Pathogenesis of Autoimmune Disease (12.02.2020) Flashcards

1
Q

What is RA?

A

SYNOVITIS

  • Chronic joint inflammation that can result in joint damage
  • Site of inflammation is the synovium
  • Associated with autoantibodies:
    • Rheumatoid factor
    • Anti-cyclic citrullinated peptide (CCP) antibodies
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2
Q

Ankylosing spondylitis

A

ENTHESITIS

  • Chronic spinal inflammation that can result in spinal fusion and deformity
  • Site of inflammation is the enthesis
  • No autoantibodies (‘seronegative’)
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3
Q

Name seronegative spondyloarthropathies.

A

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

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4
Q

What is SLE?

A

IMMUNE COMPLEXES

  • Chronic tissue inflammation in the presence of antibodies directed against self antigens
  • Multi-site inflammation but particularly the joints, skin and kidney
  • Associated with autoantibodies:
    • Antinuclear antibodies
    • Anti-double stranded DNA antibodies
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5
Q

What diseases belong to the group of connective tissue diseases?

A
  • Systemic lupus erythematosus
  • Inflammatory muscle disease: polymyositis, dermatomyositis
  • Systemic sclerosis
  • Sjogren’s syndrome
  • A mixture of the above: ‘Overlap syndromes’
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6
Q

HLA associated with RA

A

HLA-DR4

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7
Q

HLA associated with SLE

A

HLA-DR3

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8
Q

HLA associated with ankylosing spondylitis

A

HLA-B27

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9
Q

HLA molecules in AI disease

A
  • if you have the HLA it does not mean you have or will have the disease
  • if you have the disease you are likely to have the specific HLA associated with it.
  • HLA molecules are important for recognition of antigens by T-cells
  • HLA molecules were first recognised on human white cells – hence termed human leucocyte antigens (‘HLA’)
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10
Q

MHC I vs MHC II

A

MHCI

  • HLA-A/B/C
  • found on all nucleated cells
  • endogenous/intracellular AG (viral peptides, tumour antigens, self-peptides)
  • CD8 +ve T cell
  • response: cell killing

MHCII

  • HLA-DR/DQ/DP
  • found on specific antigens presenting cells (B-cells, monocytes, dendritic cells)
  • exogenous/extracellular AG (bacterial peptides, self peptides)
  • CD4 +ve T cell
  • response: AB response
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11
Q

What is the structure of the peptide binding sequence like?

A
  • Peptide-binding site made up of walls (α-helical structures) and floor (β-pleated sheet)
    • Sequence in peptide-binding groove determines which antigens can bind
    • T cells only see antigen-bound to MHC (‘MHC restriction’)
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12
Q

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
  • E.g. antigen and HLA-DR4 triggers CD4 +ve T cell response in Rheumatoid Arthritis
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13
Q

HLA molecules and pathogenesis in ankylosing spondylitis

A
  • No arthritogenic peptide that binds HLA-B27 identified
  • If you express human HLA-B27 in rats (i.e. transgenic rats) you get a similar disease that develops in the absence of CD8 +ve T cells
  • > So need new hypothesis!
  • Currently thought that the disease is due to abnormalities in both HLA-B27 and the interleukin-23 pathway:
  • HLA-B27 has a propensity to misfold and this causes cellular stress that triggers interleukin-23 release and triggers interleukin-17 production by
  • Adaptive immune cells i.e. CD4 +ve Th17 cells
  • Innate immune cells e.g. CD4 –ve, CD8 –ve (‘double-negative’) T cells
  • Interestingly these ‘double negative’ T cells have been detected in entheses and this may explain why enthesopathy occurs in Ankylosing Spondyliti
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14
Q

What are the autoantibodies in RA?

A
  • RF
  • Anti-cyclic citrullinated peptide antibody
    also termed antibodies to citrullinated peptide antigens (ACPA)
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15
Q

What are the autoantibodies in SLE?

A
  • ANA (antinuclear antibodies)
  • anti-dsDNA

(- Anti-cardiolipin antibodies
also termed anti-phospholipid antibodies and 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)

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16
Q

Which of the following diseases have autoantibodies and which ones don’t?

RA
SLE
OA
rA
AS
Gout
Systemic vasculitis
Diffuse systemic sclerosis
Limited systemic sclerosis
Dermato-/Polymyositis
Sjögren’s syndrome
Mixed connective tissue disease
A

RA (RF, ACPA)
SLE (ANA, anti-dsDNA, anti-cardiolipin)
Systemic vasculitis (ANCA -> Antinuclear cytoplasmic antibodies)
Diffuse systemic sclerosis (Anti-Scl-70 antibody)
Limited systemic sclerosis (Anti-centromere antibodies)
Dermato-/Polymyositis (Anti-tRNA transferase antibodies)
Sjögren’s syndrome (No unique antibodies but typically see ANA: Anti-Ro and anti-La antibodies and RF)
Mixed connective tissue disease (Anti-U1-RNP antibodies)

OA, rA, AS and gout do not have autoantibodies.

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17
Q

Autoantibodies in systemic vasculitis

A

Antinuclear cytoplasmic antibodies (ANCA)

18
Q

Autoantibodies in diffuses systemic sclerosis

A
  • Anti-Scl-70 antibody

- also termed antibodies to topoisomerase-1

19
Q

autoantibodies in limited systemic sclerosis

A

Anti-centromere antibodies

20
Q

autoantibodies in Dermato/polymyositis

A
  • Anti-tRNA transferase antibodies

- E.g. histidyl transferase (also termed anti-Jo-1 antibodies)

21
Q

Autoantibodies in Sjorgens syndrome

A

No unique antibodies but typically see

 - Antinuclear antibodies - Anti-Ro and anti-La antibodies
 - Rheumatoid factor

=> this is a disease that attacks exocrine glands

22
Q

Autoantibodies in mixed connective tissue disease

A

Anti-U1-RNP antibodies

23
Q

Significance of ANA

A
  • seen in all SLE cases
  • not specific to SLE

If your ANA is negative it is not lupus

24
Q

Significance of anti-dsDNA

A
  • Specific for SLE

- Serum level of antibody correlates with disease activity

25
Q

Significance of Anti-Sm antibodies (antigen is ribonucleoprotein)

A
  • Specific for SLE

- Serum level of antibody does NOT correlate with disease activity

26
Q

Significance of
Anti-Ro antibodies (antigen is ribonucleoprotein)
Anti-La antibodies (antigen is ribonucleoprotein)

A
  • Secondary Sjögren’s syndrome

- Neonatal lupus syndrome (transient rash in neonate, permanent heart block)

27
Q

Significance of anti-ribosomal P antibodies

A

Cerebral Lupus

28
Q

Antinuclear antibodies

A
  • there are many types
  • if you have a positive ANA you can look further at what exactly the AB is reaction to
  • e.g. anti-dsDNA or anti-Ro or anti-La, anti-Sm, anti-centromere etc.
29
Q

What indicates that the disease is active in SLE? How can you see if lupus is active at a specific moment in time?

A

Sick lupus patient commonly has:

  • Low complement levels
  • High serum levels of anti-ds-DNA antibodies

(immune complexes cause damage and trigger inflammatory cascade)

30
Q

What is the current paradigm of the pathogenesis of lupus?

A

incompletely understood

  • Apoptosis leads to translocation of nuclear antigens to membrane surface
  • Impaired clearance of apoptotic cells results in enhanced presentation of nuclear antigens to immune cells
  • B-cell autoimmunity
  • Tissue damage by antibody effector mechanisms e.g. complement activation and Fc receptor engagement

Failure to normally regulate apoptosis: it is associated with inflammation in lupus

31
Q

Common cytokines in AI disease

A
  • γ-IFN: T cells -> Activates macrophages
  • IL-1: Macrophages -> Activates T cells, fever, pro-inflammatory
  • IL-2: T cells -> Activates T and B cells
  • IL-6: T cells -> Activates B cells, acute phase response
  • TNF-α: Macrophages -> Similar to IL-1: more destructive
32
Q

CD4 +ve cell subsets

A
  • CD4 +ve T helper cell subsets include: Th1, Th2 and Th17
  • Th1 cells secrete IL-2 and γ-IFN and response is important in CD8 +ve cytotoxicity and macrophage stimulation
  • Th2 cells secrete IL-4 (IgE responses), IL-5 (eosinophils), IL-6 (B cells to plasma cells) and IL-10 (inhibit macrophage response)
  • Th17 cells 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
33
Q

TNF-alpha

A
  • cytokine
  • tumour necrosis factor-alpha (TNFα)
  • Produced mainly by activated macrophages in rheumatoid synovium
  • is the dominant pro-inflammatory cytokine in the rheumatoid synovium and its pleotropic actions are detrimental in this setting:
34
Q

What are some effects of TNF-alpha?

A
  • pro-inflammatory cytokine release
  • chemokine release
  • angiogenesis
  • PGE2 production
  • osteoclast activation
  • leukocyte accumulation
  • endothelial cell activation
  • hepcidin induction (acute cell response)
  • chondrocyte activation
35
Q

Cytokines targeted in treatment in rheumatology

A
  • Many other cytokines under investigation but IL-6 and IL-1 blockade now available in clinic
  • interestingly IL-1 inhibition is much less efficacious than either IL-6 or TNFα inhibition so current recommendations in England is that IL-1 inhibition (anakinra) is not recommended for RA.

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 the antibody in clinical use is termed, rituximab

36
Q

RANKL in rheumatology

A
  • RANKL is important in bone destruction in rheumatoid arthritis
  • RANKL (receptor activator of nuclear factor kappaB ligand)
  • Produced by T cells and synovial fibroblasts in rheumatoid arthritis
  • Acts to stimulate osteoclast formation (osteoclastogenesis)
    Upregulated by:
    • IL-1, TNF-alpha
    • IL-17 – potent action on osteoclastogenesis via RANKL-RANK pathway
    • PTH-related peptide
  • Binds to ligand on osteoclast precursors (RANK)
  • Action antagonized by decoy receptor – osteoprotegerin (OPG)

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

37
Q

Biological therapies in SLE

A
  • B cell hyper-reactivity is key feature of SLE
  • biological therapies targeting B cells have been used in the treatment of SLE
    These include:
    • RITUXIMAB – a chimeric anti-CD20 antibody used to deplete B cells; although anecdotal therapeutic success rituximab, clinical trials unsuccessful to date
    • BELIMUMAB - a monoclonal antibody against a B cell survival factor call BLYS;
  • Two large clinical trials showed efficacy of belimumab in SLE and the drug is licenced for:
  • add-on therapy in adult patients with active autoantibody-positive SLE, with a high degree of disease activity (e.g. positive anti-dsDNA and low complement), despite standard therapy The drug has not been studied in patients with severe active CNS lupus or severe active lupus nephritis and is not therefore recommended for use in these groups
38
Q

Belimumab

A
  • Recombinant fully human IgG1 monoclonal antibody against BLYS (also termed BAFF)
    • BAFF = B cell activating factor of the TNF family
    • BLYS = B-lymphocyte stimulator
  • Inhibits activity of BAFF resulting in impaired B cell survival and reduced B cell numbers
39
Q

Prostaglandins in rheumatology

A
  • lipid mediators of inflammation
  • in rheumatology you can inhibit them and get an anti-inflammatory and analgesic effect (by inhibiting cyclooxyrgenase pathway)
  • NSAIDs are good in inflammatory arthritis (but don’t modify the course of the disease e.g. does not stop joint destruction or in AS does not stop fusion)
  • now cytokine inhibitors are available to use.
  • do not help in lupus
  • GCs inhibit phospholipase A2
40
Q

Cyclooxygenase pathway of prostaglandins

A
  • Cyclooxygenase pathway: arachidonic acid - - - - prostaglandins
  • Prostaglandins mediate e.g. vasodilatation (PGI2, also termed prostacyclin, via receptor called IP), inhibit platelet aggregation (PGI2), bronchodilatation (e.g. PGE2 acting via receptor called EP2, PGI2), uterine contraction (PGF2alpha)
41
Q

Lipooxygenase pathway of prostaglandins

A
  • Lipooxygenase pathway: arachidonic acid - - - - leukotrienes
  • Leukotrienes mediate e.g. leucocyte chemotaxis (LTB4) and smooth muscle contraction, bronchoconstriction and mucus secretion (LTC4, LTD4, LTE4 via CysLT1 receptors)*