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Pathogenesis of autoimmune disease Flashcards

1
Q

List 3 key autoimmune disorders

A

Rheumatoid arthritis
Ankylosing spondylitis
Systemic Lupus Erythematosus (SLE)

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2
Q

What is rheumatoid arthritis

Is it associated with autoantibodies? If so, which

A

Chronic joint inflammation that can result in joint damage

Site of inflammation is the synovium (chronic synovitis)

Associated with autoantibodies:

  1. Rheumatoid factor
  2. Anti-cyclic citrullinated peptide (CCP) antibodies
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3
Q

What is ankylosing spondylitis.

Is it associated with autoantibodies? If so, which

A

Chronic spinal inflammation that can result in spinal fusion and deformity

Site of inflammation is the enthesis (area where ligaments or tendons insert into bone e.g. intervertbral disks and the achilles tendon)

No autoantibodies (‘seronegative’)

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4
Q

Ankylosing spondylitis is an example of which type of disease? List other types of this disease

A

SERONEGATIVE SPONDYLOARTHROPATHIES

  • Ankylosing spondylitis
  • Reiters syndrome and reactive arthritis
  • Arthritis associated with psoriasis (psoriatic arthritis)
  • Arthritis associated with gastrointestinal inflammation (enteropathic synovitis)
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5
Q

What is systemic lupus erythematosus (SLE)?

Is it associated with autoantodies?

A

Chronic tissue inflammation in the presence of antibodies directed against self antigens (creating of IMMUNE COMPLEXES)

Multi-site inflammation

Multi-site inflammationociated with autoantibodies:
Antinuclear antibodies
Anti-double stranded DNA antibodies

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6
Q

SLE is multi-site inflammation but particularly affects which tissues

A

Multi-site inflammation but particularly the joints, skin and kidney

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7
Q

SLE comes under which kind of disease. Give other examples

A

CONNECTIVE TISSUE DISEASES
Systemic lupus erythematosus

Inflammatory muscle disease: polymyositis, dermatomyositis

Systemic sclerosis

Sjogren’s syndrome

A mixture of the above: ‘Overlap syndromes’

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8
Q

Outline the HLA types associated with

Rheumatoid arthritis, SLE and ankylosing spondylitis

A

Rheumatoid Arthritis HLA-DR4

Systemic Lupus Erythematosus HLA-DR3

Ankylosing Spondylitis HLA-B27

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9
Q

Why are certain HLA associated with autoimmune disease

A

The MHC molecule is responsible for antigen presentation

There is a certain type of MHC that is associated with these autoimmune diseases - some MHC molecules can present the antigen in such a way that you get more of an immune response being generated

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10
Q

What determines whether a T cell will see an antigen

A

Sequence in peptide-binding groove determines which antigens can bind
T cells only see antigen-bound to MHC (‘MHC restriction’)

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11
Q

Outline where class I MHC is present and the function

A

Class 1 on all nucleated cells present endogenous antigens….
CD8 +VE T cell
Response it cell killing

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12
Q

Outline where class II MHC is present and the function

A

On APCs presenting exogenous antigens….. CD4+VE T cell

Leads to antibody response

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13
Q

Where are HLA molecules encoded

A

encoded in a gene locus called the major histocompatibility complex. They encode surface proteins. There are various serotypes.

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14
Q

Outline the HLA types associated with each MHC class

The HLA gene locus codes for which part of the MHC molecule

A

MHC Class I: HLA A, B or C

MHC Class II: DR molecules

HLA codes for the alpha chains in the MHC molecule

The beta-2 microglobulin of MHC comes from a different gene locus

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15
Q

Which MHC class is RA, SLE and AS associated with

A

Rheumatoid arthritis and SLE are associated with MHC class II molecules

*Ankylosing spondylitis is associated with MHC class I molecules

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16
Q

What is the strucutre of MHC

A

Peptide-binding site made up of walls (α-helical structures) and floor (β-pleated sheet

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17
Q

Outline the concept of MHC restriction

A

T-cells can recognise antigen when it is complexed In HLA molecules

This is referred to as MHC restriction

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18
Q

T/F ankylosing spondylitis is CD8 cell dependent

A

So

HLA-B27 binds antigens, and this triggers CD8+ T cells

This was thought to be the basis of ankylosing spondylitis

However, in mice, the CD8+ T cells were removed, and the rats still showed disease, so this theory cannot be correct

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19
Q

Outline the proposed theory for ankylosing spondylitis

A

HLA-B27 has a propensity to MISFOLD, which causes cellular stress that triggers IL-23 release and triggers IL-17 production by:

Adaptive immune cells e.g. CD4+ cells, Th17 cells

Innate immune cells e.g. CD4- + CD8- (double negative) T cells

This release of chemical mediators leads to inflammation

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20
Q

What is the proposed reason for akylosing spondylitis occurring in enthesis

A

The innate cells which release IL-23 and IL-17 due to HLA-B27 misfolding (causing cellular stress)

are present in the entheses and this may explain why enthesopathy occurs in ankylosing spondylitis

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21
Q

Outline the overall pathogenesis of HLA-associated disease

A

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

E.g. antigen and HLA-B27 triggers CD8 +ve T cell response in Ankylosing Spondylitis (although no arthritogenic peptide for HLA-B27 has been identified)

E.g. antigen and HLA-DR4 triggers CD4 +ve T cell response in Rheumatoid Arthritis (an example is citrullinated peptides)

22
Q

What are the important autoantibodies in:

  1. Rheumatoid arthritis
  2. SLE
  3. Osteoarthritis
  4. Reactive arthritis
  5. Gout
  6. Ankylosing spondylitis
A
  1. Rheumatoid factor, ACPA
  2. Antinuclear antibodies, anti-double stranded DNA antibodies, anti-cariolipin antibodies
  3. None
  4. None
  5. None
  6. None
23
Q

The anti-Scl-70 autoantibody is key for which disease

The anti-centromere antibody is key in which disease

Which autoantibody is key for dermato-polymyositis

Which autoantibody is key for mixed connective tissue disease

A

Diffuse systemic sclerosis

Limited systemic sclerosis

Anti-tRNA transferase antibodies

Anti-U1-RNP antibodies

24
Q

State the significance of antinuclear antibodies (ANA)

A

Seen in all SLE cases

Not specific for SLE

25
Q

State the significance of anti-dsDNA autoantibody

A

Specific for SLE

Serum level of antibody correlates with disease activity

26
Q

State the significance of the anti-cardiolipin autoantibody

A

associated with risk of arterial and venous thrombosis in SLE

may also occur in absence of SLE in what is termed the ‘primary anti-phospholipid antibody syndrome

27
Q

What can help to differentiate between connective tissue diseases such as lupus, systemic sclerosis, inflammatory muscle disease (polymyositis, dermatomyositis ) etc.

A

ANAs could signal the body to begin attacking itself which can lead to autoimmune diseases, including lupus, scleroderma, Sjögren’s syndrome, polymyositis/dermatomyositis, mix.

It is important to then get the more specific tests such as anti-centromere (+ve in Limited systemic sclerosis) or anti-dsDNA (+ve in SLE) to determine the exact disease

Most of these autoantibodies are affecting inside the nucleus but some affecting the cytoplasm (e.g. Anti-tRNA synthetase antibodies
Anti-ribosomal P antibodies… obvious as these appear in the cytoplasm)

28
Q

What will happen to complement levels and anti-ds-DNA levels in a SLE patient who is currently sick

A

Low complement levels (as the complement is ‘consumed’ by the immune complexes)

High serum levels of anti-ds-DNA antibodies

29
Q

Outline the current pathogenesis model in SLE

How can autoantibodies be made against antigens within the nucleus

A

Physioogically, apoptosis leads to translocationof nuclear antigens to membrane surface

In SLE there is then impaired clearance of apoptotic cells resulting in enhanced presentation of nuclear antigens to immune cells

There is B cell autoimmunity

There is tissue damage by antibody effector mechanisms e.g. complement activation and Fc receptor engagement

30
Q

Subsets of CD4+ T helper clels

A

Th1, Th2 and Th17

31
Q

Function of Th1

A

Th1 cells secrete IL-2 and γ-IFN and response is important in CD8 +ve cytotoxicity and macrophage stimulation

32
Q

Function of Th2

A

Th2 cells secrete IL-4 (IgE responses), IL-5 (eosinophils), IL-6 (B cells to plasma cells) and IL-10 (inhibit macrophage response)

33
Q

Function of Th17

A

develop in response to IL-23 and secrete IL-17, a potent cytokine which triggers IL-6, IL-8, TNFα, matrix metalloproteinases and RANKL in target cells. Important in mucosal immunity but also in disease including arthritis, psoriasis, inflammatory bowel disease and multiple sclerosis

34
Q

Which cells are the following cytokines predominately released by and to what effect:

γ-IFN
IL-1 
IL-2
IL-6
TNF-a
A

γ-IFN- T cells. Activates macrophages
IL-1 - Macrophage. Activates T cells, fever, pro-inflame.
IL-2- T cell. Activates T and B cells
IL-6- T cell. Activates B cells and the acute phase response
TNF-a- Macrophage. Like IL-1, more destructive

35
Q

How is TNFa relevant to rheumatology

A

The cytokine tumour necrosis factor-alpha (TNFα) is the main cause of rheumatoid synovitis. Downregulation of it is disease modifying

Produced by activated macrophages in rheumatoid synovium.

PLEITROPIC: Bone erosion, pain/swelling, joint space narrowing due to effects on osteoclasts, synovioctes and chondrocytes.

36
Q

Which are the key inflammatory cytokines

A

IL-1, IL-2, IL-6 and TNF-a

37
Q

Which cytokines can be targeted in practice

A

IL1, IL6 and TNF-a

38
Q

Why might chronic inflammation have its own vascular supply

A

Due to TNFa allowing angiogenesis.

It also causes endothelial cell, osteoclast activation

39
Q

In addition to cytokine blockade, what other modulation can we do in rheumatoid arthritis

A

In addition to cytokine blockade, we can also deplete B cells in rheumatoid arthritis by parenteral (intravenous) administration of an antibody against a B cell surface antigen, CD20

Similar to this is denosumab (antibody against RANKL) used in osteoporosis treamtnet

I.e

40
Q

Outline the importance of RANKL in rheumatoid arthritis

A

RANKL is important in bone destruction in rheumatoid arthritis

Produced by T cells and synovial fibroblasts in rheumatoid arthritis

OsteoClastogenesis

Upregulated by IL-1, TNFa, IL17 and PTH related peptide

41
Q

What is the indication for denosumab

A

DENOSUMAB – monoclonal antibody against RANKL
indicated for treatment of osteoporosis, bone metastases, multiple myeloma and Giant cell tumours

i.e not used in rheumatoid

42
Q

How has SLE been therapeutically targeted

A

B cell hyper-reactivity is key feature of SLE

Hence biological therapies targeting B cells have been used in the treatment of SLE

(it is immune complex mediated and b cells are important!)

43
Q

Give examples of drugs used in SLE treamtnet

A

Rituximab – a chimeric anti-CD20 antibody used to deplete B cells

Belimumab - a monoclonal antibody against a B cell survival factor call BLYS

44
Q

Explain what happens with the spine in ankylosing spondylitis

A

exaggeration of thoracic kyphosis, loss of lumbar lordosis

45
Q

What types of compounds are prostaglandins, and what are they made from

A

LIPIDS, and they are made from fatty acids

46
Q

Which two substances can be made from arachidonic acid, and how

A

Common: phospholipase A2 generates AA from DAG.

Then, AA can become:

  1. Prostaglandins, via AA using COX pathway
  2. Leukotrienes, via AA using LOX pathway
47
Q

What are the functions of the following prostaglandins:

PGI2
PGE2
PGF2a

A

PGI2: vasodilation, inhibit platelets, bronchodilation

PGE2: bronchodilation

PGF2a: uterine contractions

48
Q

What is the function of leukotrienes, produced using LOX

A

Leukotrienes mediate:

  1. Leukocyte chemotaxis
  2. Smooth muscle contraction, bronchoconstriction and mucus secretion
49
Q

Which leukotriene mediates leucocyte chemotaxis

A

LTB4

50
Q

Which drugs can be used to target prostaglandins/leukotrienes

A
  1. GC inhibits phospholipase A2

2. NSAIDs inhibit COX

51
Q

Benefits and unwanted effects of NSAIDs

A

Benefit:

  • antipyretic
  • analgesic
  • anti-inflammaotry
  • anti-platelet

Unwanted:

  • peptic ulcer
  • asthma exacerbation
  • thrombosis
  • liver and renal problems
52
Q

What are the agonist and antagonist of the RANK recepetor

A

RANKL is agonist

Action antagonized by decoy receptor – osteoprotegerin (OPG)

Musc (12 decks)

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