Imm - Autoinflammatory and Autoimmune Disease 2

Question 1

Give examples of polygenic auto-immune disease that involve organ-specific antibodies

Answer 1

Grave’s disease
Hashimoto’s thyroiditis
T1DM
Pernicious anaemia
Myasthaenia Gravis
Goodpasture’s syndrome

Question 2

Give example of polygenic auto-immune disease that involve anti-nuclear antibodies (systemic disease)

Answer 2

SLE
Sjogren’s syndrome
Systemic sclerosis
Dermato/polymyositis
ANCA-associated vasculitis

Question 3

What is the immune pathophysiology of Graves’ disease

Answer 3

Type 2 hypersensitivity
IgG antibodies against the TSH receptor → TSHr activation → excessive production of thyroid hormone

Question 4

What are the clinical features of Graves’ disease

Answer 4

Nervous
Palpitations
Heat intolerant
Diarrhoea
Exophthalmos

Question 5

What is the evidence for Graves disease as a T2HS reaction

Answer 5

Antibodies stimulate thyrocytes in vitro
Passive transfer of IgG from patients to rats produces similar symptoms
Babies born to mothers with Graves’ may show transient hyperthyroidism

Question 6

What is the immune pathophysiology of Hashimoto’s thyroiditis

Answer 6

T2 and T4 hypersensitivity
Anti-thyroid peroxidase (TPO) + anti-thyroglobulin antibodies
Thyroid becomes infiltrated with T and B cells

Question 7

What are the clinical features of Hashimoto’s thyroiditis and which investigation should be done

Answer 7

Lethargic
Dry skin and hair
Constipation
Cold intolerant
Goitre

TFTs (anti-TG and TPO Abs are highly prevalent so NOT useful)

Question 8

What is the immune pathophysiology of T1DM

Answer 8

T4 hypersensitivity
CD8 T-cells infiltrate the pancreas and recognise auto-antigens presented by MHC class I on pancreatic beta cells → destruction → lymphocyte infiltration → further islet destruction

Antibodies: anti-islet cell, anti-insulin, anti-GAD, anti-IA-2

Question 9

What are the clinical features of T1DM and what investigations should be done on first presentation

Answer 9

Thirsty
Polyuria
Malaise
Glycosuria

TFts, LFTs, coeliac screen

Question 10

What is the immune pathophysiology of Pernicious anaemia

Answer 10

T2 hypersensitivity
Autoantibodies against intrinsic factor or gastric parietal cells→ no absorption of vitamin B12 → pernicious anaemia and SCDC

Question 11

What are the clinical features of pernicious anaemia and what are the complications

Answer 11

Anaemia (macrocytosis): tired, pale, numbness of feet
May lead to sub-acute combined degeneration of the cord → peripheral neuropathy, optic neuropathy

Question 12

Which auto-antibodies are associated with the following GI diseases: Pernicious anaemia, coeliac’s disease, Ulcerative colitis

Answer 12

Pernicious anaemia: anti-parietal, anti-intrinsic factor
Coeliac’s disease: anti-tTG, anti-endomysial antibodies
UC: P-ANCA

Question 13

Which autoantibodies are associated with the following liver diseases: Autoimmune hepatitis, primary biliary cholangitis

Answer 13

Autoimmune hepatitis: Anti-nuclear (ANA), anti-smooth muscle (SMA), anti liver kidney microsomal proteins (LKM), P-ANCA

PBC: ANA, anti-mitochondrial antibodies (AMA), P-ANCA

Question 14

What is the immune pathophysiology of myasthenia Gravis

Answer 14

T2 Hypersensitivity
Autoantibodies against ACh receptors → failure of depolarisation → absence of muscle action potential

Anti-ACh-R ABs present in ~75% patients

Question 15

What are the clinical features of myasthenia Gravis and what investigations can be done for it

Answer 15

Drooping eyelids (ptosis)
Weakness on repetitive activity (fluctuating)
Symptoms worse at the end of the day

Tensilon test positive - inject edrophonium (anti-cholinesterase) to prolong the life of ACh and allow it to act on the receptors

Question 16

Which autoantibodies are associated with the following: myasthenia Gravis, neuromyelitis optica spectrum disorder (NMOS), optic neuritis, Encephalitis, seizures

Answer 16

Myasthenia Gravis: anti-ACh, anti-striational,
Neuromyelitis optica spectrum disorder (NMOS): anti-aQP4 (aquaporin)
Optic neuritis: anti-MOG
Encephalitis: anti-NMDA
Seizures: anti-GABA

Question 17

What is the immune pathophysiology of Goodpasture’s disease

Answer 17

T2 Hypersensitivity
Anti-basement membrane antibodies (lungs and kidneys) - smooth linear deposition

Question 18

What are the clinical features of Goodpasture’s

Answer 18

Haemoptysis with widespread crackles in lungs
Swelling of legs
Reduced urine ouput
Microscopic haematuria + proteinuria

Question 19

Which alleles are associated with Rheumatoid arthritis

Answer 19

HLA DR4, HLA DR1
PAD2 and PAD4
PTPN22

Leads to high levels of citrullination and binding to citrullinated peptides with a higher affinity

Question 20

Which environmental factors are associated with rheumatoid arthritis and why

Answer 20

Smoking → development of erosive disease, and increased citrullination
Gum infection with Porphyromonas gingivalis (expresses PAD)

Question 21

Which antibodies are present in rheumatoid arthritis

Answer 21

anti-cyclic citrullinated peptide (anti-CCP) - more specific and sensitive
Rheumatoid factor (directed against the Fc region of human IgG) - igM is most commonly tested

Question 22

What type of hypersensitivity reaction is involved in rheumatoid arthritis

Answer 22

T2: antibody binds to citrullinated proteins → complement, macrophage, and NK cell activation

T3: immune complex formation between RF and anti-CCP

T4: antigen presenting cells → CD4 T cell → production of IF-gamma and IL17 → production of MMPs, IL1, TNFalpha

Question 23

How are non-organ specific autoimmune diseases tested for

Answer 23

Stain Hep2 cells
Presence of anti-nuclear antibodies (ANA)

Question 24

What are the clinical features of SLE

Answer 24

CNS – seizures
Skin – butterfly rash, discoid lupus
Heart – endocarditis, myocarditis, serositis, pleuritis, pericarditis
Glomerulonephritis
Haematological – haemolytic anaemia, leukopenia, thrombocytopenia
Arthritis and lymphadenopathy

Question 25

What is the immune pathophysiology of SLE

Answer 25

T3 hypersensitivity: (1) Antibodies bind to antigens to form immune complexes (2) Immune complexes deposit in tissues (NOT binding) → skin, joints, kidney - Immune complexes activate complement → classical pathway - Immune complexes stimulate cells expressing Fc and complement receptors

Question 26

What investigations should be done for SLE

Answer 26

ANA via titre (SLE = >1: 640 [normal <1:80]) Anti-dsDNA (highly specific) Anti-ENA, Ribonucleoproteins: Ro, La, SM, U1RNP Complement depletion(C4 first then C3) ELISA: 'lumpy bumpy', speckled

Question 27

What does measurement by titre mean

Answer 27

minimal dilution at which antibody can be detected I.E. 1: 640 means it has taken 640 dilutions to get to minimal concentration I.E. 1: 60 means it has only taken 60 dilutions to get minimal concentration

Question 28

Which markers of SLE can be used to measure disease activity

Answer 28

Anti-dsDNA Complement (unactivated) Inactive lupus = normal C3 and C4 Moderate active lupus = low C4 Very active lupus = low C3 and C4

Question 29

Describe the complement classical pathway

Answer 29

1. C1, C4, C2 2. C3 3. final common pathway 4. membrane attack complex formation

Question 30

What are the clinical features of anti-phospholipid syndrome

Answer 30

Recurrent venous or arterial thrombosis Recurrent miscarriage

Question 31

What investigations are done for anti-phospholipid syndrome

Answer 31

Both parents should be tested Anti-cardiolipin antibody Anti-beta 2 glycoprotein 1 antibody Lupus anti-coagulant (cannot be assessed if the patient is on anticoagulant therapy)

Question 32

What are the clinical features of Sjogren's syndrome

Answer 32

Dry eyes Dry mouth Enlargement of parotid glands

Question 33

What is the immune pathophysiology of Sjogren's syndrome

Answer 33

Inflammatory infiltration and destruction of the exocrine glands Anti-nuclear antibodies Speckled staining ENA +ve Ro and La

Question 34

Why are Ro and La ENA significant in pregnancy

Answer 34

Can cross the placenta and cross react with foetal cardiac condition tissue to cause neonatal heart block or rash

Question 35

What are the features of limited cutaneous systemic sclerosis and which parts of the skin are involved/not involved

Answer 35

CREST Calcinosis Raynaud's Oesophageal dysmotility Sclerodactyly Telengiectasia Hands are involved (does NOT spread proximally) and peri-oral skin

Question 36

What antibodies are found in limited cutaneous systemic sclerosis

Answer 36

Anti-centromere AB

Question 37

What differentiates diffuse from limited systemic sclerosis

Answer 37

More GI, pulmonary and renal involvement Skin involvement of hands AND PROXIMAL PAST the forearms (unlike CREST) Anti-topoisomerase/Anti-scl70 Ab, RNA polymerase, Fibrillarin

Question 38

What is the immune pathophysiology of dermatomyositis

Answer 38

Within muscle → perivascular CD4 T and B cells Immune complex mediated vasculitis – T3 response Anti-Jo1 (t-RNA synthetase), Mi2, SRP

Question 39

What is the immune pathophysiology of polymyositis

Answer 39

Within muscle – CD8 T cells surround HLA Class 1 expressing myofibers CD8 cells kill myofibers via perforin/granzymes – T4 response Anti-Jo1 (t-RNA synthetase), Mi2, SRP

Question 40

Give examples of small vessel vasculitides and which auto-antibody is associated with them

Answer 40

Microscopic polyangiitis / Microscopic polyarteritis / MPA Granulomatosis with polyangiitis / Wegener’s granulomatosis / GPA Eosinophilic granulomatosis with polyangiitis / Churg-Strauss syndrome / eGPA Associated with ANCA (Anti-Neutrophil Cytoplasmic Antibody)

Question 41

What is ANCA (Anti-Neutrophil Cytoplasmic Antibody)

Answer 41

Antibodies for antigens located in primary granules within cytoplasm of neutrophils Inflammation → expression of these antigens on cell surface of neutrophils → antibody engagement with cell surface antigens leading to neutrophil activation (T2 hypersensitivity) → activated neutrophils interact with endothelial cells causing damage to vessels → VASCULITIS Different than ANA

Question 42

what is the difference between cANCA and pANCA

Answer 42

cANCA cytoplasmic fluorescence associated with antibodies to enzyme proteinase 3 occurs in >90% of patents with GPA with renal involvement pANCA perinuclear staining pattern associated with antibodies to myeloperoxidase (MPO) less sensitive and specific than cANCA associated with MPA and eGPA

Question 43

Give examples of large vessel vasculitides

Answer 43

Takayasu's arteritis Giant cell arteritis/polymyalgia rheumatica

Question 44

Give examples of medium vessel vasculitides

Answer 44

Polyarteritis nodosa Kawasaki disease