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Year 2 Collin > Musc 4 & 5 - Pathogenesis of Autoimmune disease and Rheumatoid Arthritis (RA) > Flashcards

Musc 4 & 5 - Pathogenesis of Autoimmune disease and Rheumatoid Arthritis (RA) Flashcards

1
Q

What is RA?

A

RA = Chronic joint inflammation that can result in joint damage

Site of inflammation is the synovium (often referred to as chronic synovitis)

Associated with 2 autoantibodies (Rhematoid factor and CCP antibodies)

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2
Q

Name 4 seronegative spondyloarthropathies

A
  1. Ankylosing spondylitis
  2. Reactive arthritis and Reiters syndrome
  3. Psoriatic arthritis
  4. Enteropathic synovitis
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3
Q

What is ankylosing spondylitis

A

Chronic spinal inflammation that can lead to spinal fusion and deformity

Site of inflammation = enthesis (connective tissue between tendon/ligament and bone - for spinal problems it occurs in vertebral bodies) = ENTHESITIS

It is seronegative (no antibodies)

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4
Q

What is Systemic Lupus Erythematosus (SLE) and what group of diseases does it belong to

A

SLE = chronic tissue inflammation in the presence of auto-antibodies

Inflammation occurs at various sites - particularly joints, skin and kidney

Associated with 2 antibodies - antinuclear antibodies, anti-double stranded DNA antibodies

SLE is part of the connective tissue diseases - associated w immune complexes and triggering complement system

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5
Q

Which 2 antibodies are involved in lupus

A
  1. Antinuclear antibodies

2. Anti-double stranded DNA antibodies

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6
Q

RA is associated with which HLA?

A

HLA-DR4 (MHC class 2) - i.e. exogenous, CD8

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7
Q

SLE is associated with which HLA?

A

HLA-DR3 (MHC class 2) - i.e. exogenous, CD8

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8
Q

Ankylosing spondylitis is associated with which HLA?

A

HLA-B27 (MHC class 1) - i.e. endogenous, CD4

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9
Q

Describe MHC class 1 molecules

A

HLA -A/B/C

Present on all nucleated cells

Responsible for endogenous (intracellular) antigen presentation

Recognised by CD8+ T cell

Response is cell killing

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10
Q

Describe MHC class 2 molecules

A

HLA - DR/DQ/DP

Present on antigen presenting cells

Responsible for exogenous (extracellular) antigen presentation

Recognised by CD4+ T cells

Causes antibody response

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11
Q

It is currently thought that Ankylosing Spondylitis is caused by abnormalities in HLA-B27 and IL-23. Explain

A
  1. HLA-B27 has a propensity to misfold - which causes cellular stress - which then causes IL-23 release and IL-17 cell production (inflammation) by:
  • adaptive immune cells (i.e. CD4+ Th17 cells)
  • innate immune cells (i.e. CD4 -ve, CD8 -ve, double negative T cells)
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12
Q

What are the 2 key antibodies in RA?

A
  1. Rheumatoid factor

2. Anti-cyclic citrullinated peptide antibody

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13
Q

What are the 2 key antibodies in SLE?

A
  1. Antinuclear antibodies (ANA)

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

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14
Q

Which autoimmune disorders have no antibodies involved (i.e. seronegative)

A
  1. Osteoarthritis
  2. Reactive arthritis
  3. Gout
  4. Ankylosing spondylitis
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15
Q

Which antibodies are involved in systemic vasculitis?

A

Antinuclear cytoplasmic antibodies (ANCA)

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16
Q

What is sclerosis

A

Skin thickening

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17
Q

What is the key antibody in diffuse systemic sclerosis?

A

Anti-Scl-70 antibody

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18
Q

What is the key antibody in limited systemic sclerosis

A

Anti-centromere antibodies

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19
Q

What is the antibody in dermato-/polymyositis

A

Anti-tRNA transferase inhibitors

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20
Q

What is the antibody in mixed connective tissue disease

A

Anti-u1-RNP antibodies

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21
Q

Name 4 connective tissue diseases

A
  1. SLE
  2. Inflammatory muscle disease
  3. Systemic sclerosis
  4. Sjogrens syndrome
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22
Q

What is the current paradigm for SLE understanding

A

Apoptosis = translocation of nuclear antigens to membrane surface

Impaired clearance of apoptotic cells = enhanced presentation of nuclear antigens to immune cells

B cell autoimmunity

Tissue damage by Ab effector mechanisms

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23
Q

What is the key signs of a sick SLE patient

A
  1. Low complement levels

2. High serum levels (o anti-dsDNA antibodies)

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24
Q

Which cytokine is one of the major contributors of synovitis

A

TNF-a

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25
Q

What are the CD4 +ve T helper subsets

A

Th1, Th2, Th17

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26
Q

What do Th1 cells secrete

A

IL-2 and y-IFN - important response in CD8+ve cytotoxicity and macrophage stimulation

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27
Q

What do Th2 cells secrete

A

IL-4 (IgE responses), IL-5 (eosinophils), IL-6 (B cell to plasma cell) and IL-10 (inhibit macrophage response)

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28
Q

What do Th17 cells develop in response to? And what do they secrete

A

Th17 cells develop in response to IL-23

They secrete IL-17 - potent cytokine which triggers IL-6, IL-6, TNF-a, MMPs and RANKL in target cells

Important in mucosal immunity - also in disease such as arthritis, psoriasis, IBD and MS

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29
Q

Describe y-IFN

A

Secreted by T-cells, activates macrophages

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30
Q

Describe IL-1

A

Secreted by macrophages

Activates T cells, fever, pro-inflammatory

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31
Q

Describe IL-2

A

Secreted by T-cells

Activates T and B cells

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32
Q

Describe IL-6

A

Secreted by T cells

Activates B cells, acute phase response

33
Q

Describe TNF-a (dominant cytokine)

A

Secreted by macrophages

Similar to IL-1

34
Q

What does TNF-a do in rheumatoid synovium?

A

Activates synovium, increased synovial fluid production

35
Q

Where is TNF-a mainly produced?

A

In rheumatoid synovium by activated macrophages

36
Q

Some cytokine treatments inhibit TNF-a. What effects does this have

A

Block of production of IL-1/6, chemokine, IL-8, GM-CSF

37
Q

Il-1 inhibition is more or less effective than IL-6/TNF-a inhibition?

A

Less effective, not recommended for RA

38
Q

In RA, explain the importance of RANKL in bone destruction

A
  • Made by T-cell and synovial fibroblasts –> stimulate osteoclast formation
  • Binds to receptor on osteoclast precursors
39
Q

What is RANKL unregulated by

A

IL-1, TNF-a, IL-17 (potent)

Also by PTH-related peptide

40
Q

RANKL action is antagonised by what?

A

Action of osteoprotegerin (decoy receptor)

41
Q

Name a monoclonal antibody against RANKL

A

Denosumab - used for osteoporosis, bone metastases, multiple myeloma and Giant cell tumours

42
Q

B-cell hyper-reactivity is a key feature of?

A

SLE

43
Q

Name 2 biological therapies used to target B cells

A
  1. Rituximab - chimeric anti-CD20 Ab which depletes B cells
  2. Belimumab - monoclonal Ab against B cell survival factor (“BLYS”) - used as add-on therapy - not recommended for severe CNS lupus/lupus nephritis
44
Q

What type of monoclonal antibody is belimumab

A

Recombinant fully human IgG1 monoclonal antibody against BLYS(/BAFF)

  • works by inhibiting BLYS/BAFF - causes impaired B cell survival and reduced B cell numbers
45
Q

NSAIDS are used in rheumatology. What are prostaglandins

A

Prostaglandins = lipid mediators of inflammation that act on platelets, endothelium, uterine tissue and mast cells

46
Q

How is arachidonic acid synthesises

A

Phospholipase A2 generated arachidonic acid from diacylglycerol (DAG) in cell membranes

47
Q

Which 2 pathways does arachidonic acid enter?

A
  1. COX pathway - arachidonic acid becomes prostaglandins

2. Lipooxygenase pathway - arachidonic acid becomes leukotrienes

48
Q

What do prostaglandins do

A

Mediate vasodilation, inhibit platelet aggregation, bronchodilation, uterine contraction

49
Q

What do leukotrienes do?

A

Mediate leukocyte chemotaxis and SM contraction, bronchoconstriction and mucus secretion

50
Q

Which enzyme do glucocorticoids inhibit?

A

Phospholipase A2 - hence used in rheumatology (as well as NSAIDS)

51
Q

What are the unwanted effects of glucocorticoids

A

Asthma exacerbation, GI ulcers, thrombosis, liver and renal problems

52
Q

Define RA

A

Chronic autoimmune disease characterised by pain, stiffness and SYMMETRICAL synovitis of synovial joints

53
Q

Spinal RA doesn’t mean the lumbar spine, it refers to?

A

The Atlanta-axial joint

54
Q

What are the key features of RA

A
  1. Chronic arthritis
    - Polyarthritis - swelling of many small joints of the hand/wrist
    - symmetrical
    - early morning stiffness
    - joint erosions on radiographs
  2. Extra-articular disease
    - Rheumatoid nodules
  3. Rheumatoid factor may be detected in blood
55
Q

What is rheumatoid factor?

A

IgM autoantibody against IgG

56
Q

Which gender is RA more common in?

A

F

57
Q

What are the genetic and environmental components of RA?

A

Genetic: HLA-DRB gene variants which map the DRB-chains associated with RA

Environmental: smoking correlated with RA

58
Q

What are the most commonly affected joints in RA?

A
  1. MTP
  2. MCP
  3. PIP
  4. Wrists
  5. Knees
  6. Ankles
59
Q

Name 2 deformities in the hands that show RA

A
  1. Swan neck deformity - hyperextension at PIP, hyperflexion at DIP
  2. Boutonniere deformity - hyperflexion at PIP

Look at pictures of these to remembr

60
Q

In RA, where is the primary site of pathology

A

Synovium

61
Q

What does tenosynovium wrap around?

A

Tendon sheaths

Tenosynovitis = damages tendon and impairs function

62
Q

RA may present with subcutaneous nodules.

A

T

Occurs in 30% of patient

It is a central area of fibrinoid necrosis surrounded by histiocytes and peripheral layer of connective tissue

63
Q

Rheumatoid factor antibodies, describe them

A
  1. Typically IgM antibodies
  2. Recognise the Fc portion of IgG as their target antigen

i.e. IgM anti-IgG antibody

This causes RA nodules, etc

However, testing for Rheumatoid factor isn’t diagnostic as 30% of RA is RF negative

64
Q

In RA, there are antibodies to citrullinated protein antigens (ACPAs/anti-CCPs). What do these do

A
  • They are highly specific for RA (anti-CCP antibody)
  • They cause citrullination of peptides, through enzymes called PADs (Peptidyl arginine deiminases). They convert Arginine —-> Citrulline.

ACPA is strongly linked with smoking

65
Q

Where are PADs (Peptidyl arginine deiminases) found?

A

In high concentrations in neutrophils and monocytes –> common in inflamed sites (e.g. synovium)

66
Q

In terms of HLA, when is an individual susceptible?

A

If they carry a conserved AA sequence in their HLA-DR4 antigen binding groove

67
Q

Name some extra-articular features of RA

A

Common: subcutaneous nodules, fever and weight loss

Uncommon: vasculitis, etc

Caused by abnormal cytokine response - usually rapid improvement of symptoms after treating cytokine response

68
Q

What radiographic abnormalities are present due to RA

A

Early - juxta-articular osteopenia

Later on - joint erosions at margins of the joint, followed by joint deformity and destruction after that

69
Q

Describe the composition of synovium

A

1-3 cell deep

Contains macrophage like phagocytic cells (Type A synoviocyte)

Contains fibroblast-like cells - produce Hyaluronic acid (type B synoviocyte)

Also contains type 1 collagen

70
Q

Why is synovial fluid viscous

A

Due to lots of Hyaluronic acid

71
Q

What are the 2 major constituents of articular cartilage

A

Type 2 collagen and aggrecan

72
Q

The pathogenesis of RA is still unclear but, what are some reasons for it?

A

Synovium becomes a proliferated mass of tissue (Pannus) due to:

  1. Neovascularisation
  2. Lymphangiogenesis
  3. Cytokine imbalance
73
Q

In the management of RA, what is the treatment goal?

A

To prevent joint damage

74
Q

Which 2 medications are given for management of RA

A
  1. DMARDS - Disease Modifying Anti-Rheumatic Drugs.
    Started early in disease because risk of joint damage worsens with time - “steroid sparing”, safer and better for long term use
  2. Glucocorticoid therapy - used short term, not Long term as too many SEs

There are new biological therapies being developed - Janus kinase inhibitors

75
Q

What do DMARDs do and name some commonly used DMARDs

DMARDS have complex and slow onset of action

A

They induce remission (not cure) and prevent joint damage

  • they reduce inflammation in synovium
  • slow/prevent structural joint damage

EG: Methotrexate, sulphasalazine, hydroxychloroquine, Janus kinase inhibitors

76
Q

Methotrexate is a DMARD, and has a lot of SEs. Therefore, what must happen?

A

Requires regular blood test monitoring.

77
Q

Describe the biological therapies for RA

A
  1. Infliximab - anti TNF-a antibody
  2. Rituximab - B-cell antibody against CD20 antigen (causes B cell depletion)
  3. Abatacept - modulation of T-cell costimulation
  4. Tocilizumab or Sarilumab
78
Q

What is the downside of biological therapy

A
  1. Increased infection risk
  2. Expensive
  3. TNF-a inhibition = increased susceptibility to mycobacterial infection
  4. B cell depletion therapy = Hep B reactivation
  5. B cell depletion therapy - JC virus infection and progressive multifocal leukoencephalopathy

Year 2 Collin (114 decks)

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