Immunology - Autoinflammatory and autoimmune disorders Flashcards
What is the difference between auto-immune and auto-inflammatory diseases?
Auto-inflammatory involves innate immune system
Auto-immune involves adaptive immune system
Which type of cell can produce IL1 and NFkappaB?
Neutrophil
What is the role of cryopyrin in inflammation?
Induces IL1/NFkB secretion by neutrophils
What is the role of pyrin-marenostin in inflammation?
Inhibits IL1/NFkB secretion by neutrophils
What is the inheritance pattern of Familial Mediterannean Fever?
Autosomal recessive
What is the mutation that causes Familial Mediterannean Fever?
MEFV mutation -causing inactivated pyrin-marenostrin (inhibitory of inflammation)
Cryopyrin therefore not opposed
What are 5 symptoms of Familial Mediterannean Fever?
Periodic fevers of about 2-4 days duration
chest pain (Pleurisy & pericarditis)
abdo pain (peitonitis)
Arthritis
Rash
What is the long-term risk of Familial Mediterannean Fever why by what mechanism?
AA amyloidosis
(specifically kidney deposition as leads to nephrotic syndrome)
because liver produces serum amyloid A as acute phase protein
What is the treatment for Familial Mediterannean Fever?
Colchicine 500 micrograms BD
This binds tubulin in neutrophils
What is the defect that causes APS-1? give 2 consequences
AIRE (autoimmune rgeulator)
- -> autoreactive B cells
- -> autoreactive T cells
give 2 roles of AIRE?
Upregulates expression of self antigen by T cells
promotes T cell apoptosis
Give 3 associated conditions of APS-1
Auto-immune diseases
Hypoparathyroidism
Addisons
Candidiasis - most common -
What is the pathophysiology of candida susceptibility in APECED?
Auto-antibodies vs IL17 and IL22 are produced, which are interleukins that are important in candida immunity
What does IPEX stand for?
Immune polyendocrinopathy enteropathy X-linked syndrome
What is the mutation that causes IPEX?
FOXP3
What is the usual role of FOXP3?
Required for regulatory T cell development and function
What is the pathophysiology of IPEX?
FOXP3 mutation –> failure to negatively regulate T cell responses –> lots of autoreactive *B* cells - form autoantibodies
What are the 3 symptoms of IPEX?
3Ds - Diarrhoea, Diabetes, Dermatitis
What does ALPS stand for?
Autoimmune Lympho Proliferative Syndrome
What mutation causes ALPS?
Fas pathway mutation
What are 4 the symptoms of ALPS?
Defect in lymphocyte apoptosis –>
splenomegaly and lymphadenopathy
lymphocytosis
double negative T cells (CD 4 AND C8 -ve)
Recall 2 mutations associated with Crohn’s disease
IBD1 on chromosome 16
NOD2 (stimulates TNFa)
What is the HLA association of ankylosing spondylitis?
HLA-B27
Where in the body is most affected by ankylosing spondylitis?
Areas where there are high tensile forces
Recall 2 genetic associations of Grave’s disease
HLA-DR3
CTLA4
Recall 3 genetic associations of SLE
HLA-DR3
CTLA4
PTPN22
What are 2 HLA association of Rheumatoid Arthritis?
HLA-DR4
HLA DR1
What is the HLA association of Goodpasture’s disease?
HLA-DR15
Recall the Gel and Coombs classification of hypersensitivity
Type 1: immediate and IgE mediated
Type 2: Antibody to cellular antigen mediated
Type 3: Immune complex mediated
Type 4: Delayed type - T cell mediated
Recall four type 2 hypersensitivity diseases
Grave’s
Goodpasture’s
Pemphigus vulgaris
Myasthaenia
Against what is the auto-antibody directed in Goodpasture’s disease?
Non-collagenous domain of type 4 collagen in the basement membrane
autoantibody = anti GBM (glomerular basement membrane)
Against what is the auto-antibody directed in pemphigus vulgaris?
Cadherin
Against what is the auto-antibody directed in Grave’s?
TSH receptor (stimulating)
Against what is the auto-antibody directed in myasthaenia gravis?
Acetylcholine receptor
Recall two examples of type 3 hypersensitivity disorders
SLE
Rheumatoid arthritis
What is rheumatoid factor?
Antibody directed against the Fc portion of IgG
Mutations in which enzymes are associated with rheumatoid arthritis and why?
PAD enzymes - these are involved in citrullinisation
How can you test for anti-nuclear antibody (ANA)?
Stain Hep-2 cells with indirect immunofluorescence.
get homogenous pattern
Which antibody is most specific for SLE?
Anti-dsDNA
Recall the expected C3 and C4 levels in active vs severe SLE
inactive: both normal
Active: low C4
Severe: both low
Which 2 antibody tests should be done to investigate anti-phospholipid syndrome?
- Lupus anti-coagulant
- Anti-cardiolipin
What are the 2 types of systemic sclerosis?
CREST (limited cutaneous systemic sclerosis)
Diffused cutaneous systemic sclerosis
What is the autoantibody involved in CREST?
Anti-centromere
What is the autoantibody involved in diffuse cutaneous systemic sclerosis?
Anti-topoisomerase (Scl70)
What are the 6 symptoms of CREST?
Calcinosis
Raynaud’s
Esophageal dysmotility
Sclerodactyly
Telangiectasia
PLUS PRIMARY PULMONARY HTN (important)
What are the symptoms of diffuse cutaneous systemic sclerosis?
Same as CREST, but additionally:
- More GI disease
- Interstitial lung disease
- Renal crisis
What are the 2 forms of idiopathic inflammatory myopathy?
Dermatomyositis
Polymyositis
What is the phrase “helicopter rash” pathognemonic for?
Dermatomyositis
Recall 2 symptoms of dermatoyositis
periorbital Rash
gottron’s papules
What is the main symptom of polymyositis?
Proximal myopathy
NO rash
What is the main autoantibody association of small vessel systemic vasculitides?
ANCA
Recall 3 examples of small vessel systemic vasculitides
- Microscopic polyangiitis
- Granulomatosis with polyangiitis
- Eosinophilic granulomatosis with poly-angiitis
Which of the small vessel vasculitides is associated with cANCA?
Granulomatosis with polyangiitis (previously Wegener’s)
Which of the small vessel vasculitides is associated with pANCA?
Microscopic polyangiitis
Eosinophillic granulomatosis with polyangiitis (previously Churg Strauss)-
EGPA - Patients affected typically have severe allergies or sinus problems, which progress to severe asthma prior to the systemic vasculitis.
It is treated with corticosteroids.
What is cANCA?
Antibody to proteinase 3
What is pANCA?
Antibody to myeloperoxidase
in addition to colchicine, give 2 drugs that can be used in FMF
anakira - IL 1 receptor antagonist
etanercept - TNFalpha inhibitor
what 4 things increase in FMF
lots of neutrophils so increased
IL 1
NFKappaB to TNFa
apoptosis
state 4 monogenic auto immune diseases
- Familial med fever
- Autoimmune polyglandular syndrome type I (APS1) aka APECED
- IPEX - Immune dysregulation, polyendocrinopathy, enteropathy, X linked syndrome
- ALPS - autoimune lymphoprolifertaive syndrome
give the abnormalities of IPEX, APS-1 and ALPS
IPEX = abnormal Regulation of T cells
APS -1 = abnormality in tolerance
ALPS = abnormality of lymphocyte apoptosis
2 drugs for crohns disease
corticosteroid (pred)
anti TNFA antibody - infliximab
management of crohns
diet induced remission (whole protein modular diet)
maintain remission w mesalazine (an aminosalicylate)
give an example of a polygenic auto inflammatory disease
crohns
give an example of a mixed pattern disease
ankylosing spondy
typically NO autoantibodies
mixed = innate AND adapative
3 symptoms of AS
low back pain and stiffness
enthesisits
large joint arthritis
define a polygenic autoimmune disease
mutationS in genes condoning proteins in pathwayS of ADAPTIVE immune
is hashimotos thyroiditis hyper or hypo? what 2 antibodies
HYPOthyroidism
anti TPO antibodies (thyroid peroxidase antibodies)
anti thyroglobulin antibodies
hashimotos is a combo of what 2 hypersensitivity reaction types
type 2 and 4
give a type 4 hypersensitivity condition
type 1 diabetes
1st presentation of T1DM, what 3 things to screen for
TFTs
LFTs
coeliac
what 2 antibodies in pernicious anaemia? what type of hypersensitivity reaction
type 2 hypersen
autoantibodies against intrinsic factor (so can’t absorb B12 - causing pernicious, megalomaniac anaemia & SCDC)
Gastric parietal cell antibodies
tensilon test is positive in what type 2 hypersensitivity condition
myasthenia gravis
(drooping eyelids, weakness worse on repetition at end of day)
what 4 autoantibodies in T1DM
they pre date development of disease
anti - glutamic acid decarboxylase (anti GAD)
anti-insulin antibodies
anti islet cell
anti IA 2
what polymorphism in RA
PTPN22
What antibody is most specific for RA
anti CCP (cyclic citrullinated peptide)
butterfly rash in what condition
SLE
what other antibody may be found in SLE. give 4 ribonucleoproteins
anti ENA (extractable nuclear antigen)
Ro
La
Sm
U1RNP
do NOT need these for diagnosis
recurrent miscarriage or VTE seen in what condition?
anti phospholipid
what skin is involved in CREST
hands
peri oral skin
what skin is involved in diffuse cutaneous systemic sclerosis
hands AND proximal past forearms
what type hypersensitivity is dermatomyositis
type 3
what type of hypersensitivity is polymyositis
type 4
what ribonuclear proteins in sjogren’s
Ro
La
give an antibodiy in the myopathies
Anti-Jo1
Anti-Mi2 DM>PM
anti SRP -PM
state 2 large vessel vasculitis
takayasu’s
GCA/polymyalgia rheumatica
state 2 medium vessel vasculitis
kawasaki
polyarteritis nodosa
what is ANA used to screen for vs ANCA
ANA - connective tissue diseases
ANCA- small subset of the vasculitides
what autoantibody in ITP
anti-glycoprotein IIb antibodies
what 2 autoantibodies in autoimmune hepatitis
anti-liver kidney microsomal-1 antibody and anti-smooth muscle antibody.
what autoantibody in Primary Biliary Cirrhosis
Anti-Mitochondrial antibody (AMA
Middle aged women are predominantly affected in a ratio of 9:1 F:M.
what HLA in coeliac
HLA dq2
whats Jaccoud’s arthropathy and in what condition
condition characterised clinically by ‘reversible’joint deformities such as swan neck, thumb subluxation, ulnar deviation, ‘boutonniere’ and hallux valgus, along with an absence of articular erosions on a plain radiograph.
SLE
antibodies against Myelin Basic Protein?
multiple sclerosis
arteritis reveals a “rosary bead” appearance of small aneurysms = which vasculitis
PAN
There may be other signs present, such as livedo reticularis.
If a biopsy is required, a typical site is the Sural nerve (a superficial nerve in the calf of the leg).
in addition to anti TTG and anti endomysial, what else should be checked in coeliac
Hence, in IgA deficiency (1 in 600 people), they may be falsely negative.
IgA levels should always be assessed at the same time when assessing for coeliac disease.
classic presentation of wegeners
A rapidly progressive glomerulonephritis in addition to nosebleeds or coughing blood suggests Wegener’s granulomatosis. Nosebleeds suggest Wegner’s - as this is a site classically affected.
As a small-to-medium vessel vasculitis, it may also cause peripheral neuropathy and the elevated CRP is due to the high levels of inflammation. Wegener’s is associated with C-ANCA.
electrophoresis shows oligoclonal IgG, what condition
multiple sclerosis
What specific malignancy are people with Sjogren’s syndrome at greater risk of?
malt lymphoma
What virus is polyarteritis nodosa associated with?
hep b
what 3 antibodies in PBC
ANA
AMA
p ANCA
is pANCA more common in CD or UC
UC
Which cytokine is important in the pathogenesis of rheumatoid arthritis, anyklosing spondylitis and inflammatory bowel disease?
TNFa
what susbset of T cells are associated w the transcription of FOXP3
T regulatory cels
