Autoinflammatory and autoimmune Flashcards
Problems in monogenic autoinflammatory disease and examples
Single gene mutation in innate immune function
Abnormal signalling via cytokine pathways involving TNF / IL-1
Examples: Familial mediterranean fever (AR), TNF receptor associated protein syndrome (AD)
Familial Mediterranean Fever gene mutated? Clinical presentation? Treatment?
Autosomal recessive - MEFV gene - that encodes pyrin-manostrin
Pyrin-manostrin negatively regulates neutrophil activation (unregulated cyropyrin activation of neutrphils)
Periodic fevers of 48-96 hrs Abdo pain (peritonitis) Chest pain (pleurisy and pericarditis) Arthritis Rash
Complication AA amyloidosis - deposits in KIDNEY (proteinurea, nephrotic syndrome), liver, spleen
Bloods - raised CRP, raised serum AA, need genetic test for MEFV mutation
Tx - colchicine (disrupts neutrophil function), IL-1 R antagonist, TNFa inhibitor
Problem in monogenic autoimmune disease. Examples and where they affect
single gene mutation in adaptive immunity
Problems with T cell tolerance (APS1/APCED), T cell regulation (IPEX), lymphocyte apoptosis (ALPS)
APS1/APACED. What is the mutation, inheritance pattern, how does it cause autoimmunity. Clinical features
Autosomal recessive defect in AIRE (autoimmune regulator)
AIRE- TF in T cell tolerance - promotes auto-reactive T apoptosis. Defect -> autoreactive T/B cells
Multiple autoimmune- hypoPTH, addisons, hypoT4, DM, vitiligo, enteropathy.
Abs vs IL-17&IL-22 -> candidiasis
IPEX. What is the mutation, inheritance pattern, how does it cause autoimmunity. Clinical features
X-linked mutation in Foxp3 - required for development of Treg cells
Failure to neg reg T cell response, autoreactive B cells
Autoimmune disease - DM, hypoT4, enteropathy, dermatitis
ALPS. What is the mutation, inheritance pattern, how does it cause autoimmunity. Clinical features
Autosomal dominant mutation in FAS pathway e.g. TNFRSF6 that encodes Fas
Defect in lymphocyte apoptosis -> no tolerance
High lymphocyte count CD4-CD8- T cells Large spleen, lymph nodes Autoimmune cytopenia Lymphoma
What are some examples of some polygenic autoinflammatory condition. General mechanism
Crohns, UC, osteoarthritis, giant cell arteritis, Takayasu’s arteritis
Local factors at sites predisposed -> activation of innate immune cells i.e. macrophages and neutrophils with resulting tissue damage
Less strong HLA association
NOD2 role and associations
IBD1 gene on chromosome 16 identified as NOD2 (CARD-15)
NOD2 is expressed in cytoplasm of myeloid cells - macrophages, neutrophils, dendritic cells -> receptor that detects bacterial muramyl dipeptise and promotes clearance
Associated with Crohns risk mostly (also Blau syndrome, sarcoidosis)
Crohns factors leading to disease. clinical features, treatment
Epigenetic factors mRNAs + genetic mutation affecting innate immunity + intestinal microbiota + environmental factors smoking –> expression of pro-inflam cyto/chemokine + leukocyte recruitment + release of free radicals –> focal inflam in/around crypts, formaltion of granuloma, tissue damage with mucosal ulceration
Abdo pain, tenderess, diarrhoea w/ blood/pus/mucus, fevers, malaise
Corticosteroid, anti-TNFa Ab
Examples of mixed autoinflam, autoimmune disease
Axial spondyloarthritis
Psoriatic arthritis
Behcets syndrome
Axial spondyloarthritis/Anykylosing spondylitis genetic associations, where inflam occurs clinical presentation
HLA B27, IL23 receptor, IL receptor T2
Enhanced inflam at specific sites with high tensile forces - entheses, ligaments, tendons
Low back pain, stiffness, enthesitis, large joint arthritis
Tx - NSAIDS, immunosupression- anti-TNFa, anti-IL17
Genetic polymorphisms of T cell activation and which diseases they are associated with
PTPN22 - tyrosine phophatase that suppressed T cell activation - variants in Rh arth, SLE, T1DM
CTLA4 - receptor for CD80/CD86 that inhibits T cells - variants in SLE, T1DM, autoimmune thyroid disease
Graves: antigen, diagnosis and treatment
TSH receptor
Diagnosis: Anti-TSH receptor Ab
Treatment: Carbimazole and propylthiouracil
Hashimoto’s thyroiditis
Anti-thyroid peroxidase Abs
Anti-thryroglobulin Abs
Goitre - thyroid infiltrated by T and B cells
Pernicious anaemia: antigen, pathology, diagnosis and treatment
Intrinsic factor and gastric parietal cells
Macrocytic anaemia, low B12, normal folate
Anti-IF Ab, Anti Gastric parietal cell Ab, Schilling test
Dietary/IM B12
Myasthenia Gravis
Clinically: drooping eyelids, weakness esp on repetitive activity, Sx worse at night, double vision
Anti-ACh receptor Abs - important at post-synaptic membrane of motor cells-> fail to depolarise, absence of muscle action potential
Abnomal EMG, tensilon test
Tx - neostigmine, pyridostigmine, (IVIG, plasmaphoresis)
Goodpastures disease: clin picture, diagnosis, treatment
Clinical: Haemoptysis with crackles, sidespread shadowing on CXR, haematuria + proteinurea, odoema, reduced urine output, increased creatinine, pulmonary haemorrhage
Anti-basement membrane Ab
Crescentic glomerulonephritis on biopsy
Linear smooth deposits of Ab on G BM
Corticosteroids and immunosupporession
Rheumatoid arthritis clinical features, genetic and environmental predisposition, Abs/diagnosis, Tx
Pain, stiffness, swelling of multiple small hand joints, normochromic anaemia, high ESR/CRP
Genetic predisposition:
- HLA DR4, HLADR1 alleles - bind arthritic peptides e.g. citrullinated peptide with high affinity
- Peptidyl arginine deaminase (PAD) involed in creatting citrulline. type 2 and 4 polymorphisms -> increased citrullination -> increased load of citrullinated proteins
- PTPN22 polymorphism
Environmental factors that increase citrullination:
Smoking
Gum infection with porphyromonas gingivlis (known to express PAD enzymes
Abs: Anti-CCP - bind to peptides citrullinated by PAD
RF - Ab against the common Fc region of human IgG
+ Raised ESR, CRP
Tx - analgesia, steroids, DMARDs
SLE
Fatgiue, hair fall, mouth ulcers, butterfly rash, generalised arthralgia, particularly small joints of hands
Genetic predisp:
- Abnormalities in clearance of apoptotic cells - genes encoding complement, MBL, CRP (intracellular debris from uncleared cells)
- Abnormalities in activation - genes of cyto/chemokines, co-stim molecules or intracellular signalling molecules (B cell hyperactivity + loss of tolerance)
- Antibodies for intracellular proteins form: Nuclear antigens (DNA histones, snRNP), cytoplasmic antigens (ribosome, snRNP)
Immune complexes: deposit in the skin, joints, kidneys, activate complement
Lupus nephritis: immune complex deposition, detection of granular ‘lumpy bumpy’ pattern with fluorosin sonjuygated anti-human Ig
Abs: ANA, anti-dsDNA, anti-ENA, anti-sm, anti-histone, anti-Ro, anti-La, anti-U1RNP
Check complement: C4 low. C3 low if severe
Analgesia, steroids, cyclophosphamine
Anti-phospholipid syndrome
Recurrent venous or arterial thrombosis, miscarriage, livedo reticularis skin, cardiac valve defect
Abs:
- Lupus anticoagulant - prolongation of phospholipid-dependent coagulation test
- Anti-cardiolipin - Ab for neg charged phospholipids
- Anti-B2 glycoprotein 1 - neg charged phospholipids
Limited cutaneous systemic sclerosis features and antibody
Skin involvement not beyond forearms Calcinosis - Ca deposits in soft tissue Raynauds Eosophogoeal dysmotility Sclerodactyly Telangectasia \+ primary pulmonary HTN
Anti-centromere Abs
Diffuse cutaneous systemic sclerosis
Skin involvement beyond forearms Calcinosis, Raynauds, Esophogeal dysmotility, Sclerodacyly, Telangectasia \+ More extensive GI disease \+ Interstitial pulmonary disease \+ Scleroderma renal crisis
Anti-topoisomerase Abs - Scl70
Anti-RNA polymerase I, II, III
Anti-Fibrillarin
Idiopathic inflam myopathy symptoms and pathology
Weakness, malaise, rash
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. Kill myofibres via perforin/granzymes
Abs: sometimes ANA
Anti-aminoacyl transfer RNA synthetase e.g. Jo-1 cytoplasmic
Anti-signal recognition peptide (nuclear and cytoplasmic) - polymyositis
Anti-Mi2 (nuclear) - dermato>polymyositis
Examples of systemic vasculitis disease affecting large, medium and small vessels
Large: Takayasu arteritis, Giant cell/Temporal arteritis (polymyalgia rheumatica)
Medium: polyarteritis nodosa, Kowasaki disease
Small: ANCA associated - microscopic polyarteritis/polyangitis, eosinophilic granulomatosis with polyangitis (Churg-Strauss syndrome), granulomatosis with polyangitis (Wegener’s granulomatosis)
Mixed vessel: Behcets disease
ANCA pathway leading to vasculitis. c vs p ANCA
Abs for Ags in granules in neutrophil cytoplasm. Inflam -> expression of Ag on neutrophil surface where Abs interact and activate neutrophils -> activated neutrophils damage endothelial cells/vessels
c-ANCA - cytoplasmic fluorescence
- Abs to enzyme proteinase 3
- granulomatous polyangitis
p-ANCA - perinuclear staining pattern
- Abs to myeloperoxidase
- microscopic polyangitis and eosinophilic granulomatous polyangitis
Treating microscopic polyarteritis, eosinophilic granulomatosis with polyangitis (Churg-Strauss syndrome), granulomatosis with polyangitis (Wegener’s granulomatosis)
MPA - prednisolone, cyclophosphamine, azathioprine, plasmaphoresis
eGPA - prednisolone, azathioprime, cyclophophamine
GPA - corticosteroids, cyclophosphamide, co-trimoxazole
Presentation of autoimmune thrombocytopenic purpura (ITP), antibodies and treatment
Bruising, bleeding, purpura
Anti-platelet Abs against Glycoprotein IIb/IIIa on platelets
Steroids, IVIG, Anti-D Ab, splenectomy
MS disease, diagnosis, Tx
Demyelinating, perivascular inflammation, paralysis, ocular lesions
CSF shows oligoclonal bands of IgG on electrophoresis
Tx- corticosteroids, IFN-b
Sjogrens syndrome
F>M, late 40s
Dry mouth, dry eyes, nose and skin
May affect kidneys, vessels, lungs, liver, pancreas, PNS
Parotid/salivary gland enlargement
Anti-Ro, anti-La
