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Kat's Pathology > Autoinflammatory and Autoimmune Disease 2 > Flashcards

Autoinflammatory and Autoimmune Disease 2 Flashcards

1
Q

What are some organ specific autoimmune diseases (6)

A 
Graves disease. 
Hashimotos thyroiditis. 
T1DM
Pernicious anaemia 
Myasthenia gravis 
Goodpastures disease
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2
Q

What are some organ non-specific autoimmune diseases (5)

A 
SLE
Sjorgren's syndrome 
Systemic sclerosis 
Dermato/Polymyositis
ANCA-Associated vasculitis
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3
Q

What antibodies are present in SLE

A

Anti-nuclear antibody

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4
Q

What antibodies are present in Sjogren’s syndrome

A

Anti-nuclear antibody

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5
Q

What antibodies are present in Systemic sclerosis

A

Anti-nuclear antibody

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6
Q

What antibodies are present in rheumatoid arthritis (2)

A

Rheumatoid Factor.

Anti-CCP antibody

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7
Q

What antibodies are present in ANCA associated vasculitis

A

Anti-neutrophil cystoplasmic antibody

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8
Q

What is Graves disease

A

Excessive production of thyroid hormones

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9
Q

What is the pathophysiology of Graves disease

A

Mediated by IgG which stimulate the TSH receptor.
Stimulates autoantibodies against TSH-receptor bind to receptor - act as TSH agonists.
Induce uncontrolled overproduction of thyroid hormones - negative feedback cannot override antibody stimulation.

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10
Q

What type of reaction is Graves disease

A

Type II hypersensitivity

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11
Q

What are some symptoms of hypothyroidism (4)

A

Lethargic
Dry skin and hair
Constipation
Cold intolerance

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12
Q

Is the diagnosis of Graves disease dependant on the biochemistry

A

No - testing for auto-antibodies is not usually required for diagnosis

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13
Q

What is the commonest cause of hypothyroidism

A

Hashimoto’s thyroiditis is the commonest cause of hypothyroidism in iodine-repleate areas

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14
Q

What causes a goitre in hypothyroidism

A

Enlarged thyroid is infitrated by T and B cells

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15
Q

What is hashimoto’s thyroiditis associated with (2)

A

Anti-throid peroxidase antibodies

The presence of these correlates with thyroid damage and lymphocyte inflammation
Some shown to induce damage to thyrocytes.

Anti-thyroglobulin antibodies

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16
Q

What type of hypersensitivity reaction is hashimoto’s thyroiditis

A

Type 2 and 4 hypersensitivity reactions

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17
Q

Is detection of anti-thyroid antibodies clinically useful (3)

A

Not really.

Many women >65 have anti-thyroid antibodies
Some post-menopausal women with anti-thyroid antibodies have subclinical hypothyroidism
Small proportion of post-menopausal women with anti-thyroid antibodies have overt hypothyroidism

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18
Q

What is used to diagnose thyroid disorders

A

Thyroid biochemistry

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19
Q

What is the histology of T1DM

A

CD8+ T cell infiltration of pancreas which destroy beta islet cells over time.

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20
Q

What type of hypersensitivity reaction is T cell destruction of beta islet cells in T1DM

A

Type 4 hypersensitivity (CD8 mediated)

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21
Q

What receptors do CD8+ T cells detect and attack on the beta cells of the pancreas in T1DM (2)

A

Develop auto-antigens against GAD65 and IA2

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22
Q

When do auto-antibodies develop in T1DM

A

Long before disease detectable

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23
Q

What auto-antibodies can be generated in T1DM (4)

A

Anti-islet antibodies
Anti-insulin antibodies
Anti-GAD antibodies
Anti-IA2 antibodies

Individuals with 3-4 of the above are highly likely to develop T1DM

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24
Q

What role does auto-antobody detection play in diagnosing T1DM

A

No current role

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25
Q

What is the hallmark of pernicious anaemia

A

Auto-antibodies against IF, preventing absorption of B12

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26
Q

What are the clinical features of pernicious anaemia (4)

A

Vitamin B12 deficiency
Failure of vitamin B12 absorption
Macrocytic anaemia
Neurological features with subacute degeneration of cord (posterior and lateral columns), peripheral neuropathy, optic neuropathy.

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27
Q

What are auto-antibodies generated against in pernicious anaemia (2)

A

Gastric parietal cells or intrinsic factor - useful in diagnosis.

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28
Q

What auto-antiboides are generated in myaesthenia gravis

A

Antibodies against ACh receptors on postsynaptic muscle membranes

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29
Q

What are the clinical feature of myaesthenia gravis (4)

A

Fluctuating weakness
Extra-ocular weakness or ptosis is very common
EMG studies are abnormal
Tensilon test is positive (inject edrophonium (an anti-cholinesterase) to prolong life of acetylcholine and allow it to act on residual receptors)

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30
Q

What is useful in the diagnosis of myaesthenia gravis

A

Anti-acetylcholine receptor antibodies are present in 75% of patients - diagnostically useful

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31
Q

What type of hypersensitivity reaction is myaesthenia gravis

A

Type 2 hypersensitivity reaction

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32
Q

What can occur to the offspring of mothers with myaesthenia gravis

A

May experience transient neonatal maesthenia

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33
Q

What type of disease is Goodpasture’s disease

A

An anti-glomerular basement membrane disease

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34
Q

What is useful in the diagnosis of Goodpasture’s disease

A

Antibodies specific for glomerular basement membrane disease underpin the pathology and are useful in the diagnosis of anti-glomerular basement membrane disease

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35
Q

What type fo hypersensitivity reaction is Goodpasture’s disease

A

Type 2 hypersensitivity reaction

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36
Q

What is the pathological hallmark of Goodpasture’s disease on biopsy

A

Crescentic nephritis

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37
Q

How are auto-antibodies detected in the kidney

A

Flourescein conjugated polyclonal anti-human immunoglobulin detects auto-antibodies.

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38
Q

How do flourescent auto-antibody markers appear in Goodpasture’s disease

A

Smooth linear deposition of antibody along the glomerular basement membrane

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39
Q

Anti-GAD antibody is seen in _____

A

Diabetes mellitus (Type 1)

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40
Q

Anti-thyroglobulin antibody is seen in ____

A

Hashimotos thyroiditis

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41
Q

Anti-basement membrane antibody is seen in ____

A

Goodpasture’s disease

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42
Q

Anti-intrinsic factor antibody is seen in ____

A

Pernicious anaemia

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43
Q

Anti-acetylcholine receptor antibody is seen in _____

A

Myaesthenia gravis

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44
Q

Anti-TSH receptor antibody is seen in ___

A

Grave’s disease

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45
Q

Symptoms: nervous, palpitations, heat intolerant, diarrhoea

A

Grave’s disease

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46
Q

Symptoms: lethargic, dry skin and hair, constipation, cold intolerant

A

Hashimotos thyroiditis

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47
Q

8 Year old boy.
Thirsty, polyuria, malaise.
Urine dipstick confirms glycosuria

A

T1DM

48
Q 
Symptoms: tired, pale, mild numbness of feet. 
Anaemic (Hb 8.4)
Macrocytosis MCV 108
Urine dipstick negative 
Folate normal 
Vitamin B12 very low
A

Pernicious anaemia

49
Q

Drooping eyelids.

Weakness, particularly on repetitive activity. Symptoms worse at the end of the day

A

Myaesthenia gravis

50
Q

48 year old man. haemoptysis with widespread crackles in the lungs. Swelling of legs, reduced urine output.
Creatinine 472
Microscopic haematuria and proteinuria.
CXR - widespread shadowing
Elevated TLCO suggesting pulmonary haemorrhage.
Anti-neutrophic cytoplasmic antibody negative.
Anti-basement membrane positive
Crescentic nephritis on biopsy

A

Goodpasture’s syndrome.

51
Q

Pain, stiffness and swelling of multiple small joints within hands.
Normochromic anaemia. High ESR and CRP
Grossely deformed hands.

A

Rheumatoid arthritis.

52
Q

What polymorphisms are assocaited with a genetic predisposition to Rheumatoid arthritis (4)

A

HLA DR4 (DRB1, 0401, 0404, 0405) and HLA DR1.
PTPN22 polymorphisms.
Polymorphisms affecting TNF, IL1, IL6, IL10.
PAD2 nad PAD4 polymorphisms.

53
Q

What do the HLA DR4 and HLA DR1 alleles predispose to developing rheumatoid arthritis

A

Susceptible alleles share a sequence at positions 70-74 of the HLA DR beta chain (shared epitope)
These alleles may bind ‘arthritogenic peptides’ and have been shown to bind to citrullinated peptides with high affinity

54
Q

What do the PAD2 and PAD4 alleles predispose to developing rheumatoid arthritis

A

They are enzymes involved in deimination of arginine to create citrulline.
Polymorphisms are associated with increased citrullination - creating a high load of citrullinated proteins.
Peptides from these citrullinated proteins may be presented by HLA DR4 and DR1 molecules to T cells to stimulate Th cells which will promote development of an antibody response to the citrullinated proteins

55
Q

What environmental factors are associated with the development of rheumatoid arthritis (2)

A

Smoking

Gum infection with porphyromonas gingivalis

56
Q

What antibodies are present in RA (2)

A

Antibodies to cyclic citrullinated peptide (Anti-CCP)

Antibodies against rheumatoid factor

57
Q

How sensitive is anti-CCP for the diagnosis of RA

A

60-70% sensitivity

58
Q

How specific is anti-CCP for the diagnosis of RA

A

95% specificity

59
Q

What is rheumatoid factor

A

An IgM anti-IgG antibody directed against the common (Fc) region of human IgG

60
Q

How specific/sensitive is rheumatoid factor for the detection of RA

A

60-70% specific and sensitive

61
Q

What two B cell immune responses occur in RA (2)

A

Type 2 response - antibody binding to citrullinated proteins may lead to: activation of complement, activation fo macrophages via Fc R and complement receptors, NK cell activation with ADCC

Type 3 response - immune complex formation (RF and anti-CCP) and deposition with complement activation.

62
Q

What T cell reaction is involved in RA

A

Type 4 response = T cell activation.

63
Q

How does a RA joint differ to a normal joint (2)

A

Increased synovial fluid volume

Inflamed synovial tissue forms a ‘pannus’ overlaying and invading articular cartilage and adjacent bone tissues

64
Q

What are anti-nuclear antibodies

A

Group of antibodies that bind to nuclear proteins

65
Q

How are anti-nuclear antibodies detected

A

Test by staining of Hep-2 cells

66
Q

How specific are anti-nuclear antibodies in disease detection

A

Low titre antibodies (<1:80) often found in normal individuals (especially in older women)

67
Q

19 year old female.
4 month history of fatigue, generalised arthralgia, particularly of small joints of hands. Hall fall, mouth ulcers, butterfly rash.

A

SLE

68
Q

What are the clinical features of SLE (8)

A 
CNS: seizures. 
Skin: butterfly rash, discoid lupus. 
Heart: endocarditis, myocarditis. 
Glomerulonephritis. 
Lungs: serositis, pleuritis, pericarditis. 
Blood: haemolytic anaemia, leukopenia, thrombocytopenia
Arthritis 
Lymphadenopathy
69
Q

What are the genetic predispositions of SLE (4)

A

Abnormalities in clearance of apoptotic cells (polymorphisms in genes encoding complement, MBL, CRP)
Abnormalities in cellular activation (polymorphisms in genes encoding/controlled expression of cytokines, chemokines, co-stimulatory molecules, intracellular signalling molecules)
B cell hyperactivity and loss of tolerance.
Antibodies directed particularly at intracellular proteins (nuclear antigens - DNA, histones, snRNP; cytoplasmic antigens - ribosome, cRNP)

70
Q

What is the pathogenesis of SLE

A

Antibodies bind to antigen to form immune complexes.
Immune complexes deposit in tissues (skin, joints, kidneys)
Immune complexes activate complement (classical pathway)
Immune complexes stimulate cells expressing Fc and complement receptors

71
Q

What type of hypersensitivity reaction is involved in SLE

A

Type 3 hypersensitivity

72
Q

How do type 3 immune complexes deposit on the basement membrane (SLE)

A

Immune complex deposition - detection of granular ‘lumpy-bumpy’ pattern with flouroscein

73
Q

How are antibody levels quantified

A

Measured by titre (the minimal dilution at which the antibody can be detected) or by concentration in standardised units

74
Q

What are the two targets of anti-nuclear antibody (ANA)

A

dsDNA

Extractable nuclear antigens (ENAs) - ribonucleoproteins, enzymes (e.g. RNA polymerase or topoisomerase)

75
Q

In ANA detection, what does a homogenous staining associated with

A

dsDNA

76
Q

What type of antibody detected is most specific for SLE

A

dsDNA

They are highly specific for SLE (95%)
Occur in 60-70% of SLE patients at some point in time of their disease.
Very high titres are often associated with more severe disease - including renal or CNS involvement
Useful in disease monitoring - an increase in antibody titre is associated with disease activity and may precede disease relapse

77
Q

In ANA detection, what is a speckled staining associated with

A

ENA 4

78
Q

What are the anti-ENA antibodies (4)

A

Ribonucleoproteins (Ro, La, Sm, RNP)

Titres are not helpful in monitoring disease activity

79
Q

What condition are anti-Ro and La characteristically found in

A

Sjogren’s syndrome

80
Q

What anti-ENA antibodies are associated with diffuse cutaneous systemic sclerosis (3)

A

Scl70
RNA polymerase
Fibrillarin

81
Q

What anti-ENA antibodies are associated with idiopathic inflammatory myopathies (2)

A

Mi2

SRP

82
Q

What parts of the complement pathway are associated with disease activity in SLE

A

C3 and C4

Important to measure unactivated complement proteins, not activated forms

83
Q

What will happen to C3 and C4 in severe active SLE

A

Reduced C3 and C4

84
Q

What will happen to C3 and C4 in active SLE

A

Normal C3

Reduced C4

85
Q

What is anti-phsopholipid syndrome associated with (2)

A

Recurrent venous or arterial thrombosis

Recurrent miscarriage

86
Q

What auto-antibodies are present in anti-phsopholipid syndrome

A

Anti-phospholipid antibodies

87
Q

What is measured in anti-phospholipid syndrome (2)

A

Anti-cardiolipin antibody (immunoglobulins directed against phospholipids, and beta2 glycoprotein-1)
Lupus anti-coagulant (prolongation of phospholipid-dependent coagulation tests, cannot be assessed if the patient is on anticoagulant therapy)

88
Q

What are the pathological features of systemic sclerosis (4)

A

Inflammation with Th17 and Th2 cells dominating
Cytokines lead to activation of fibroblasts and the development of fibrosis (polymorphisms within type 1 collagen alpha 2 chains and fibrillin 1 may be important, polymorphisms in TGF-beta have also been described)
Cytokines lead to activation of endothelial cells and contribute to microvascular disease
Loss of B cell tolerance to nuclear antigens

89
Q

What occurs in limited cutaneous systemic sclerosis (CREST)

A

Skin involvement does not progress beyond forearms (although it may involve peri-oral skin)

90
Q

What are the hallmarks of CREST syndrome (6)

A 
Calcinosis 
Raynauds 
Oesophageal dysmotility 
Sclerodactyly
Telangectasia

(also primary pulmonary hypertension)

91
Q

What occurs in diffuse cutaneous systemic sclerosis

A

Skin involvement does progress beyond forearms

92
Q

What CREST features are present in diffuse cutaneous systemic sclerosis (3)

A

More extensive gastrointestinal disease
Interstitial pulmonary disease
Scleroderma kidney/renal crisis

93
Q

What is an important prognostic indicator in systemic sclerosis

A

ANA staining

94
Q

What ANA staining is characteristic of diffuse systemic sclerosis (4)

A

Nucleolar pattern
Anti-topoisomerase antibodies (Scl70)
RNA polymerase
Fibrillarin

95
Q

What ANA staining is characteristic of limited cutaneous systemic sclerosis

A

Anti-centromere antibodies

96
Q

Weakness, malaise, rash

A

Idiopathic inflammatory myopathy

97
Q

What are the main two idiopathic inflammatory myopathies

A

Dermatomyositis

Polymyositis

98
Q

What are the pathological features of dermatomyositis (2)

A

Within muscle - perivascualr CD4 T cells and B cells

Immune complex mediated vasculitis - type 3 response

99
Q

What are the pathological features of polymyositis (2)

A 
Within muscle - CD8 T cells surround HLA class 1 expressing myofibres 
CD8 T cells kill myofibres via perforin/granzymes - type 4 response
100
Q

What ANA can sometimes be detected in dermatomyositis (2)

A

Anti-aminoacyl transfer RNA synthetase antibody eg Jo-1 (cytoplasmic)

Maybe: Anti-Mi2 (nuclear)

101
Q

What ANA can sometimes be detected in polymyositis

A

Anti-signal recognition peptide antibody (nuclear and cytoplasmic)

102
Q

What condition is characterised by ANA+ve dsDNA +ve

A

SLE

103
Q

What conditions are characterised by ANA+ve, ENA+ve: Ro, La, Sm, RNP +ve (2)

A

SLE (any)

Sjogrens (Ro, La)

104
Q

What condition is characterised by ANA+ve, ENA+ve:SCL70 +ve

A

Diffuse cutaneous systemic sclerosis

105
Q

What condition is characterised by ANA+ve ENA+ve:Centromere +ve

A

Limited cutaneous systemic sclerosis (CREST)

106
Q

What condition is characterised by ANA+ve, cytoplasmic +vve t-RNA synthetase (jo1) +ve

A

Myositis

107
Q

What are the large vessel vasculitis (2)

A

Takayasu’s arteritis

Giant cell arteritis/polymyalgia rheumatica

108
Q

What are the medium vessel vasculitis (2)

A

Polyarteritis nodosa

Kawasaki disease

109
Q

What are the small vessel vasculitis (ANCA associated) (3)

A

Microscopic polyangiitis (MPA_
Granulomatosis with polyangiitis (GPA)
Eosinophilic granulomatosis with polyangiitis (eGPA)

110
Q

What are the small vessel vasculitis (immune complex) (3)

A

Anti-GBM disease
IgA disease
Cryoglobinaemia

111
Q

What are ANCA

A

Anti-neutrophil cytoplasmic antibodies - different from anti-nuclear antibodies

Antibodies specific for antigens located in primary granules within
cytoplasm of neutrophils
Inflammation may lead to expression of these antigens on cell surface of neutrophils
Antibody engagement with cell surface antigens may lead to neutrophil activation (type II hypersensitivity)
Activated neutrophils interact with endothelial cells causing damage to vessels - vasculitis

112
Q

What are the two types of ANCA antibodies

A

cANCA

pANCA

113
Q

What are cANCA antibodies (3)

A

Cytoplasmic fourenscence
Associated with antibodies to enzyme proteinase 3
Occurs in >90% of patients with granulomatous polyangitis with renal involvement

114
Q

What are pANCA antibodies (4)

A

Perinuclear staining pattern
Associated with antibodies to myeloperoxidase
Less sensitive and specific than cANCA
Associated with microscopic polyangiitis and eosinophilic granulomatous polyangiitis

115
Q

What is ANA (anti-nuclear antibody) for

A

Screening test for a connective tissue disease

116
Q

What is ANCA (anti neutrophil cystoplasmic antibody) for

A

Associated with a subset of small vessel vasculitides including MPA< GPA and eGPA

Kat's Pathology (105 decks)

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