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IMMUNO - Abbie > 8. Autoinflammatory and autoimmune diseases 2 > Flashcards

8. Autoinflammatory and autoimmune diseases 2 Flashcards

1
Q

What happens in Graves disease?

A

Excessive production of thyroid hormones

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2
Q

What is Graves disease mediated by? And what does it result in?

A

Mediated by IgG antibodies that stimulate the TSH receptor. The antibodies bind to the TSH receptor and stimulate it leading to overproduction of thyroid hormones. Negative feedback does NOT override antibody stimulation.

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3
Q

What does the evidence base show about Graves disease?

A

These antibodies stimulate thyrocytes in vitro. Passive transfer of IgG from patients to rats often produces the same symptoms. Babies born to mothers with Graves’ disease may show transient hyperthyroidism.

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4
Q

What type of hypersensitivity is Graves disease?

A

Type II hypersensitivity reaction (however, it is stimulatory rather than destructive)

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5
Q

What is Hashimoto’s thyroiditis the most common cause of?

A

MOST COMMON cause of hypothyroidism in iodine-replete areas

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6
Q

How might Hashimoto’s thyroiditis present?

A

May present with a goitre - enlarged thyroid infiltrated by T and B cells

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7
Q

What antibodies is Hashimoto’s thyroiditis associated with?

A

Associated with anti-TPO antibodies. Also associated with the presence of anti-thyroglobulin antibodies

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8
Q

What does the presence of anti-TPO antibodies show?

A

Their presence correlates with thyroid damage and lymphocyte inflammation. Some have been shown to induce damage to thyrocytes.

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9
Q

What hypersensitivity reactions are involved in Hashimoto’s thyroiditis?

A

Type II and type IV hypersensitivity reaction

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10
Q

Why don’t we normally measure anti-thyroid antibodies to diagnose hypothyroidism?

A

We don’t tend to measure anti-thyroid antibodies to diagnose hypothyroidism because these antibodies are present in a lot of normal people who do not have hypothyroidism

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11
Q

What do experiments with non-obese diabetes (NOD) mouse model for T1DM show?

A

CD8+ T cell infiltration of the pancreas

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12
Q

What is the pathogenesis of T1DM?

A

CD8+ T cells infiltrate the pancreas. The T cell clones have specificity for islet antigens. The CD8+ lymphocytes bind to peptides presented by MHC Class I molecules on the beta-cells of the pancreas. These autoantigens include GAD and IA2. There are specific antibodies agaisnt these antigens which pre-date the development of disease.

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13
Q

The presence of which antibodies against these antigens will pre-date the development of T1DM?

A

Anti-islet cell, anti-insulin, anti-GAD, anti-IA2. NOTE: individuals with 3-4 of the above are highly likely to develop T1DM. (IMPORTANT: detection of antibodies does NOT currently play a role in diagnosis)

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14
Q

What occurs in pernicious anaemia?

A

In pernicious anaemia, patients develop antibodies against intrinsic factor which leads to failure of absorption of vitamin B12

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15
Q

What can vitamin B12 deficiency lead to?

A

Subacute degeneration of the spinal cord. This involves the posterior and lateral columns

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16
Q

What are neurological features of pernicious anaemia?

A

Subacute degeneration of the spinal cord. Other neurological features include peripheral neuropathy and optic neuropathy.

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17
Q

What antibodies are useful in the diagnosis of pernicious anaemia?

A

Antibodies against gastric parietal cells or intrinsic factor are useful in diagnosis

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18
Q

In myasthenia gravis, what does the patient develop antibodies against?

A

Antibodies against the nicotinic acetylcholine receptor

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19
Q

What does antibodies against the nicotinic acetylcholine receptor in myasthenia gravis lead to?

A

This leads to a failure of depolarisation

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20
Q

What is myasthenia gravis characterised by? And what are common features?

A

Characterised by fluctuating weakness. Ptosis is a common feature. EMG studies are usually abnormal.

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21
Q

What test is used to confirm diagnosis of myasthenia gravis?

A

Tensilon test

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22
Q

What is the tensilon test?

A

Used to diagnose myasthenia gravis. This involves administering a very short-acting anticholinesterase (edrophonium bromide), which will cause a rapid improvement in symptoms

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23
Q

Which antibodies are present in most myasthenia gravis patients?

A

Anti-acetylcholine receptor antibodies are present in 75% of patients and so they are useful in diagnosis

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24
Q

What may offspring of mothers with myasthenia gravis experience?

A

Offspring of affected mothers may experience transient neonatal myasthenia

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25
What type of hypersensitivity reaction is seen in myasthenia gravis?
Type II hypersensitivity reaction
26
What is Goodpasture's syndrome also known as?
Also known as anti-glomerular basement membrane disease
27
What does Goodpasture's syndrome lead to damage in?
Leads to lung and kidney damage
28
Describe the appearance of the basement membrane as a result of Goodpasture's syndrome
The deposition of antibodies along the basement membrane gives a smooth linear appearance
29
How are antibodies in Goodpasture's syndrome detected?
They are detected using fluorescein conjugated anti-human immunoglobulin
30
What genetic predispositions does RA lead to?
HLA DR4 (DRB1 0401, 0404, 0405); HLA DR1 (DRB1 0101); PTPN22; polymorphisms affecting TNF, IL1, IL6 and IL10; PAD2 and PAD4 polymorphisms. Also HLA-DRB1 alleles that code a “shared epitope” (SE) – a five amino acid sequence motif in residues 70–74 of the HLA-DRβ chain.
31
What is the shared epitope associated with rheumatoid arthritis?
HLA-DRB1 alleles that code a “shared epitope” (SE) – a five amino acid sequence motif in residues 70–74 of the HLA-DRβ chain
32
What does the shared epitope associated with RA cause?
These alleles may enable binding of HLA to arthritogenic peptides and have been shown to bind to citrullinated peptides with high affinity
33
What do peptidylarginine deaminases (PAD 2 and 4) do?
These are enzymes that are involved in the deamination of arginine to form citrulline. Polymorphisms in these genes are associated with increased citrullination leading to a high load of citrullinated peptides
34
What is a key enzyme involved in rheumatoid arthritis?
Peptidylarginine deaminases (PAD 2 and 4). These convert arginine to citrulline and leads to increased citrullination. This generates the protein target of anti-citrullinated protein antibodies. PAD2 and PAD4 are observed in the tissue and fluid of inflamed RA joints; and both enzymes can generate citrullinated autoantigens.
35
What are environmental factors associated with RA?
Smoking (associated with development of erosive disease due to increased citrullination); gum infection with Porphyromonas gingivalis (only bacterium known to express PAD, thereby promoting citrullination).
36
What antibodies are involved in RA?
Anti-cyclin citrullinated peptide antibodies; rheumatoid factor
37
What does anti-cyclin citrullinated peptide bind to?
Bind to peptides in which arginine has been converted to citrulline by PAD
38
How specific and sensitive are anti-cyclin citrullinated peptide antibodies?
Around 95% specific for rheumatoid arthritis. 60-70% sensitive for the diagnosis of rheumatoid arthritis
39
What is rheumatoid factor directed against?
An antibody directed against the Fc region of human IgG. IgM anti-IgG antibody is the most commonly tested although you can get IgA and IgG variants.
40
How are B cells involved in rheumatoid arthritis?
Type II response: antibodies bind to citrullinated peptides leading to activation of complement, macrophages and NK cells. Type III: immune complexes form and get deposited; this leads to complement activation.
41
How are T cells involved in rheumatoid arthritis?
Antigen presenting cells will present peptides to CD4 cells which will then lead to the production of IFN-gamma and IL17. These cytokines act on fibroblasts and macrophages. This, in turn, leads to the productions of: MMPs, IL-1, TNF-alpha.
42
What happens to the joint in RA?
In rheumatoid arthritis, the synovium becomes very inflamed forming a pannus. This invades the articular cartilage and adjacent bone. There is also an increase in synovial fluid volume
43
What mechanisms are involved in RA?
1. Genetic predispositions: HLA DR4, HLA DR1, PTPN22, TNF/IL1/IL6/IL10. 2. Shared epitope (HLA susceptibility alleles share a sequence at position 70-74 of HLA beta chain) which enable binding of HLA to arithrogenic peptides and bind to citrullinated peptides with high affinity. 3. Peptidylarginine deaminases (PAD 2 and 4) result in increased citrullination. Smoking (increased citrullination) and gum infection (express PAD). 4. Antibodies: anti-cyclin citrullinated peptide antibodies; rheumatoid factor. 5. B cell: type II and type II response. 6. T cells lead to production of cytokines which lead to production of MMPs, IL-1, TNF-alpha.
44
What are anti-nuclear antibodies?
These are a group of antibodies that bind to nuclear proteins
45
How are anti-nuclear antibodies tested?
They are tested by staining Hep-2 (human epidermoid cancer line) cells
46
How common are anti-nuclear antibodies?
Very common - sometimes present in normal individuals
47
What are genetic predispositions leading to SLE?
1. Abnormalities in clearing apoptotic cells (polymorphisms in genes encoding complement, MBL, CRP) 2. Abnormalities in cellular activation (polymorphisms in genes encoding/controlling expression of cytokines, chemokines, co-stimulatory molecules and intracellular signalling molecules) 3. B cell hyperactivity and loss of tolerance 4. antibodies directed particularly at intracellular proteins (could bind to debris from apoptic cells that have not been cleared, nuclear antigens, and cytoplasmic agents)
48
What occurs in SLE?
Patient may have genetic predispositions (related to clearing apoptotic cells, cellular activation, B cell hyperactivity and loss of tolerance, ABs directed at intracellular proteins). Antibodies bind to antigens forming immune complexes, which deposit in tissues, activate complement via the classical pathway, stimulate cells that express Fc and complement receptors.
49
What type of hypersensitivity reactions are lupus nephritis vs. Goodpasture's disease?
Lupus nephritis = immune complex (type III). Goodpastures disease = antibody-mediated disease (type II).
50
How can lupus nephritis be detected?
Immune complex deposition, detection of granular 'lumpy-bumpy' pattern with fluorescein conjugated anti-human Immunoglobulin.
51
What are immunological investigations in SLE?
Test for anti-nuclear antibodies. Normal range is <1:80. Result is >1:640 homogeneous. The unit is the minimum dilution at which the antibody can be detected (i.e. the bigger the second number the greater the antibody titre).
52
What are the targets of anti-nuclear antibodies?
dsDNA, extractable nuclear antigens (ENAs) such as ribonucleoproteins, enzymes (e.g. RNA polymerase or topoisomerase)
53
What is the homogenous pattern in dsDNA staining associated with?
A homogenous (diffuse) pattern appears as total nuclear fluorescence and is common in people with SLE.
54
What are positive nuclear patterns of SLE?
Homogenous and speckled patterns
55
Homogenous pattern suggests SLE. How can specificity be confirmed?
Homogenous staining associated with staining for dsDNA. Specificity is confirmed using ELISA.
56
Which antibody is highly specific for SLE? What percentage of patients is it present in?
Anti-dsDNA antibodies are highly specific for SLE. These will be present in 60-70% of SLE patients at some point
57
What is associated with severe SLE disease?
HIGH titres of anti-dsDNA are associated with SEVERE disease, including renal or CNS involvement. Useful in disease monitoring - an increase in antibody titres is associated with disease activity and may preceded relapse
58
How common are false positives of anti-dsDNA in SLE?*******
False positive results are unusual (<3%)
59
What does a speckled pattern suggest?
Associated with antibodies to extractable nuclear antigens (ENA) 4. Seen in SLE patients
60
Speckled pattern suggests antibodies to ENA 4 (in SLE). What does it show specificity for?
Specificity is for some ribonucleoproteins (e.g. Ro, La, Sm, U1RNP)
61
How can results of speckled pattern be confirmed?
Confirmed with ELISA
62
What ribonucleoproteins are seen in SLE?
Ro, La, Sm, U1RNP
63
What ribonucleoproteins are characteristically found in Sjogren's syndrome?
Ro and La
64
Is measuring titres of antibodies to ENA 4 useful?
Titres are NOT helpful in monitoring disease activity
65
What are other antibodies in SLE, other than anti-dsDNA and antibodies to ENA 4?
Scl70, RNA polymerase, fibrillarin (may occur in diffuse cutaneous systemic sclerosis); Mi2, SRP (may occur in idiopathic inflammatory myopathies)
66
How does complement activation work?
Formation of antibody-antigen immune complexes will activate complement via the classical pathway. Complement components become depleted if constantly consumed. Quantification of C3 and C4 acts as a surrogate marker
67
What does the complement profile look like in inactive SLE disease?
C3 = normal, C4 = normal. NOTE: we measure unactivated complement proteins rather than activated ones
68
What does the complement profile look like in active SLE disease?
C3 = normal, C4 = lowered. NOTE: we measure unactivated complement proteins rather than activated ones.
69
What does the complement profile look like in severe active SLE disease?
C3 = low, C4 = low. Complement components become depleted if constantly consumed. NOTE: we measure unactivated complement proteins rather than activated ones
70
What is the triad seen in antiphospholipid syndrome?
Recurrent venous or arterial thrombosis; recurrent miscarriage; thrombocytopaenia.
71
What does antiphospholipid syndrome occur with?
May occur alone (primary) or in conjunction with autoimmune disease (secondary)
72
What are two major types of antibody tests for antiphospholipid syndrome?
Anti-cardiolipin antibody and lupus anticoagulant
73
What is anti-cardiolipin antibody directed against?
Antiphospholipid antibodies (aPL) exist as a family of autoantibodies directed against phospholipids/phospholipid-binding plasma proteins, most commonly β2-glycoprotein-I.
74
How would lupus anticoagulant be tested (for antiphospholipid syndrome)?
Prolongation of phospholipid-dependent coagulation tests. Cannot be assessed if the patient is on anticoagulant therapy.
75
What percentage of patients have discordant antibodies?
40% have discordant antibodies - if there is clinical suspicion of anti-phospholipid syndrome, both tests should be performed
76
Which cells predominate in systemic sclerosis?
Inflammation with Th2 and Th17 cells predominating
77
What happens in systemic sclerosis?
Inflammation of Th2 and Th17 cells predominating. Cytokines lead to activation of fibroblasts and development of fibrosis. Cytokines lead to activation of endothelial cells and contribute to microvascular disease. Loss of B cell tolerance to nuclear antigens.
78
What are important polymorphisms in systemic sclerosis?
Polymorphisms in type I collagen alpha 2 chains and fibrillin 1 may be important. Polymorphisms in TGF-beta have also been described.
79
What is limited cutaneous systemic sclerosis characterised by?
Skin involvement does NOT progress beyond forearms (although it may involve perioral skin). Characterised by CREST: calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia (and also primary pulmonary hypertension).
80
What are is diffuse cutaneous systemic sclerosis characterised by?
Skin involvement DOES progress beyond the forearms. CREST features (calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia). More extensive gastrointestinal disease; interstitial pulmonary disease; scleroderma kidney/renal cysts
81
What staining is an important prognostic factor in systemic sclerosis?
ANA staining
82
What does diffuse cutaneous systemic sclerosis show in ANA staining?
Nucleolar pattern, anti-topoisomerase antibodies (Scl70), RNA polymerase, fibrillarin. Staining pattern is mutually exclusive from limited cutaneous systemic sclerosis and highly specific.
83
What does limited cutaneous systemic sclerosis show in ANA staining?
Anti-centromere antibodies. Staining pattern is mutually exclusive from diffuse cutaneous systemic sclerosis and highly specific.
84
What are types of idiopathic inflammatory myopathies?
Dermatomyositis and polymyositis
85
What are features of dermatomyositis?
Within muscle - perivascular CD4 T cells and B cells; immune complex mediated vasculitis (type III response)
86
What are features of polymyositis?
Within muscle - CD8 T cells surround HLA Class I expressing myofibres. CD8 T cells kill myofibres via perforin/granzyme - type IV response
87
What is the difference in presentation between dermatomyositis and polymyositis?
Polymyositis, which affects many different muscles, particularly the shoulders, hips and thigh muscles. It's more common in women and tends to affect people aged 30 to 60. Dermatomyositis, which affects several muscles and causes a rash. It's more common in women and can also affect children (juvenile dermatomyositis).
88
What are the positive ANA results (in some patients) in dermatomyositis?
Anti-aminoacyl tRNA synthetase antibody (e.g. Jo-1) (cytoplasmic)
89
What are the positive ANA results (in some patients) in polymyositis?
Anti-signal recognition peptide antibody (nuclear and cytoplasmic)
90
In which conditions is anti-Mi2 (nuclear) seen in ANA staining?
Dermatomyositis > Polymyositis
91
Which ANA+ve condition is dsDNA+ve?
SLE (homogeneous pattern)
92
Which ANA+ve conditions are ENA +ve?
SLE, Sjogrens, diffuse cutaneous systemic sclerosis, limited cutaneous systemic sclerosis (speckled pattern)
93
Of the ENA+ve conditions, which conditions have Ro, La, Sm, U1RNP ribonucleoproteins?
SLE: any. Sjogren's: Ro, La
94
Of the ENA+ve conditions which condition has Scl70 antibodies?
Diffuse cutaneous systemic sclerosis
95
Of the ENA+ve conditions which condition has centromeres (/anti-centromere antibodies)?
Limited cutaneous systemic sclerosis
96
Which ANA+ve condition is cytoplasmic?
Myositis
97
Which cytoplasmic ANA+ve condition has t-RNA synthetase (Jo1)?
Dermatomyositis
98
Which cytoplasmic ANA+ve condition has anti-signal recognition peptide antibody (nuclear and cytoplasmic)?
Polymyositis
99
Which systemic vasculitis conditions affect the large vessels?
Takayasu's arteritis, giant cell arteritis/polymyalgia rheumatica
100
Which systemic vasculitis conditions affect the medium vessels?
Polyarteritis nodosa, Kawasaki disease
101
Which systemic vasculitis conditions affect small vessels (ANCA associated)?
Microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis
102
Which systemic vasculitis conditions affect small vessels (immune complex)?
Anti-GBM disease, IgA disease, cryoglobulinaemia
103
What is the name of the classification used in systemic vasculitis and what are the categories?
Chapel Hill classification of systemic vasculitis. Categories include: large vessel, medium vessel, small vessel (ANCA associated) and small vessel (immune complex)
104
Which small vasculitis conditions are associated with ANCA?
Microscopic polyangiitis; granulomatosis with polyangiitis; Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis)
105
What is the pathophysiology of ANCA?
1. Antibodies specific for antigens located in primary granules within cytoplasm of neutrophils. 2. Inflammation may lead to expression of these antigens on cell surface neutrophils. 3. Antibody engagement with cell surface antigens may lead to neutrophil activation (type II hypersensitivity). 4. Activated neutrophils interact with endothelial cells causing damage to vessels - vasculitis.
106
What are the types of ANCA?
cANCA and pANCA
107
How does cANCA appear vs. pANCA?
cANCA: cytoplasmic fluorescence. pANCA: perinuclear staining pattern.
108
What antibodies are cANCA associated with?
Antibodies to enzyme proteinase 3
109
What antibodies are pANCA associated with?
Antibodies to myeloperoxidase
110
Which condition does cANCA tend to occur in?
Occurs in > 90% of patients with granulomatous polyangiitis with renal involvement
111
Which is less sensitive and specific, pANCA or cANCA?
pANCA
112
Which conditions is pANCA associated with?
Associated with microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis

IMMUNO - Abbie (11 decks)

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