Imm - Autoinflammatory and Autoimmune Disease 2 Flashcards
Give examples of polygenic auto-immune disease that involve organ-specific antibodies
Grave’s disease
Hashimoto’s thyroiditis
T1DM
Pernicious anaemia
Myasthaenia Gravis
Goodpasture’s syndrome
Give example of polygenic auto-immune disease that involve anti-nuclear antibodies (systemic disease)
SLE
Sjogren’s syndrome
Systemic sclerosis
Dermato/polymyositis
ANCA-associated vasculitis
What is the immune pathophysiology of Graves’ disease
Type 2 hypersensitivity
IgG antibodies against the TSH receptor → TSHr activation → excessive production of thyroid hormone
What are the clinical features of Graves’ disease
Nervous
Palpitations
Heat intolerant
Diarrhoea
Exophthalmos
What is the evidence for Graves disease as a T2HS reaction
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
What is the immune pathophysiology of Hashimoto’s thyroiditis
T2 and T4 hypersensitivity
Anti-thyroid peroxidase (TPO) + anti-thyroglobulin antibodies
Thyroid becomes infiltrated with T and B cells
What are the clinical features of Hashimoto’s thyroiditis and which investigation should be done
Lethargic
Dry skin and hair
Constipation
Cold intolerant
Goitre
TFTs (anti-TG and TPO Abs are highly prevalent so NOT useful)
What is the immune pathophysiology of T1DM
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
What are the clinical features of T1DM and what investigations should be done on first presentation
Thirsty
Polyuria
Malaise
Glycosuria
TFts, LFTs, coeliac screen
What is the immune pathophysiology of Pernicious anaemia
T2 hypersensitivity
Autoantibodies against intrinsic factor or gastric parietal cells→ no absorption of vitamin B12 → pernicious anaemia and SCDC
What are the clinical features of pernicious anaemia and what are the complications
Anaemia (macrocytosis): tired, pale, numbness of feet
May lead to sub-acute combined degeneration of the cord → peripheral neuropathy, optic neuropathy
Which auto-antibodies are associated with the following GI diseases: Pernicious anaemia, coeliac’s disease, Ulcerative colitis
Pernicious anaemia: anti-parietal, anti-intrinsic factor
Coeliac’s disease: anti-tTG, anti-endomysial antibodies
UC: P-ANCA
Which autoantibodies are associated with the following liver diseases: Autoimmune hepatitis, primary biliary cholangitis
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
What is the immune pathophysiology of myasthenia Gravis
T2 Hypersensitivity
Autoantibodies against ACh receptors → failure of depolarisation → absence of muscle action potential
Anti-ACh-R ABs present in ~75% patients
What are the clinical features of myasthenia Gravis and what investigations can be done for it
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
Which autoantibodies are associated with the following: myasthenia Gravis, neuromyelitis optica spectrum disorder (NMOS), optic neuritis, Encephalitis, seizures
Myasthenia Gravis: anti-ACh, anti-striational,
Neuromyelitis optica spectrum disorder (NMOS): anti-aQP4 (aquaporin)
Optic neuritis: anti-MOG
Encephalitis: anti-NMDA
Seizures: anti-GABA
What is the immune pathophysiology of Goodpasture’s disease
T2 Hypersensitivity
Anti-basement membrane antibodies (lungs and kidneys) - smooth linear deposition
What are the clinical features of Goodpasture’s
Haemoptysis with widespread crackles in lungs
Swelling of legs
Reduced urine ouput
Microscopic haematuria + proteinuria
Which alleles are associated with Rheumatoid arthritis
HLA DR4, HLA DR1
PAD2 and PAD4
PTPN22
Leads to high levels of citrullination and binding to citrullinated peptides with a higher affinity
Which environmental factors are associated with rheumatoid arthritis and why
Smoking → development of erosive disease, and increased citrullination
Gum infection with Porphyromonas gingivalis (expresses PAD)
Which antibodies are present in rheumatoid arthritis
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
What type of hypersensitivity reaction is involved in rheumatoid arthritis
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
How are non-organ specific autoimmune diseases tested for
Stain Hep2 cells
Presence of anti-nuclear antibodies (ANA)
What are the clinical features of SLE
CNS – seizures
Skin – butterfly rash, discoid lupus
Heart – endocarditis, myocarditis, serositis, pleuritis, pericarditis
Glomerulonephritis
Haematological – haemolytic anaemia, leukopenia, thrombocytopenia
Arthritis and lymphadenopathy
What is the immune pathophysiology of SLE
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
What investigations should be done for SLE
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
What does measurement by titre mean
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
Which markers of SLE can be used to measure disease activity
Anti-dsDNA
Complement (unactivated)
Inactive lupus = normal C3 and C4
Moderate active lupus = low C4
Very active lupus = low C3 and C4
Describe the complement classical pathway
- C1, C4, C2
- C3
- final common pathway
- membrane attack complex formation
What are the clinical features of anti-phospholipid syndrome
Recurrent venous or arterial thrombosis
Recurrent miscarriage
What investigations are done for anti-phospholipid syndrome
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)
What are the clinical features of Sjogren’s syndrome
Dry eyes
Dry mouth
Enlargement of parotid glands
What is the immune pathophysiology of Sjogren’s syndrome
Inflammatory infiltration and destruction of the exocrine glands
Anti-nuclear antibodies
Speckled staining
ENA +ve Ro and La
Why are Ro and La ENA significant in pregnancy
Can cross the placenta and cross react with foetal cardiac condition tissue to cause neonatal heart block or rash
What are the features of limited cutaneous systemic sclerosis and which parts of the skin are involved/not involved
CREST
Calcinosis
Raynaud’s
Oesophageal dysmotility
Sclerodactyly
Telengiectasia
Hands are involved (does NOT spread proximally) and peri-oral skin
What antibodies are found in limited cutaneous systemic sclerosis
Anti-centromere AB
What differentiates diffuse from limited systemic sclerosis
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
What is the immune pathophysiology of dermatomyositis
Within muscle → perivascular CD4 T and B cells
Immune complex mediated vasculitis – T3 response
Anti-Jo1 (t-RNA synthetase), Mi2, SRP
What is the immune pathophysiology of polymyositis
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
Give examples of small vessel vasculitides and which auto-antibody is associated with them
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)
What is ANCA (Anti-Neutrophil Cytoplasmic Antibody)
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
what is the difference between cANCA and pANCA
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
Give examples of large vessel vasculitides
Takayasu’s arteritis
Giant cell arteritis/polymyalgia rheumatica
Give examples of medium vessel vasculitides
Polyarteritis nodosa
Kawasaki disease
