4
Q

SLE

A
  • Chronic tissue inflammation in the presence of self antigen antibodies
  • multi-site inflammation=particularly joints, skin and kidneys
  • autoantibody assocation=ANTINUCLEAR antibodies and anti-double stranded DNA antibodies
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5
Q

Types of connective tissue diseases

A
  • SLE
  • Systemic sclerosis
  • Sjogren’s syndrome
  • Inflammatory muscle disease=polymyositis, dermatomyositis
  • overlap syndromes=mixture of above problems
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6
Q

HLA molecules

A

HUMAN LEUKOCYTE ANTIGEN

  • major histocompatibility complex in humans
  • genes within MHC class I and class II regions encode cell surface proteins

Association between MHC and disease:

  • rheumatoid arthritis and HLA-DR4=class II
  • SLE and HLA-DR3=class II
  • Anklyosing spondylitis and HLA-B27=class I
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7
Q

HLA molecule function

A
  • HLA molecules present antigens to T lymphocytes
  • Class I on all nucleated cells=CD8+ T cells=cell killing
  • Class II on antigen presenting cells=CD4+ T cells=antibody response
  • peptide binding site made up of walls (alpha-helical structures) and floor (beta-pleated sheet)
  • sequence in peptide-binding groove determines which antigens bind
  • T cells only see antigen-bound MHC=MHC restriction
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8
Q

Pathogenesis of HLA-associated diseases/////

A

-due to peptide antigen (exogenous or self) that is able to bind to HLA molecule and trigger disease=arthritogenic antigen
Examples include:
-antigen and HLA-B27 tirggers CD8+ T cell response in ankylosing spondylitis
-antigen and HLA-DR4 triggers CD4+ T cell response in rheumatoid arthritis

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9
Q

Auto-antibodies in rheumatoid arthritis

A
  • rheumatoid factor

- anti-cylic citrullinated peptide antibody

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10
Q

Auto-antibodies in SLE

A
  • antinuclear antibodies=ALWAYS
  • anti-double stranded DNA antibodies=SPECIFIC FOR SLE (serum level correlates with disease activity)
  • anti-cardiolipin antibodies (association with risk of arterial and venous thrombosis)
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11
Q

Auto-antibodies in osteoarthritis, reactive arthritis, ankylosing spondylitis and gout

A

NONE

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12
Q

Auto-antibodies in systemic vasculitis

A

-Antinuclear cytoplasmic antibodies

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13
Q

Auto-antibodies in diffuse systemic sclerosis

A

-anti SCl-70 antibody

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14
Q

Auto-antibodies in limited systemic sclerosis

A

-anti-centromere antibodies

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15
Q

Auto-antibodies in dermato/polymyositis

A

-anti-tRNA transferase antibodies

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16
Q

Auto-antibodies in Sjogren’s syndrome

A

No unique antibodies but typically see antinuclear antibodies (anti-Ro and anti-La) and rheumatoid factor

17
Q

Auto-antibodies in mixed connective tissue disease

A

-Anti-U1-RNP antibodies

18
Q

Antinuclear antibodies

A
  • directed against nucleus contents

- if positive for ANA in lab, further tests performed to determine ANA type (screening)

19
Q

Disease activity in SLE

A

Sick lupus patient commonly has:

  • low complement levels
  • high serum levels of anti-ds-DNA antibodies
20
Q

Current pathogenesis of SLE//////

A

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=complement activation and Fc receptor engagement

21
Q

Cytokines in rheumatology

A

TNFalpha=dominant pro-inflammatory cytokine in rheumatoid synovium and its many (pleotropic) actions are detrimental here:

  • chemokine release
  • endothelial cell activation
  • leukocyte accumulation
  • angiogenesis
  • osteoclast activation
  • PGE2 production
  • pro-inflammatory cytokine release

KEY IN RHEUMATOID ARTHRITIS

22
Q

RANKL

A

IMPORTANT IN BONE DESTRUCTION IN RHEUMATOID ARTHRITIS

  • produced by T cells and synovial fluid fibroblasts in rheumatoid arthritis
  • stimulates osteoclastogenesis (osteoclast formation=BREAKS DOWN)
  • binds to ligand on osteoclast precursors (RANK)=production
  • RANKL action antagonised by osteoprotegerin (decoy receptor)

Upregulated by:

  • IL-1, TNFalpha
  • IL-17 (potent action on osteoclastogenesis via RANKL-RANK pathway)
  • PTH related peptide
23
Q

Denosumab

A
  • monoclonal antibody against RANKL
  • indicated for treatment of osteoporosis, bone metastases, multiple myeloma and giant cell tumours (slowing bone turnover=aim of Tx)
24
Q

B cell hyper-reactivity/////

A
  • key feature of SLE=modern treatments targeting B cells have been developed (number or turnover)
  • Rituximab=chimeric anti-CD20 antibody to deplete B cells
  • Belimumab=monoclonal antibody against B cell survival factor BLYS
  • shown to be effective in reducing SLE symptoms
25
Q

Belimumab

A
  • Recombinant fully human IgG1 monoclonal antibody against BLyS (B-lymphocyte stimulator)
  • inhibits BAFF activity leading to impaired B cell survival and reduced B cell numbers
26
Q

Treatment against cytokines

A
  • complex network of pro-inflammatory cytokines in inflammatory cascade=TNFalpha is dominant
  • IL-6 and IL-1 blockade available in clinic
  • inhibition of TNFalpha
  • can also deplete B cells in rheumatoid arthritis by I.V. administration of antibody against CD20 (B cell surface antigen) such as Rituximab
27
Q

Primary anti-phospholipid antibody syndrome

A

Anti-cardiolipin antibodies in absence of SLE

28
Q

Detecting presence of antinuclear antibodies

A

/

29
Q

Ankylosing spondylitis and HLA molecules

A
  • no arthritogenic peptide binding to HLA-B27 identified
  • Ankylosing spondylitis independent of CD8+ T cells
  • new theory suggests due to abnormalities in HLA-B27 and IL-23 pathway
  • HLA-B27 has tendency to misfold which causes cellular stress=triggers IL-23 release and IL-17 production by adaptive immune cells (CD4+ Th17 cells) and innate immune cells (CD4-, CD8- T cells=double negative)
  • double negative T cells detected in entheses=explanation for enthesopathy occurring in ankylosing spondylitis
30
Q

Prostaglandins in rheumatology

A

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

Musculoskeletal (8 decks)

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