Immuno 11: Autoinflammatory and AI disease 2

Question 1

Name the autoantigen in the following diseases:
Goodpastures disease
Pemphigus vulgaris
Graves
Myasthenia gravis

Answer 1

Goodpasture’s disease
Non-collagenous domain of basement membrane collagen IV

Pemphigus vulgaris
Epidermal cadherin

Graves’ disease
TSH receptor

Myasthenia gravis
Nicotinic acetylcholine receptor

Question 2

What is the autoantigen in:
SLE
Rheumatoid arthritis

Answer 2

SLE:
DNA
Histones
RNP

Rheumatoid arthritis:
Fc portion of IgG

Question 3

Describe the pathophysiology of Graves’ disease

Answer 3

Excessive production of thyroid hormones mediated by IgG antibodies that stimulate the TSH receptor

Question 4

What type of reaction is seen in T1DM + what antibodies?

Answer 4

T1DM - type II and IV

Anti-GAD (glutamic acid decarboxylase) = MOST IMPORTANT
Anti-islet cell
Anti-insulin
Anti-IA2

Question 5

What type of reaction is seen in pernicious anaemia + what antibodies?

Answer 5

Pernicious anaemia – type II

Anti-gastric parietal cell – most sensitive
Anti-intrinsic factor – most specific

Question 6

What type of reaction is seen in Myasthenia gravis + what antibodies?

Answer 6

Myasthenia gravis – type II

Anti-nAChR (MAIN)
Anti-MuSK (muscle-specific kinase )
Anti-VGCC (Voltage gated calcium channel) – Lambert-Eaton

Question 7

What type of reaction is seen in Goodpastures disease + what antibodies?

Answer 7

Goodpasture’s syndrome – type II

Anti-basement membrane type IV collagen

Question 8

List some genetic polymorphisms that predispose to rheumatoid arthritis.

Answer 8

PAD 2 and PAD 4 polymorphisms - MOST IMPORTANT

HLA DR1
HLA DR4
PTPN22
Polymorphisms affecting TNF, IL1, IL6 and IL10

Question 9

Name and describe the antibodies that are often detected in the diagnosis of rheumatoid arthritis

Answer 9

Anti-cyclic citrullinated peptide antibodies – bind to peptides where arginine has been converted to citrulline, 95% specific, 60-70% sensitive

Rheumatoid factor – IgM antibody directed against Fc region of human IgG
NOTE: there are IgA and IgG variants of RF

Question 10

B cell involvement in the pathophysiology of rheumatoid arthritis

Answer 10

Type II – antibodies bind to citrullinated peptides leading to activation of macrophages, NK cells and complement

Type III – immune complexes form and get deposited leading to complement activation

Question 11

T cell involvement in the pathophysiology of rheumatoid arthritis

Answer 11

CD4 activation -> IFNg and IL17 production -> fibroblast and macrophage activation -> MMPs, IL-1, TNFa

CD8 infiltrate synovium -> inflammation -> pannus formation -> invades cartilage and bone

Question 12

What Gell and Coombs classification is myasthenia gravis?

Type I
Type II
Type III
Type IV

Answer 12

Type II – anti-nAChR antibodies

Question 13

What are antinuclear antibodies and how are they tested?

Answer 13

Group of antibodies against nuclear proteins

Tested by staining Hep-2 (human epidermoid cancer line) cells

NOTE: these are very common and are often present in healthy individuals

Question 14

What are the two different types of antinuclear antibodies + what conditions are they seen in?

Answer 14

Anti-dsDNA (looks homogenous) - V. specifc for SLE

Anti-ENA (looks speckled) - there are different types:

• Ro, La, Sm, RNP – SLE, Sjogrens (Ro and La)
• Centromere – limited cutaneous systemic sclerosis
• Scl70 – diffuse cutaneous systemic sclerosis
• Jo1 – dermatomyositis
• SRP – polymyositis

Question 15

Other than dsDNA, which other quantifiable component can be measured as a surrogate marker for disease activity in SLE? what to use in sle flare ups?

Answer 15

C3 and C4 – C4 will decrease before C3

Classical pathway affected

nb in flares ESR is better than CRP

Question 16

What is the triad of antiphospholipid syndrome?

Answer 16

Recurrent venous or arterial thrombosis
Recurrent miscarriage
Thrombocytopaenia

Question 17

What antibodies are present in antiphospholipid sydrome?

Answer 17

Anti-cardiolipin antibody – immunoglobulins directed against phospholipids and β2 glycoprotein-1

Lupus anticoagulant – prolongation of phospholipid-dependent coagulation tests (aPTT)

NOTE: cannot be assessed if the patient is on anticoagulant therapy
NOTE: both tests should be performed as 40% of patients have disconcordant antibodies

Question 18

What test maybe be falsely raised in antiphospholipid syndrome?

Answer 18

APTT

Question 19

What is the mechanism of systemic sclerosis?

Answer 19

Systemic sclerosis aka scleroderma:

Th2 and Th17 mediated inflammation

Cytokines activate fibroblasts -> fibrosis
Endothelial cell activation -> microvascular disease

Question 20

What are the two different types of systemic sclerosis?

Answer 20

Limited cutaneous systemic sclerosis (CREST Syndrome)

Diffuse cutaneous systemic sclerosis

Question 21

What antibody for:

Limited cutaneous systemic sclerosis

Answer 21

Anti-centromere antibodies

Anti-Scl70 (topoisomerase) antibodies

Question 22

What are the features of limited cutaneous systemic sclerosis

Answer 22

CREST:

Skin involvement of hands, forearms, feet and face

Calcinosis
Raynaud’s phenomenon
Esophageal dysmotility
Sclerodactyly
Telangiectasia
(can also get pulmonary hypertension)

Question 23

Features of diffuse cutaneous systemic sclerosis?

Answer 23

More extensive skin involvement

Gastrointestinal disease

Interstitial pulmonary disease/fibrosis

Scleroderma renal crisis – endothelial cells proliferate leading to a small lumen and poor renal blood supply –> severe hypertension (like renal artery stenosis)

Question 24

Which pts are likley to have the following ANA antibodies raised:
Anti-Jo1
Anti- Mi2
Anti-SRP

Answer 24

Anti-Jo1 – dermatomyositis, associated with lung involvement

Anti-Mi2 – more commonly found in dermatomyositis (but can be found in polymyositis)

Anti-SRP – polymyositis

Question 25

Features of dermatomyositis v polymyositis?

Answer 25

Dermatomyositis – perivascular CD4+ T cell and B cells are seen, this can cause an immune complex-mediated vasculitis (type III response) Polymyositis – CD8+ T cells surround HLA Class I expressing myofibres, CD8+ T cells kill these myofibres via granzyme/perforin (type IV response)

Question 26

Features of Polymyositis?

Answer 26

Within the muscle, you will see CD8 T cells surrounding myofibres that express HLA class I CD8 T cells kill myofibres via perforin/granzyme (type IV)

Question 27

Which classification system is used for systemic vasculitides?

Answer 27

Chapel Hill

Question 28

What are ANCA (anti-neutrophil cytoplasmic antibody) associated vasculitidies?

Answer 28

Small vessel vasculitidies

Question 29

How does ANCA cause vasculitis?

Answer 29

Anti-neutrophil cytoplasmic antibody – antigens located in granules within neutrophil cytoplasm Inflammation can lead to expression of these antigens on neutrophil cell surface – antibody binding can activate neutrophils (type II hypersensitivity) Neutrophils then interact with endothelial cells --> vasculitis

Question 30

Which small vessel vasculitides are associated with ANCA?

Answer 30

``` Microscopic polyangiitis (pANCA) Churg-Strauss syndrome (pANCA) ``` Granulomatosis with polyangiitis (cANCA) - aka wegners disease

Question 31

What condition shows: Glomeruloephritis Epitaxis Necrosis of nasal cartilage -> saddle nose

Answer 31

Granulomatosis with polyangiitis (cANCA) - aka wegners disease

Question 32

Describe the key difference between cANCA and pANCA

Answer 32

cANCA - CYTO Cytoplasmic fluorescence Associated with antibodies against proteinase 3 Occurs in > 90% of Wegener’s patients with renal involvement pANCA - PERINUC Perinuclear staining pattern Associated with antibodies to myeloperoxidase Less sensitive and specific than cANCA Associated with MPA and Churg-Strauss syndrome

Question 33

Link the following antibodies to the disease they are most associated with. ``` Anti-IgG antibody Anti-Sm cANCA pANCA Anti-centromere ```

Answer 33

Anti-IgG antibody - Rheumatoid arthritis Anti-Sm - form of ANA associated w SLE cANCA - GPA pANCA - MPA Anti-centromere - Limited cutaneous systemic sclerosis

Question 34

A patient presents with lesions over their knuckles and shortness of breath. He is slow to take a seat in your clinic. Which of the follow antibodies is most likely to be positive in this patient? Anti-Jo1 Anti-dsDNA Anti-Ro Anti-Scl70

Answer 34

Anti-Jo1 – associated with Mechanic’s hands and pulmonary involvement (Dermatomyositis)

Question 35

Which of the following antibodies is most sensitive for rheumatoid arthritis? Rheumatoid factor Anti-SRP Anti-CCP Anti-RNP

Answer 35

Anti-CCP – more sensitive for RA than rheumatoid factor

Question 36

What are the following associated w/ antibodies against? cANCA pANCA

Answer 36

cANCA = proteinase 3 pANCA = myeloperoxidase

Question 37

What ANAs are found in the following diseases: ``` SLE Sjorgens Limited Cutaneous Systemic Sclerosis Diffuse Cutaneous Systemic Sclerosis Dermatomyositis Polymyositis ```

Answer 37

SLE = Anti-dsDNA (MAIN), anti-Ro, anti-La, anti-RNP, anti-RNP Sjorgens = Anti-Ro and Anti-La Limited Cutaneous Systemic Sclerosis = Anti-centromere Diffuse Cutaneous Systemic Sclerosis = Anti-scl70 (topoisomerase) Dermatomyositis = Anti-Jo1 Polymyositis = Anti-SRP