auto-inflammatory and autoimmune diseases Flashcards
1
Q
what is immunopathology
A
Damage to the host caused by the immune response
2
Q
what causes damage to the host in each of these cases
A
it is not the pathogen, even when present - it is the immune system
3
Q
how does the type of immuen response lead to different disease
A
innate -> auto-inflammatory
mixed -> mixed
adaptive -> auto-immune
4
Q
definition of auto-inflammatory condition
A
Activation of innate immune cells such as macrophages and neutrophils, with resulting tissue damage
Absence of known pathogen
5
Q
define autoimmune disease
A
Activation of aberrant T cell and B cell responses in primary (marrow and thymus - central tolerance) and secondary lymphoid organs (nodes - abnormalities of ag specific response)
-> breaking of tolerance with development of immune reactivity towards self-antigens
Organ-specific antibodies may predate clinical
disease by years
Adaptive immune response
6
Q
genetic involvement of auto-inflammatory or auto-immune conditions
A
Can have mutation in single gene
More common to have many mutation in many different genes
7
Q
what are germline mutations
A
Alteration in DNA that occurs in germ cells (sperm and ova and progenitors)
will be passed on to offspring
8
Q
what are somatic mutations that affect DNA sequence
A
Alteration in DNA that occurs in a single body cell after conception, does not affect germ cells and so is not inherited
9
Q
what is epigenetics
A
(Heritable) change in gene expression
(eg via DNA methylation)
10
Q
what is microRNA
A
Small, non-coding, single stranded RNA
targets mRNA and regulate protein production
11
Q
monogenic auto-inflammatory diseases include
A
12
Q
summarise the inflammasome complex and how it is affected by familial mediterranean fever
A
Pyrin part of the inflammasome complex in neurtaphils
Toxin, bacteria and urate signal through this pathway.
In FMF – inhibit the –ve regulator (pyrin) -> inappropriate activation of inflammation
13
Q
pathogenesis of familial mediterranean fever
A
Autosomal recessive condition
Mutation in MEFV gene
MEFV gene encodes pyrin-marenostrin
Pyrin-marenostrin expressed mainly in neutrophils
Failure to regulate cryopyrin driven activation of neutrophils
-> uncontrolled inflammation
14
Q
clinical presentation of familial mediterranean fever
A
Periodic fevers lasting 48-96 hours associated with:
Abdominal pain due to peritonitis
Chest pain due to pleurisy and pericarditis
Arthritis
Rash
15
Q
what is a complication of familial mediterranean fever
A
AA amyloidosis - Liver produces serum amyloid A as acute phase protein - deposits in kidneys, liver, spleen
kidney most important -> nephrotic syndrome = protein leak (proteinuria) = CKD = dialysus
16
Q
ix for familial mediterranean fever
A
high CRP
high serum amyloid A
genetics on blood - MEFV mutation
17
Q
treatment of familial mediterranean fever
A
Colchicine 500mcg bd - binds to tubulin in neutrophils and disrupts neutrophil functions including migration and chemokine secretion
IL-1 blocker (anakinra, canukinumab)
TNF alpha blocker
18
Q
what are the monogenic autoimmune responses
A
Mutation in a gene encoding a protein involved in a pathway associated with adaptive immune cell function
Abnormality of regulatory T cells - IPEX
Abnormality of lymphocyte apoptosis - ALPS
19
Q
what does IPEX stand for
A
Immune dysregulation, polyendocrinopathy, enteropathy, X- linked syndrome
20
Q
pathophysiology of IPEX
A
Mutations in Foxp3 (Forkhead box p3)
needed for CD25+ reg T cells
-> cant reg T or B cell
-> autoreactive B cells
-> autoimmune disease
21
Q
sx/presentation with IPEX
A
T1 Diabetes Mellitus
Hypothyroidism
Enteropathy
Eczema
‘diarrhoea, dm, dermatitis’
22
Q
pathophysiology of ALPS
A
mutation in FAS pathway
eg mutations in TNFRSF6 which encodes FAS
heterogeneous depending on the mutation
-> defect in apoptosis of lymphocytes
-> failure of tolerance
-> failure of lymphocyte homeostasis
23
Q
features of ALPS
A
High lymphocyte numbers with large spleen and lymph nodes
Auto-immune disease - commonly auto-immune cytopenias
Lymphoma
24
Q
what does ALPS stand for
A
Auto-immune lymphoproliferative syndrome
25
what are the polygenic autoinflammatory diseases
Crohns disease
Ulcerative colitis
Osteoarthritis
Giant cell arteritis
Takayasu’s arteritis
26
summarise Polygenic Auto-inflammatory Diseases
Mutations in genes encoding proteins involved in pathways associated with innate immune cell function
local factors -> activation of innate immune cells eg macrophages and neutrophils -> tissue damage
HLA associations are less strong *(in mixed/autoimmune)*
not characterised by auto-Ab *(autoimmune)*
27
is there a genetic predisposition to IBD
yes - very strong
15% of people with it have affected family
more concordance inn monozygotic twins
28
genetics of crohn's disease
IBD1 gene on chr 16 - **NOD2** (CARD-15, caspase activating recruitment domain -15).
3 mutations of this gene have been associated with Crohn's
NOD2 mutation in 30% - so **not necessary**
abnormal NOD2 allelle **increases risk - but not sufficient** to give crohn's
expressed in cytoplasm of myeloid cells (macrophages, neutrophils, DC)
Intracellular receptor for muramyl dipeptide on bacterial products and promotes their clearance
so fail to clear bacterial cells -> more inflammatory
*mutations also in Blau syndrome and some forms of sarcoidosis*
29
factors leading to crohn's
mutations - affect innate immune response
epigenetics
miRNA
intestinal microbiota
env eg smoking
all -> expression of pro-inflammatory cytokines/chemokines, leukocyte recruitment, release of proteases and free radicals
-> focal inflammation in and around crypts, granulomata, tissue damage with mucosal ulceration
30
clinical features of crohn's
Abdominal pain and tenderness
Diarrhoea (blood, pus, mucous)
Fevers, malaise
31
treatment of crohn's
Corticosteroid
Anti-TNF alpha antibody
32
what are the mixed pattern diseases
Axial spondyloarthritis
Psoriatic arthritis
Behcet’s syndrome
33
summarise mixed pattern diseases
Mutations in genes encoding proteins involved in pathways associated with innate AND adaptive immune cell function
HLA associations may be present
Auto-antibodies are not usually a feature
34
summarise ankylosing spondylitis mutations
Highly heritable - 90% of the risk of developing disease is genetic
35
features of axial spondyloarthritis
*local factors are important*
plantar fasciitis, achillis tendonitis, sacroillitis, enthesitis (site of insertion of ligaments or tendons)
at plantar fasciitis and achillis tendonitis - have IL23+ve Th17 or IL17 producing cells
low back pain
large joint arthritis
36
treatment of ankylosing spondylitis
NSAIDs
immunosuppression - anti-TNFa, anti-IL17
37
what are the polygenic autoimmune diseases
Rheumatoid arthritis
Myaesthenia Gravis
Pernicious anaemia
Addison disease
Systemic lupus erythematosus
Primary biliary cholangitis
38
summarise polygenic auto-immune disease
Mutations in genes encoding proteins involved in pathways associated with **adaptive immune cell function (including HLA molecules)**
**Aberrant T and B cell responses in primary and secondary lymphoid organs** lead to **breaking of tolerance** with development of immune reactivity towards self-antigens
**Auto-antibodies are found**
39
HLA associations with the following diseases
40
mutations in polygenic auto-immune disease
Abnormal allele in PTPN 22 means less functional – predispose to these things
Mutation in CTLA4 – don’t reg T cells as well = diseease
41
what are the Gel and Coombs classification for effector mechanisms of immunopathology
Type I: Anaphylactic hypersensitivity - Immediate hypersensitivity which is IgE mediated – rarely self antigen
Type II: Cytotoxic hypersensitivity - Antibody reacts with cellular antigen
Type III: Immune complex hypersensitivity - Antibody reacts with soluble antigen to form an immune complex
Type IV: Delayed type hypersensitivity - T-cell mediated response
42
summarise type 2 hypersensitivity
Auto ab to ag on cell
Fc activates complement in classical complement pathway
Bind to Fc on NKC – granules = kill
Phagocytosis
Ab can also block/stim receptor
So Ab mediated cell damage
43
what are the type 2 hypersensitivity autoimmune conditions - their antigens and pathology/sx
44
summarise type 3 hypersensitivity reactions
Ab bind to soluble ag = circ immune complex
= deposit
Local damage to blood vessels
45
type 3 hypersensitivity autoimmune condition - their antigens and pathology/sx
46
summarise type 4 hypersensitivity - HLA class1
T cell response
Can be CD8 T cell response
Cytotoxic – kill
47
summarise class 4 hypersensitivity - HLA class 2
CD4 -> inf-y -> activate macrophage, inflammation -> cell damage
48
example of class 4 hypersensitivity autoimmune condition - ag and pathology
CD8 kill pancreatic B cells
49
classify the polygenic autoimmune conditions into organ specific diseases and multisystem diseases
50
summarise grave's disease and the evidence for the path
excess production of thyroid hormones
IgG ab stimulate the TSH receptor
*ab stim thyrocytes in vitro
passive transfer of IgG from pts to rats -> similar sx
babies to mums with graves get temp hyperthyroidism - pass through placenta*
51
pathophysiology of graves
autoAb stim the TSH receptor
-> uncontrolled over prodyction of thyroid hormones
-ve feedback can't override Ab
52
summarise hishimoto thyroiditis
commonest cause of hypothyroidism in iodine replete areas
goitre - enlarged thyroid infiltrated by T and B cells
anti-thyroid peroxidase Ab - correlates with thyroid damage and lymphocyte inflammation -> destruction of thyroid gland -> hypothyroidism
anti-thyroglobin ab
53
should we test for anti thyroid peroxidase and anti-thyroglobulin ab
no just do thyroid biochem
a lot of normal people have these ab
54
pathology of T1dm
CD8+ T-cell infiltration of pancreas, T cell clones have specificity for islet antigens - class 4 hypersensitivity. Recognise autoag presented by MHC class 1 molecules on pancreatic B cells -> kill B cells
auto Ag - Glutamic acid dehydrogenase (GAD 65) and Islet antigen 2 (IA2)
Also if have 3/4 of these Ab (predate disease) - likely to get t1dm
* Anti-islet cell antibodies
* Anti-insulin antibodies
* Anti-GAD antibodies
* Anti-IA-2 antibodies
55
summarise pernicious anaemia
Not absorbing B12
IF normally bidns to B12 – faasciliatted absorption
PA – get **Ab against parietal cells/IF **– don’t absorb -> B12 def -> macrocytic anaemia
56
features of B12 deficiency
Neurological features with subacute combined degeneration of cord (posterior and lateral columns),
peripheral neuropathy,
optic neuropathy
57
disease with the following auto ab
58
mx of pernicious anaemia
B12 injection
59
disease with
60
summarise myaesthenia gravis
normally - ACh is released into synaptic cleft - bind receptor -> depol post synaptic membrane -> muscle action
here there are Ab against Ach receptor (in 75%) -> cant depol
offspring can get it transiently - ab cross placenta
61
62
48 year old man
Haemoptysis with widespread crackles in lungs
Swelling of legs
Reduced urine output
Creatinine 472
Microscopic haematuria and proteinuria
CXR – widespread shadowing
Elevated TLCO suggesting pulmonary haemorrhage
Anti-basement membrane antibody positive
Crescentic nephritis on biopsy
dx?
anti-glomerular basement membrane disease (Goodpasture’s disease)
Antibodies specific for glomerular basement membrane disease underpin the pathology and are useful in diagnosis
63
ix for goodpasture disease
Antibodies may also be detected in tissue sections.
Antibodies have been deposited along the basement membrane to give ‘smooth linear staining’ visible when the secondary fluorescein conjugated anti-human immunoglobuline is added.
Biopsy
Flurescence – all the way across have band
Smooth linear deposition of antibody along
the glomerular basement membrane
**Type II hypersensitivity – Ab against cell**
64
65
genetic predisposition to rheumatoid
class 2 HLA HLA DR4 and HLA DR1 alleles
Peptidyl arginine deiminase (PAD)2 and PAD4 polymorphisms - involved in citrullination of proteins
PTPN22 polymorphism – involved in T cell activation
66
pathogenesis of rheumatoid arthritis
HLA DR4 and DR 1 - Susceptible alleles share a sequence at positions 70-74 of the HLA DR beta chain
the alleles bind arthritogenic peptides and citrullinated peptides with high affinity
PAD type 2 and 4 - Enzymes involved in deimination of arginine to create citrulline - Polymorphisms -> increased citrullination -> high load of citrullinated proteins
-> more likely RA
smoking also associated with high citrullination - so associated with development of invasive disease
Gum infection with Porphyromonas gingivalis associated with rheumatoid arthritis
P gingivalis is only bacterium known to express PAD enzyme and thus promote citrullination
67
ab in RA
Ab to cyclic citrullinated peptide
Bind to peptides in which arginine has been converted to citrulline by peptidylarginine deiminase (PAD)
95% specificity
lower sensitivity
rheumatoid factor is Ab against Fc of IgG - IgM anti-IgG is most commonly tested for, IgA adn IgG may be present
68
what are antinuclear antibodies and how do you test for them
Group of antibodies that bind to nuclear proteins
Test by staining of Hep-2 cells (human epidermoid cancer line)
Very common
Low titre antibodies (<1:80) often found in normal individuals (esp older women)
69
pathophysiology of SLE
* **abnormalities in clearance of apoptotic cells** - polymorphisms in genes for complement, MBL adn CRP
* **abnormalities in cellular activation** - polymorphisms in genes for cytokines, chemokines, co-stimulatory molecules, intracellular signalling molecules -> B cell hyperactivity and **loss of tolerance**
-> Ab directed at intracellular proteins:
* ? Debris from apoptotic cells that have not been cleared
* Nuclear antigens - DNA, histones, snRNP
* Cytoplasmic antigens - ribosome, scRNP
70
pathophysiology of SLE
* **abnormalities in clearance of apoptotic cells** - polymorphisms in genes for complement, MBL adn CRP
* **abnormalities in cellular activation** - polymorphisms in genes for cytokines, chemokines, co-stimulatory molecules, intracellular signalling molecules -> B cell hyperactivity and **loss of tolerance**
-> **Ab directed at intracellular proteins**:
* ? Debris from apoptotic cells that have not been cleared
* Nuclear antigens - DNA, histones, snRNP
* Cytoplasmic antigens - ribosome, scRNP
Ab bind to ag -> immune complex ->
* deposit in skin, joints, kidney
* activate complement on the classical pathway
* stimulate cells expressing Fc and complement receptors
71
how are lupus nephritis and goodpastures nephropathy different
lupus is type 3 hypersensitivity
goodpastures is type 2
Immune complexes deposit in basement membrane in a type III response
Note the contrast in staining pattern compared with a type II response where antibody specific for the basement membrane (rather than immune complexes) despoit.
Deposition of immune complex – buts of immune complex deposited
72
immunological investigations for lupus
quantification of Ab levels - Measured by titre (the minimal dilution at which the antibody can be detected) or by concentration in standardised units
73
what are the specific ANA
dsDNA
Ro, La, Sm, U1RNP - Ribonucleoproteins
SCL70 - Topoisomerase
Centromere
74
how do you determine which ANA ab is present
Pattern of staining helps
Homogenous – usually because Ab is directed at dsDNA
Then do elisa for Ab for dsDNA
75
summarise anti-dsDNA ab
very specific for SLE
v high titres associated with very severe disease, including renal or CNS impairment
increase may suggest relapse - useful in disease monitoring
Final confirmation may be done with staining of Crithidia luciliae (dsDNA in kinetoplast)
76
speckled ANA
Associated with antibodies to extractable nuclear antigens
Specificity is for some **ribonucleoproteins (Ro, La, Sm, U1RNP)** – confirm with ELISA/EliA
77
summarise anti-ENA ab
Ro, La, Sm, RNP (all are ribonucleoproteins)
ab may be in SLE
ro and la - characteristically in sjogrens
not helpful in monitoring disease activity - no need to repeat
78
what are the pathways of complement activation and how it relates to SLE
immune complex - activate complement by classical pathway. complement components become depleted if constantly consumed
quantitation of C3 and C4 act as surrogate marker for disease activity for SLE
79
complement profiles in SLE
80
crp and esr in SLE
ESR high
CRP can be normal - if high, think infection
81
sx of antiphospholipid syndrome
Recurrent venous or arterial thrombosis
Recurrent miscarriage
May be associated with livedo reticularis, cardiac valve disease
May occur alone (primary) or in conjunction with autoimmune disease (secondary)
82
when should you test for anti-phospholipid ab
sx of APS
anyone with SLE
83
test for antiphospholipid ab
Three immunology/haematology tests:
**Anti-cardiolipin antibody** -specific for negatively charged phospholipids
**Anti-beta 2 glycoprotein 1** antibody - specific for glycoprotein found associated with negatively charged phospholipids
**Lupus anti-coagulant** - Antibody to phospholipid results in **prolongation of phospholipid-dependent coagulation** tests **in vitro.** Clotting time **corrects/shortens with addition of excess phospholipids**
cannot be assessed if the patient is on anticoagulant therapy
84
what is sjogren's
Inflammatory infiltration and destruction of exocrine glands
Particular involvement of lacrimal glands (dryness of eyes) and salivary glands (dryness of mouth)
Dry eyes
Dry mouth
Arthralgias
Fatigue
Increased risk of certain lymphomas – eg MALT lymphoma – scan for this and if worried biopsy
involves B cell activation - so high levels of IgG
85
ab in sjogren
**ANA +ve**
**Speckled staining
ENA+ve: Ro and/or La antibody positive****
*Anti-Ro and Anti-La may cross react with foetal cardiac conduction tissue and cause neonatal heart block or neonatal rash - so need special fetal cardiac scans*
86
what is Limited Cutaneous Systemic Sclerosis (CREST)
* Calcinosis
* Raynauds
* Oesophageal dysmotility
* Sclerodactyly
* Telangectasia
Association with Primary pulmonary hypertension
skin involvement doesnt go past forearms, can be perioral
87
what is Diffuse Cutaneous Systemic Sclerosis
CREST features
More extensive gastrointestinal disease
Interstitial pulmonary disease
Scleroderma kidney / renal crisis
Vascular problem – thickening of renal arterial system -> high renin-angiotensin – htn
skin involvement goes past the forearms
88
difference in ANA staining between limited and diffuse systemic sclerosis
it is an important px factor
89
what is dermatomyositis
Within muscle – perivascular **CD4** T cells and B cells
**Immune complex mediated vasculitis**
heliotrope rash
90
what is polymyositis
Within muscle – CD8 T cells surround HLA Class I expressing myofibres
CD8 T cells kill myofibres via perforin / granzymes
91
ab for myositis
+ve ANA in some pts - need extended myositis panel
92
differentiation of connective tissue disease by ANA
93
94
what ab do ANCA associated vasculitis have
**Anti-neutrophil cytoplasmic antibody**
Most vasculitis don’t have Ab – some do
95
what are the vascilitides
96
summarise ANCA
Anti-neutrophil cytoplasmic antibodies
ab for ag in primary granules on cytoplasm of neutrophils
inflammation -> expression of the ag on the surface of neutrophils
ab engagement with ag -> neutrophil activation (type 2 hypersensitivity)
neutrophils interact with endothelial cells -> damage to vessels - vasculitis
97
what are cANCA
Cytoplasmic fluorescence - **Stain throughout cytoplasm**
Associated with **antibodies to enzyme proteinase 3** – important if specific for this.
Occurs in > 90% of patients with g**ranulomatous polyangiitis with renal involvement**
Immunosuppress and steroids
98
what are pANCA
**Perinuclear staining pattern** - Stain around nucleus rather than in whole cytoplasm
Associated with **antibodies to myeloperoxidase **
**Less sensitive and specific than cANCA **
Associated with **microscopic polyangiitis and eosinophilic granulomatous polyangiitis **
99
