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BSMS204- Symposium > Systemic Inflammatory Disease > Flashcards

Systemic Inflammatory Disease Flashcards

1
Q

Describe the causes for auto-immunity?

A
  • Immune responses to self antigens
  • Represents a breakdown of immunological tolerance
  • Immune reactions to self antigens can occur as part of the controlled inflammatory reaction
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2
Q

Describe the role of cytokines in RA?

A

Acute- removal of pathogen/tissue repair

-Chronic- Tissue destruction

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3
Q

What is the consequence of chronic inflammation?

A
  • Chronic inflammation causes tissue damage

- Inflammation associated with auto-immunity are chronic, unregulated and persistent

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4
Q

Describe the clinically observed long term complications in patients with RA?

A 
-Liver: Acute phase response
Iron redistribution
-Fat: free fatty acids, adipocytes
-Muscle: Insulin resistance
-Blood vessels: Atherogenesis, Myocardial infraction
Stroke
-Brain: Low stress tolerance
-Depression
Bone: Low  bone mineral density
-Fracture
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5
Q

Describe the joint damage in RA?

A

1) Usually multiple joints in symmetrical fashion
- Morning stiffness
- Swelling, heat, redness and pain
- Loss of function
2) Destructive process
- Bone erosion
- Synovial and cartilage damage

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6
Q

What are the clinical markers of RA?

A

-Elevated ESR
-Elevated CRP
-Presence of auto-antibodies:
Rheumatoid factor (RF)
Cyclic citrullinated peptide (CCP) antiboides

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7
Q

Describe the role of Rheumatoid factor in RA?

A

RF are antibodies directed against the FC portion of another antibody leading to immune complex formation
-Presents in 6060-70% of the patients with RA

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8
Q

What are the limitations of RF in diagnosing RA?

A
  • Not specific for RA (also present in other auto-immune diseases , infectious diseases and healthy individuals
  • Some RA patients are seronegative
  • Levels do not correlate with disease activity
  • RF +ve patients have a more severe disease
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9
Q

What is the role of anti-cyclic citrullinated peptide (CCP) antibody in diagnosis of RA?

A
  • Antibodies directed against CCP are found in 60-70% of the patients with RA
  • Very rarely found in healthy people who do not go on to develop RA
  • Detectable in blood many years before the disease onset
  • Anti CCP +ve has more aggressive clinical course of disease
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10
Q

Describe the role of citrullination in RA?

A
  • Process of replacing protein arginnine residues with citrulline residue
  • Occurs normally in the body but if occurs on an unusual part of the protein, they may be recognised as foreign leading to antibody response
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11
Q

What is the etiology of RA?

A

Genes- autoimmune disease

  • Immune dysfunction
  • Environment
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12
Q

Describe the genetics of RA?

A
  • Relatively low gene penetrance
  • no particular gene
  • susceptibility and severity is determined by a combination of genes
  • Must be other factors in addition to genetics that have a role in the susceptibility and severity of autoimmune disease
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13
Q

Name the genes associated with RA?

A
  • HLA-DRB1 SE: Human leukocyte antigen accounts for 30-50% the overall genetic risk
  • PTPN22 - Negative regulator of antigen receptor signalling in T and B cells (protein tyrosine phosphatsase 22)
  • CTLA4: co-stimulation supressor that regulates interactions between T cells and antigen presenting cells (down regulated in RA)
  • TFAAIP3: inhibitor of NF-kB and TNF a mediated apoptosis (down regulated in RA)
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14
Q

what are the roles of hormones in R diagnosis?

A
  • Men have low testosterone
  • RA patients experience remission during pregnancy with less disease activity and increased T regulatory cells
  • Risk of RA is elevated after giving birth
  • Early menopause has been associated with both an increased of risk of RA
  • Use of oral contraceptives modestly decreases risk of ACPA+RA
  • Mixed data on HRT
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15
Q

What is the role of smoking in RA?

A
  • Heavy smoking of both sexes increases the of RA

- Smoking and HLA-DRB1 alleles increase the risk of being anti- CCP+ve

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16
Q

Describe the molecular mechanism of joint destruction?

A
  • Swelling over extensor tendons, writs and MCP joints
  • Synovium hyperplasia ( an increase in cell numbers)
  • Synovial fibroblasts have reduced apoptosis, enhanced anchorage, up regulated adhesion molecules and increased proliferation
17
Q

Describe the joint pathology in RA?

A
  • Pannus- inflamed synovial membrane
  • Synovial fluid: rich in neutrophils
  • Synovitis
  • Cartilage erosion
  • Bone erosion
18
Q

Describe the composition of synovial tissue?

A
  • Macrophages (40%)
  • T lymphocytes (40%)
  • B lymphocytes and plasma cells (5%)
  • Fibroblasts and endothelial cells (10-15%)
19
Q

Describe osteoblast bone erosion?

A
  • Cytokines including IL-17, RANKL, TNF -alpha, IL-1 and IL-6 promote osteoclast differentiation and activation
  • Little repair as cytokines inhibit the differentiation of osteoblast
  • Deep bone resorption pits develop, which become filled with inflammatory tissue
  • Worse at mechanically vulnerable sites, such as the 2nd and 3rd metacarpal
  • 80% of the RA patients within 1 year of diagnosis
20
Q

Describe mechanism if cartliage erosion?

A
  • Fibroblasts make matrix metalloproteases MMO which break down the collagen network in the cartilage
  • Chondrocytes undergo apoptosis
  • Fibroblasts adhere to an invade the cartilage
  • Leads to bio- mechanical dysfunction and joint space narrowing
21
Q

What are the role of T cells in RA?

A
  • Human Leukocyte antigen (HLA) association suggest T cell role
  • RA synovium is rich in activated T cells (Th17 cells and Th1 cells predominate)
  • Increasingly Th17 cells have been suggested as a major pathogenic subset
22
Q

What is the role of IL17 is known to?

A
  • Activate synovial fibroblast and osteoclast
  • Favour cartliage resorption
  • T regulatory cells are enriched in RA joint but appear to be a defect that can be reversed by blocking TNF
23
Q

What are the roles of B cells in RA?

A
  • Auto-antibodies associated with disease are usually present before the onset of symptoms
  • B cells form diffuse or follicular infiltrates in the RA synovium
  • B cells depletion using monoclonal anti-CD20 is effective treatment
  • B Cells also produce cytokines and are important for antigen presentation
24
Q

What are the roles of innate immune cells in RA?

A
  • Infiltrating macrophages, mast cells and NK cells in the synovium
  • Macrophages appear to be key effectors:
    1) phagocytosis
    2) Antigen presentation
    3) TNF, IL-1 and IL-6
25
Q

What is the role of the immune therapies in RA?

A
  • Most therapies decrease macrophages cytokine production

- Decreased macrophage infiltration strongly correlates with the degree of clinical improvement to therapies

26
Q

Describe the role of neutrophDo a

A
  • When activated neutrophils can undergo a special form of cell death termed ‘Netosis’ releasing nuclear chromatin
  • Neutrophils infiltrate synovial fluid
  • Enhanced ‘Netosis’ correlates with the presence of anti-CCP antibodies
  • NET’s release citrullinated proteins
27
Q

Do anti-CCP antibodies have pathogenic role?

A

Anti-CCP antibodies are unable to induce arthritis alone- but can enhance the development and severity of inflammation in mice when a mild synovitis

28
Q

Describe the mechanism of anti-CCP antibodies for RA?

A

1) activation of inflammatory cells by anti-CCP immune complex
2) Anti-CCP mediated neutrophils cell death produced by NETs
3) Direct binding of anti-CCPs to drive osteoclastogenesis

29
Q

Which cytokines does the macrophages produce?

A

-IL-6
-IL-1beta
-TNF
All these cause the osteoclasts formation and activation
-RANKL and M-CSF produced by synovial fibroblast proliferation and activation have the same effect

BSMS204- Symposium (4 decks)

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