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Module 204, Theme 1: Immunology > RA > Flashcards

RA Flashcards

1
Q

3 major immunologic features of RA

A

Rheumatoid factors:
- Autoantibodies against Fc IgG

Infiltration of lymphocytes and activated macrophages into synovium.

Local production of TNF and pro-inflammatory cytokines in synovium

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2
Q

Epidemiology of RA

A

More common women than men
3:1

Worldwide prevalence
- 1%

Age diagnosed: 40-50

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3
Q

Long term complications of RA

A

Atherogenesis [complement complexes, IL-6, TNF]

  • MI
  • Stroke

Fatigue, depression

Decreased bone mineral density/ Susceptibility to fractures

Insulin resistance/ impaired glucose tolerance

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4
Q

Joint damage pattern in RA

A

Symmetrical, polyarthritic

  • Morning stiffness
  • Inflammation: swelling, hear, red, pain, loss of function

Bone erosion

Synovitis

Cartilage erosion

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5
Q

Synovitis

A

Inflammation of the synovium
- The cardinal feature of RA

Features:
- Swelling over extensor tendons, wrists, MCP joints

  • Synovium hyperplasia

Synovium fibroblast:

  • reduced apoptosis
  • enhanced anchorage
  • Upregulated adhesion molecules
  • Increased proliferation
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6
Q

Composition of synovial tissue

A

Mainly macrophages and T cells

Fibroblasts

Endothelial cells

B cells + plasma cells

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7
Q

Main pro inflammatory cytokines involved in RA

A

IL-1

TNF-a

IL-6

IL-17

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8
Q

Role of innate immune cells in RA

A

Macrophages, mast cells and NK cells invade synovium
- Macrophages: phagocytosis, Ag-presentation, release of TNF, IL-1, IL-6

Neutrophils invade fluid with and undergo enhanced NETosis

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9
Q

Role of T cells in RA

A

Th17= release of Il-17
- activates synovial fibroblasts and osteoclast= cartilage reabsorption

Th1 cells= release of inflammation cytokines

T reg cells
- Defective (can be reversed by blocking TNF)

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10
Q

Role of B cells in RA

A

Auto-antibodies are present before onset of symptoms

B cells form follicular and diffuse infiltrates in synovium

Also produce cytokines, and antigen present

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11
Q

Cartilage erosion

  • Fibroblasts
  • Chondrocytes
A

Fibroblasts

  • Make metalloproteases= break down collagen
  • Adhere to and invade cartilage

Chondrocytes
- Undergo apoptosis

All leads to joint space narrowing, biomechanics dysfunction

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12
Q

Bone erosion

A

Osteoclast differentiation and activation= bone resorption

  • IL-17, RANKL, TNF, IL-1, IL-6
  • Cytokines inhibit the differentiation of osteoblasts

Pits develop and fill with inflammatory tissue

Sites worse- 2nd and 3rd metacarpal

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13
Q

Rheumatoid factor

  • Description
  • Prevalence
  • Limitations
A

Antibodies against Fc portion of Ab form immune complex

Present in 60-70%

Limitations

  • Not specific (86%), also in other AI disease, Healthy individuals
  • Not all RA patients have it
  • Levels do not correlate with disease activity
  • Positive patients= more severe disease
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14
Q

CCP

A

Cyclic citrullinated peptide antibody

Found in 60-70% of RA patients

98% specificity:
- Rarely found in healthy people who do not develop RA

Detected in blood many years before onset

Positive= more aggressive clinical course of disease

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15
Q

Citrullination

A

Process of replacing arginine with citrulline in proteins

If it changes a protein significantly enough, protein can be recognised as foreign and Ab response can occur

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16
Q

Cirullinated self proteins in RA

A

Ab are made against these proteins in RA:

  • Alpha-enolase
  • Keratine
  • Fibronogen
  • Fibronectin
  • Collegen
  • Vimentin
17
Q

CCP antibodies role in pathogenesis

A

Can enhance the development and severity of inflammation when mild synovitis is present (in mice)

Possible mechanisms
- Activation of inflammatory cells by anti-CCP complexes

  • Anti-CCP neutrophil cell death= NETs
  • Anti-CCPs drive osteoclastogenesis
18
Q

Genetics and RA

A

Polygenic: no single gene is necessary or sufficient

Polymorphisms
- HLA etc

Some hereditary factors (monozygotic have higher inheritance than dizygotic)

19
Q

Hormones and RA

A

Testosterone are protective

Pregnancy:

  • Risk increase after given birth and breastfeeding after first pregnancy
  • Remission during pregnancy (increased of Treg cells)

Risk after menopause not affected by HRT

20
Q

Smoking and RA

A

Increases risk with HLA-DR4
alleles

Effect of smoking is greater in genetically susceptible individuals (esp. HLA DRB1)
- Increases anti-CCP positive risk

21
Q

Environmental influences on RA

A

Smoking

Infections

Periodontitis

Hormones

22
Q

Rituximab

A

Partially humanised anti-CD20 monoclonal Ab.

Mechanism
- Opsonised B cells and forms complex which are attacked

Mechanisms of attack

  • Complement mediated cytotoxicity
  • Ab-dependent Cytotoxicity
  • CR mediated opsonic phagocytosis
  • Apoptosis
23
Q

Infliximab

A

Partially humanised mAb

  • Against TNF
  • Combined with methotrexate

Mechanism
- Neutralises TNF and stimulates ADCC

Administration

  • IV
  • 3mg per kg of body weight
  • Repeat 2, then 6 weeks, then every 8 weeks
24
Q

Methotrexate

  • Drug type
  • Mechanism (4)
  • Administration
A

Synthetic disease modifying anti-rheumatic drug (DMARD)

Mechanism

  • Inhibits cell proliferation
  • Increases adenosine level (anti-inflammatory)
  • Reduces production of damaging polyamine
  • Induces apoptosis of activated CD4, CD8

Administration:

  • 7.5 and 25mg weekly
  • Subcutaneous/ orally

Outcomes

  • Reduces inflammation and controls it
  • Reduces CVD death in RA
  • Anchor drug in combination with other therapies
25
Q

Symptom relievers in RA

A

NSAIDs

  • Non-selective COX1/2: aspirin, ibuprofen, diclofenac
  • Celecoxib

Glucocorticoids: prednisone

Module 204, Theme 1: Immunology (22 decks)

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