IMMUNO: Autoimmune and Autoinflammatory Disease Flashcards
1
Q
What is immunopathology? Give some examples.
A
Damage to host caused by the immune response
2
Q
In the context of immunopathology, what is auto-inflammatory or auto-immune disease? What are the types?
A
Immunopathology in the absence of infection
Innate immune response cause = auto-inflammatory
Mixed innate adaptve = mixed
Adaptive immuno response cause = auto-immune
3
Q
What is the cause of auto-inflammatory disease?
A
Local factors at sites predisposed to disease lead to activation of innate immune cells such as macrophages and neutrophils, with resulting tissue damage
4
Q
What is the cause of auto-immune diseases?
A
Aberrant T cell and B cell responses in primary and secondary lymphoid organs lead to breaking of tolerance with development of immune reactivity towards self-antigens
Organ-specific antibodies may predate clinical disease by years
Adaptive immune response plays the predominant role in clinical expression of disease
5
Q
How do genetics influence the formation of auto-inflammatory/immune disease? Which are most common?
A
Polygenic or monogenic (mixed disease is only polygenic, others can be both)
Polygenic is most common
6
Q
What type of genetic changes, apart from just inherited DNA, can cause these conditions?
A
- Germline mutations affecting DNA sequence - Alteration in DNA that occurs in germ cells (sperm and ova and progenitors) and will be passed on to offspring
- Somatic mutations affecting DNA sequence - Alteration in DNA that occurs in a single body cell after conception, does not affect germ cells and so is not inherited
- Epigenetics - (Heritable) change in gene expression (eg via DNA methylation)
- MicroRNA (miRNA) - Small, non-coding, single stranded RNA targets mRNA and regulate protein production
7
Q
Give 2 examples of rare monigenic auto-inflammatory diseases.
A
Familial Mediterranean fever
TRAPS
8
Q
How do monogenic auto-inflammatory conditions classically present?
A
Classically present with
- periodic fevers
- skin/joint/serosal/CNS etc inflammation
- high CRP
9
Q
What is the cause of monogenic auto-inflammatory conditions? Which cytokines are most involved?
A
Mutations in a gene encoding a protein involved in a pathway associated with innate immune cell function
Abnormal signalling via key cytokine pathways involving TNF-alpha and/or IL-1 is common
10
Q
What is the pathophysiology of familial mediterranean fever?
A
- Autosomal recessive condition
- Mutation in MEFV gene
- MEFV gene encodes pyrin-marenostrin
- Pyrin-marenostrin expressed mainly in neutrophils (negative regulator for inflammation)
- Failure to regulate cryopyrin driven activation of neutrophils
11
Q
What is the clinical presentation of familal mediterranean fever?
A
Periodic fevers lasting 48-96 hours associated with:
- Abdominal pain due to peritonitis
- Chest pain due to pleurisy and pericarditis
- Arthritis
- Rash
Usually in people of Mediterranean origin.
12
Q
What are the complications of FMF?
A
Complication - AA amyloidosis
Liver produces serum amyloid A as acute phase protein
Serum amyloid A deposits in kidneys, liver, spleen
Deposition in kidney often most clinically important
- Proteinuria - nephrotic syndrome
- Renal failure
13
Q
What investigations are done to diagnose FMF?
A
- High CRP, high SAA
- Blood sample to specialist genetics laboratory to identify MEFV mutation
14
Q
What is the treatment for FMF?
A
- Colchicine 500ug bd (1st)- binds to tubulin in neutrophils and disrupts neutrophil functions including migration and chemokine secretion
- IL-1 blocker (anakinra, canukinumab) - 2nd
- TNF alpha blocker
15
Q
Give 3 examples of Rare Monogenic Auto-immune Diseases.
A
- APS-1, APECED
- ALPS
- IPEX
16
Q
What are the main abnormalities in IPEX and ALPS?
A
Mutation in a gene encoding a protein involved in a pathway associated with adaptive immune cell function
- Abnormality of regulatory T cells - IPEX
- Abnormality of lymphocyte apoptosis - ALPS
17
Q
What does IPEX stand for? What is the pathophysiology?
A
Immune dysregulation, polyendocrinopathy, enteropathy, X- linked syndrome = IPEX
Mutations in Foxp3 (Forkhead box p3) which is required for development of Treg cells
Failure to negatively regulate T cell responses –>
- Autoreactive B cells
- limited repertoire of autoreactive B cells
18
Q
What are the clinical complications of IPEX?
A
Autoimmune diseases –>
- Diabetes Mellitus
- Hypothyroidism
- Enteropathy
- ‘Diarrhoea, diabetes and dermatitis’
19
Q
What does ALPS stand for? What is the pathophysiology?
A
Auto-immune lymphoproliferative syndrome = ALPS
Mutations within FAS pathway
- Eg mutations in TNFRSF6 which encodes FAS
- Disease is heterogeneous depending on the mutation
Defect in apoptosis of lymphocytes –>
- Failure of tolerance
- Failure of lymphocyte ‘homeostasis’
High lymphocyte numbers with large spleen and lymph nodes
20
Q
What is seen clinically in ALPS?
A
- High lymphocyte numbers with large spleen and lymph nodes
- Auto-immune disease - commonly auto-immune cytopenias
- Lymphoma
21
Q
Give 3 examples of Polygenic Auto-inflammatory Diseases.
A
- Crohns disease
- Ulcerative colitis
- Osteoarthritis
- Giant cell arteritis
- Takayasu’s arteritis
22
Q
How important is HLA association in Polygenic Auto-inflammatory Diseases? Are auto-antibodies present?
A
- Not a strong association in HLA
- In general these disease are not characterised by presence of auto-antibodies
23
Q
What are the genetics of IBD in general? Is FH important? What about dizygotic twins?
A
Polymorphisms, >200 loci identified
Familial association studies and twin studies suggested genetic predisposition to disease
- 15% patients have an affected family member
- 50% vs <10% disease concordance in monozygotic vs dizygotic twins
*
24
Q
Which mutations are important in Crohn’s disease?
A
IBD1 gene = NOD2 gene mutation
- IBD1 gene on chromosome 16 identified as NOD2 (CARD-15, caspase activating recruitment domain -15).
- Three different mutations of this gene have each been shown to be associated with Crohn’s disease.
- NOD2 gene mutations are present in 30% patients (ie not necessary)
- Abnormal allele of NOD2 increases risk of Crohn’s disease by 1.5-3x if one copy and 14-44x if two copies (ie not sufficient)
- Mutations also found in patients with Blau syndrome and some forms of sarcoidosis
25
How does NOD2 mutation cause Crohn's?
* **NOD2** expressed in cytoplasm of **myeloid cells** – macrophages, neutrophils, dendritic cells
* **NOD2** is a **cytoplasmic microbial sensor** which recognises _muramyl dipeptide_ on bacterial products--\> stimulates _NFK-beta_ (--\> TNFa)
* Activation induces autophagy in dendritic cells
26
What are the clinical features of Crohn's disease? What is the treatment?
Clinical features
* Abdominal pain and tenderness
* Diarrhoea (blood, pus, mucous)
* Fevers, malaise
Treatment may include
* Corticosteroid
* Anti-TNF alpha antibody
27
Which factors can affect the following in Crohn's?
* Expression of pro-inflammatory cytokines/chemokines
* Leukocyte recruitment
* Release of proteases, free radicals
28
Give 3 examples of mixed pattern diseases.
1. Axial spondyloarthritis
2. Psoriatic arthritis
3. Behcet’s syndrome
29
Is there HLA association and presence of autoantibodies in mixed pattern disease? What are the genetics?
HLA associations may be present
Auto-antibodies are not usually a feature
Mutations affect pathways in adaptive and innate immune pathways
30
What role do genetics play in ankylosing spondylitis?
Highly heritable - 90% of the risk of developing disease is genetic
HLAB27, IL23R and ILR2 are invovled
31
What sites are most affected in ankylosing spondylitis?
* Enhanced inflammation occurs at specific sites where there are high tensile forces
* (**entheses** - sites of insertions of ligaments or tendons)
32
What is the presentation of ankylosing spondylitis? What is the treatment?
Presentation
* Low back pain and stiffness
* Enthesitis
* Large joint arthritis
Treatment
* Non-steroidal anti-inflammatory drugs
* Immunosuppression
* Anti-TNF alpha
* Anti-IL17
33
FMF
34
IPEX
35
Crohn's
36
Give 5 examples of Polygenic Auto-immune Diseases.
Rheumatoid arthritis
Systemic lupus erythematosus
Myaesthenia Gravis
Primary biliary cholangitis
Pernicious anaemia
Addison disease
37
Are there autoantibodies/HLA associations in polygenic autoimmune diseases? What are the genetics?
HLA associations are common
Aberrant **B cell and T cell responses** in primary and secondary **lymphoid organs** lead to breaking of tolerance with development of immune reactivity towards self-antigens
Auto-antibodies are found
Mutations affect pathways in the adaptive immune response
38
Name some polymorphisms causing T cell actication in polygenic auto-immune disease.
39
How does HLA association relate to polygenic autoimmune disease? How does HLA association correspond to risk?
HLA presentation of antigen is required for development of T cell and T cell-dependent B cell responses
40
41
How did Gel and Coombs classify effector mechanisms of immunopathology?
Gel and Coombs (1960s) classified skin test ‘hypersensitivity’ reactions **according to the type of immune response observed**
Effector mechanisms for immunopathology
42
What is the Gel and Coombs classification for polygenic auto-immune disease?
* **Type I: Anaphylactic hypersensitivity**
* Immediate hypersensitivity which is IgE mediated – rarely self antigen
* **Type II: Cytotoxic hypersensitivity**
* Antibody reacts with cellular antigen
* **Type III: Immune complex hypersensitivity**
* Antibody reacts with soluble antigen to form an immune complex
* **Type IV: Delayed type hypersensitivity**
* T-cell mediated response
43
Which type of reaction is antibody-driven according to Gel and Coombs?
Type II
Antibody (autoantibody) binds to cell associated antigen e.g. cell or matrix-associated antigen
44
Give 3 examples of type II driven auto-immune disease.
* Goodpasture disease - against non-collagenous domain of BM collagen type IV
* Pemphigus vulgaris - against epidermal cadherin
* Graves disease - against TSHR
* MG - against AChR
45
Give the 2 types of immunopathogenic mechanisms present in type II disease.
1. **Antibody dependent destruction (NK cells, phagocytes, complement)**
1. Complement activation --\> cell lysis
2. Ig Fc R interaction with NK cells --\> release of cytolytic granules and membrane attack
3. Phagocyte --\> phagocytosis
2. **Receptor activation or blockade (sometimes considered type V response)**
46
Which types of reactions are immune complex driven in autoimmune disease?
Type III - antibody binds to soluble antigen to form cicrulating immune complex
47
What are the mechanisms of T3 disease?
* Antibodies bind to soluble antigen to form circulating **immune complex**
* Immune complexes deposit in blood vessels
* Complement activation, infiltration of macrophages and neutrophil
* Cytokine and chemokine expression
* Granule release from neutrophils
* Increased vascular permeability
* Inflammation and damage to vessels
* Cutaneous vasculitis
* Glomerulonephritis
* Arthritis
48
Give an example of type III complex driven autoimmune disease.
49
Which delayed-type hypersensitivity reaction in autoimmunity is mediated by T cells? What are the 2 mechanisms?
Tissue destruction by…
1. HLA class 1 present **SELF**-antigens _to CD8 T cells_ → **_cell lysis_**
2. HLA class 2 present **SELF**-antigen _to CD4 T cells_ → cytokine production → **_inflammation and tissue damage_**
50
Give an example of type IV T-cell mediated disease.
Insulin dependent DM - autoantigen is the pancreatic beta-cell antigen
51
How are polygenic autoimmune diseases classified?
Organ specific diseases vs multisystem diseases
52
What are the clinical features of Graves' disease?
* Nervous
* Palpitations
* Heat intolerant
* Diarrhoea
53
What is the pathophysiology of Graves disease?
Excessive production of thyroid hormones
Mediated by IgG antibodies which stimulate the TSH receptor
Evidence
* Antibodies stimulate thyrocytes in vitro
* Passive transfer of IgG from patients to rats often produces similar symptoms (!)
* Babies born to mothers with Graves' may show transient hyperthyroidism
Cause
* Stimulating autoantibodies against TSH-receptor bind to receptor
* Act as TSH agonists
* Induce uncontrolled overproduction of thyroid hormones
* Negative feedback cannot override antibody stimulation
54
What types of antibodies are present in Graves?
Mediated by IgG antibodies which stimulate the TSH receptor
55
What is the clinical presentation of hypothyroidism? What is the most common cause?
* Lethargic
* Dry skin and hair
* Constipation
* Cold intolerant
Hashimoto's thyroiditis
56
What is the pathophysiology of Hashimoto's?
Commonest cause of hypothyroidism in iodine-replete areas
Goitre – enlarged thyroid infiltrated by T and B cells
Associated with anti-thyroid peroxidase antibodies
* Presence correlates with thyroid damage and lymphocyte inflammation
* Some shown to induce damage to thyrocytes
Associated with presence of anti-thyroglobulin antibodies
57
Is measuring anti-thyroglobulin and anti-thyroid peroxidase antibodies clinically useful?
High prevalence so no - do TFTs
58
What is the pathophysiology of T1DM? What does the NOD mouse model of it show?
Non obese diabetes (NOD) mouse model for type 1 diabetes
CD8+ T-cell infiltration of pancreas
T cell clones have specificity for islet antigens
Progressive increase in lymphocyte infiltration and islet destruction in the non-obese diabetic (NOD) mouse
59
What comes first in T1DM, autoantibodies or disease by other means?
Antibodies pre-date development of disease
* Anti-islet cell antibodies
* Anti-insulin antibodies
* Anti-GAD antibodies
* Anti-IA-2 antibodies
Individuals with 3-4 of the above are highly likely to develop type I diabetes
Detection of antibodies does not currently play a role in diagnosis
60
Which autoantibodies are present in T1DM?
1. Anti-islet cell antibodies
2. Anti-insulin antibodies
3. Anti-GAD antibodies
4. Anti-IA-2 antibodies
61
In terms of the classification (types 1-4) what effects mechanisms is present in T1DM?
CD8 T-cell mediated type IV pathology – recognise autoantigens presented by
MHC Class I molecules on beta cells
62
Where are these autoantibodies present?
1. Graves disease (hyperthyroidism)
2. Hashimoto disease
3. Hashimoto disease
63
What is the cause?
* Tired
* Pale
* Mild numbness of feet
* Anaemic Hb 8.4
* Macrocytosis MCV 108
* Urine dipstick –ve
* Folate normal
* Vitamin B12 very low
Pernicious Anaemia
64
What is the pathophysiology of pernicious anaemia? What is useful in diagnosis?
* Failure of vitamin B12 absorption
* Vitamin B12 deficiency
* Macrocytic anaemia
* Neurological features with subacute combined degeneration of cord (posterior and lateral columns), peripheral neuropathy, optic neuropathy
## Footnote
**Antibodies to gastric parietal cells or intrinsic factor - are useful in diagnosis**
65
Where are these autoantibodies present?
1. Pernicious anaemia
2. Pernicious anaemia
3. Coeliac
4. Coeliac
5. Ulcerative colitis\>Crohns
66
Where are these autoantibodies present?
1. Autoimmune hepatitis, Primary biliary cholangitis
2. Autoimmune hepatitis
3. Autoimmune hepatitis
4. Primary biliary cholangitis
5. Autoimmune hepatitis, Primary biliary cholangitis
67
What is the diagnosis?
* Drooping eyelids
* Weakness, particularly on repetitive activity
* Symptoms worse at end of day
MG
68
Myaesthenia gravis
69
What is the most important autoantibody in MG?
**Anti-acetylcholine recepto**r antibodies present in ~75% patients and are useful in diagnosis
## Footnote
*Offspring of affected mothers may experience transient neonatal myaesthenia*
70
Where are these autoantibodies present in terms of neurological disease?
1. Myaesthenia Gravis
2. Myaesthenia Gravis with myositis
3. Neuromyelitis optica spectrum disorder (NMOS)
4. Optic neuritis, encephalomyelitis
5. Encephalitis (may be malignancy associated)
6. Seizures (may be malignancy associated)
71
What is the pathophysiology of Goodpasture syndrome?
**Anti-basement membrane antibody positive -** these are specific for glomerular basement membrane disease and underpin the pathology so are useful in diagnosis of anti-glomerular basement membrane disease (Goodpasture’s disease)
72
What is the diagnosis?
* 48 year old man
* Haemoptysis with widespread crackles in lungs
* Swelling of legs
* Reduced urine output
* Creatinine 472
* Microscopic haematuria and proteinuria
* CXR – widespread shadowing
* Elevated TLCO suggesting pulmonary haemorrhage
* Anti-basement membrane antibody positive
* Crescentic nephritis on biopsy
Goodpasture disease
* Circulating antibodies specific for GBM are useful in diagnosis
* Also important in pathogenesis (Type II)
* **Antibodies** specific for **glomerular basement membrane disease** underpin the pathology and are useful in diagnosis of anti-glomerular basement membrane disease (Goodpasture’s disease)
73
How are antibodies in Goodpasture syndrome detected? What do they show? What is seen on biopsy?
**Fluorescein conjugated polyclonal anti-human immunoglobulin** viewed under UV source and fluorescence microscope
Antibodies may be detected in tissue sections. --\> shows smooth linear deposition of antibody along the glomerular basement membrane
**Crescentic nephritis** is seen on biopsy
74
Which renal diseases are these present in?
1. Goodpasture disease
2. ANCA associated vasculitis - Microscopic polyangiitis / Eosinophilic granulomatosis with polyangiitis
3. ANCA associated vasculitis - Granulomatosis with polyangiitis
75
What is the diagnosis?
* Pain, stiffness and swelling of multiple small joints within hands
* Normochromic anaemia
* High ESR and CRP
RhA
76
What are the genetic associations of RhA?
* HLA DR4 (DRB1 0401, 0404, 0405) and HLA DR1 (DRB1 0101) alleles
* Susceptible alleles share a sequence at positions 70-74 of the HLA DR beta chai
* These alleles may bind ‘arthritogenic peptides’ and have been shown to bind to citrullinated peptides with high affinity
* Peptidyl arginine deiminase (PAD)2 and PAD4 polymorphisms
* PTPN22 polymorphism
77
How do peptidylarginine deaminases PAD type 2 and 4 contribute to pathophysiology of RhA?
* Enzymes involved in deimination of arginine to create citrulline
* Polymorphisms are associated with increased citrullination
* This creates a high load of citrullinated proteins
78
What is the role of antibodies in RhA? Why are they useful?
Antibodies to cyclic citrullinated peptide:
* Bind to peptides in **which arginine has been converted to citrulline** by peptidylarginine deiminase (PAD)
* Around 95% specificity for diagnosis of rheumatoid arthritis*
* Around 60-70% sensitivity for diagnosis of rheumatoid arthritis*
* Best blood test for diagnosis of Rheumatoid arthriti*s
79
Which environmental factors contribute to pathophysiology (by increasing citrullination) of RhA?
* **Smoking** associated with development of erosive disease - Smoking associated with increased citrullination
* Gum infection with **Porphyromonas gingivalis** associated with rheumatoid arthritis - P gingivalis is only bacterium known to express PAD enzyme and thus promote citrullination
80
What is rheumatoid factor? What type of Ig is this? How useful is it for diagnosis?
A rheumatoid factor is an **antibody directed against the common (Fc) region of human IgG**
IgM anti-IgG antibody is most commonly tested although IgA and IgG rheumatoid factors may also be present in some individuals
Around 60-70% specificity and sensitivity for diagnosis of rheumatoid arthritis
81
Menti: Which of the following is an example of Gel and Coombs type III hypersensitivity:
* Goodpasture disease
* Eczema
* SLE
* Multiple sclerosis
* Graves disease
82
Anti AChR
83
Which of the following antibodies are characteristically found in Pernicious Anaemia?
* Anti-GAD antibody
* Anti-thyroglobulin antibody
* Anti-basement membrane antibody
* Anti-intrinsic factor antibody
* Anti-acetylcholine receptor antibody
* Anti-cyclic citrullinated peptide antibody
* Anti-TSH receptor antibody
Anti IF
84
Give 4 examples of polygenic auto-immune diseases causing **multi-system diseases**.
* SLE
* Sjogren’s syndrome
* Systemic sclerosis
* Dermato/Polymyostis
= all associated with anti-nuclear antibodies
85
How do we detect anti-nuclear antibodies? What do they bind? How common are they?
**Group of antibodies that bind to nuclear proteins**
Test by staining of Hep-2 cells (human epidermoid cancer line) and Fluorescein conjugated polyclonal anti-human immunoglobulin
*Very common - Low titre antibodies (\<1:80) often found in normal individuals (esp older women)*
86
What is the diagnosis?
* 19yo with 4 month history of fatigue
* Generalised arthralgia, particularly of small joints of hands
* Hair fall
* Mouth ulcers
* Butterfly rash
SLE
87
What are the possible causes of SLE in terms of genetic predisposition?
* **Abnormalities in clearance of apoptotic cells**
* = polymyorphisms in genes encoding complement, MBL, CRP
* **Abnormalities in cellular activation**
* = polymorphisms in genes encoding/controlling expression of cytokines, chemokines, co-stimulatory molecules, intracellular signalling molecules
* **-\> B cell hyperactivity and loss of tolerance**
* **Antibodies directed particularly at intracellular proteins**
* ?Debris from apoptotic cells that have not been cleared
* Nuclear antigens - DNA, histones, snRNP
* Cytoplasmic antigens - Ribosome, scRNP
88
What is the pathophysiology (immune system dysregulation) in SLE?
1. Antibodies bind to antigen to form immune complexes
2. Immune complexes deposit in tissues --\> Skin, joints, kidney
3. Immune complexes activate complement (classical pathway)
4. Immune complexes stimulate cells expressing Fc and complement receptors
89
Compare/contrast these images of renal pathology in SLE and Goodpasture's disease.
**Lupus nephritis =** Immune complex deposition, detection of granular ‘lumpy-bumpy’pattern with fluorescein conjugated anti-human Immunoglobulin used; type III hypersensitivity
**Goodpasture's syndrome =** Smooth linear deposition of antibody along the glomerular basement membrane; Type II hypersensitivity; fluorescein conjugated polyclonal anti-human Ig used
90
What titres of ANA are usually found in SLE?
Ani-nucelar antibody - \>1:640 homogenous (normal levels \<1:80)
91
What are the targets of ANA (anti-nuclear antibody) in general?
1. dsDNA
2. Ro, LA, Sm, U1RNP ribonucleoproteins
3. SCL70 topoisomerase
4. Centromere
## Footnote
*Therefore a positive ANA will trigger the laboratory to investigate for dsDNA and ENA antibodies.*
92
What is shown in this SLE investigation?
ANA Pattern
* Homogeneous staining associated with specificity for dsDNA
* Specificity investigated with ELISA based assay
93
How good are anti-dsDNA antibody investigations for SLE diagnosis? Does it tell you anything else about the disease?
V good - highly **specific** (95%) for SLE, occur in 60-70% of those with SLE so **common** and false positive is uncommon (\<3%)
Uses in SLE:
1. Very **high titres are associated with more severe diease**, including renal or CNS involvement
2. AND **useful in disease monitoring**
94
What test for SLE is shown by this image? What does this mean? What is a follow up test for this result?
Speckled antibodies shown which are often associated with antibodies to extractable nuclear antigens;
Could suggest presence of some ribonucleoproteins (Ro, La, Sm, U1RNP) – but needs to be confirmed with ELISA
95
Where else are anti-Ro and La antibodies characteristically found?
Sjogren's syndrome
96
What are anti-ENA (extractable nuclear antigen) antibodies in SLE? Are they useful?
Antibodies against Ro, La, Sm, RNP (all ribonucleoproteins)
They _may_ occur but **usually are not found**
Titres NOT helpful in disease monitoring
97
What are complement levels usually like in SLE? Is measurement of C3/4 a useful marker in SLE?
Formation of antibody-antigen immune complexes --\> activate complement cascade via **classical pathway** --\> complement components become depleted if constantly consumed
Quantitation of C3 and C4 acts as a surrogate marker of **disease activity**
* **C4 may be low in active disease**
* **C3 and C4 will be low in severe active disease**
*[NB we measure UNACTIVATED complement proteins, not activated forms]*
98
What are the clinical features of anti-phospholipid syndrome? What are the 2 types?
* Recurrent venous or arterial thrombosis
* Recurrent miscarriage
* May be associated with livedo reticularis, cardiac valve disease
May occur **alone (primary) or in conjunction with autoimmune disease (secondary)**
99
Name three antibody tests used to in anti-phospholipid syndrome.
1. **Lupus anti-coagulant** - Prolongation of phospholipid-dependent coagulation tests; cannot be assessed if the patient is on anticoagulant therapy
2. **Anti-cardiolipin antibody** - Antibody specific for negatively charged phospholipids
3. **Anti-B2 glycoprotein 1 antibody** - Antibody specific for glycoprotein found associated with negatively charged phospholipids
CHECK ALL 3 in those with unexplained thrombosis and recurrent pregnancy loss.
100
What is the diagnosis?
Systemic sclerosis
101
What are the two types of systemic sclerosis?
1. **Limited** cutaneous systemic sclerosis (CREST)
2. **Diffuse** cutaneous systemic sclerosis (CREST + other features)
102
What are the clinical features of CREST (limited cutaneous systemic sclerosis)?
Skin involvement does not progress beyond forearms (although it may involve peri-oral skin)
* Calcinosis
* Raynauds
* Oesophageal dysmotility
* Sclerodactyly
* Telangectasia
* Primary pulmonary hypertension
103
What are the features of diffuse cutaneous systemic sclerosis?
Skin involvement does progress beyond forearms
* CREST features
* More extensive gastrointestinal disease
* Interstitial pulmonary disease
* Scleroderma kidney / renal crisis
104
Which types is diffuse vs limited systemic sclerosis in these ANA stains?
1. Limited cutaneous systemic sclerosis -
* anti-centromere antibodies
2. Diffuse cutaneous systemic sclerosis
* nucleolar pattern
* anti-topoisomerase antibodies (Scl70)
* RNA polymerase
* Fibrillarin
Mutually exclusive, highly specific
105
What is the diagnosis?
* Weakness
* Malaise
* Rash
**Idiopathic inflammatory myopathy** - dermatomyositis + polymyositis
106
What is the pathophysiology of the two types of idiopathic inflammatory myopathy?
**Dermatomyositis**
* Perivascular CD4 T cells and B cells **within muscle**
* Immune complex mediated vasculitis
**Polymyositis**
* CD8 T cells surround HLA Class I expressing myofibres within **muscle**
* CD8 T cells kill myofibres via perforin / granzymes
107
What investigations are diagnostic in idiopathic inflammatory myopathy?
1. Positive ANA (may be present in some patients)
2. Extended myositis panel
* Anti-aminoacyl transfer RNA synthetase antibody eg Jo-1 (cytoplasmic)
* Anti-signal recognition peptide antibody (nuclear and cytoplasmic) (PM)
* Anti-Mi2 (nuclear) (DM\>PM)
108
What type of staining is shown in this investigation for idiopathic inflammatory myopathy?
Cytoplasmic anti-Jo1 staining - this is a type of anti-aminoacyl tRNA synthetase antibody
109
110
Which rheumatological conditions are these autoantibodies found in ?
1. Rheumatoid arthritis
2. Rheumatoid arthritis + Primary Sjogrens
3. Connective tissue disease (screening)
4. Systemic lupus erythematosus
5. Systemic lupus erythematosus
6. Systemic lupus erythematosus or mixed connective tissue disease
111
Which rheumatological conditions are these autoantibodies found in ?
1. Systemic lupus erythematosus or mixed connective tissue disease
2. Primary Sjogren’s or SLE
3. Limited cutaneous systemic sclerosis
4. Diffuse cutaneous systemic sclerosis
5. Idiopathic inflammatory myositis
6. Anti-phospholipid syndrome
112
Which antibodies are found in ANCA associated vasculitis?
Anti-neutrophil cytoplasmic antibody
113
What is the diagnosis?
## Footnote
*Patient 54 year old woman is referred with recurrent nose bleeds and breathlessness*
Systemic vasculitis - small vessel (ANCA associated) e.g microscopic polyangitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis.
114
How are systemic vasculitidies classified?
115
What are the 3 types of small vessel vasculitis associated with ANCA?
1. Microscopic polyangiitis / Microscopic polyarteritis / MPA
2. Granulomatosis with polyangiitis / Wegener’s granulomatosis / GPA
3. Eosinophilic granulomatosis with polyangiitis / Churg-Strauss syndrome / eGPA
Associated with anti-neutrophil cytoplasmic antibody (ANCA) which is DIFFERENT FROM ANA
116
What is the pathophysiology of vasculitis associated with 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 of 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
117
What are the diffferences between these ANCA stains?
1. Cytoplasmic fluorescence - antibodies to enzyme **proteinase 3**
2. Perinuclear staining pattern - antibodies to **myeloperoxidase**
118
Compare and contrast cANCA and pANCA. Which is associated with MPA, GPA and eGPA?
**cANCA**
* ****_C_**ytoplasmic** fluorescence
* Associated with antibodies to enzyme proteinase 3
* Occurs in \> 90% of patients with granulomatous polyangiitis (**GPA**) with renal involvement
**p-ANCA**
* ****_P_**erinuclear** staining pattern
* Associated with antibodies to myeloperoxidase
* Less sensitive and specific than cANCA
* Associated with microscopic polyangiitis (**MPA**) and eosinophilic granulomatous polyangiitis (**eGPA**)
119
SLE - dsDNA antibodies are quite specific
120
ANCA-associated vasculitis
