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PATHOLOGY > auto-inflammatory and autoimmune diseases > Flashcards

auto-inflammatory and autoimmune diseases Flashcards

1
Q

what is immunopathology

A

Damage to the host caused by the immune response

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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

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3
Q

how does the type of immuen response lead to different disease

A

innate -> auto-inflammatory
mixed -> mixed
adaptive -> auto-immune

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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

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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

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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

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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

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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

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9
Q

what is epigenetics

A

(Heritable) change in gene expression

(eg via DNA methylation)

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10
Q

what is microRNA

A

Small, non-coding, single stranded RNA
targets mRNA and regulate protein production

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11
Q

monogenic auto-inflammatory diseases include

A
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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

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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

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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

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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

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16
Q

ix for familial mediterranean fever

A

high CRP
high serum amyloid A
genetics on blood - MEFV mutation

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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

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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

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19
Q

what does IPEX stand for

A

Immune dysregulation, polyendocrinopathy, enteropathy, X- linked syndrome

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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

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21
Q

sx/presentation with IPEX

A

T1 Diabetes Mellitus
Hypothyroidism
Enteropathy
Eczema

‘diarrhoea, dm, dermatitis’

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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

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23
Q

features of ALPS

A

High lymphocyte numbers with large spleen and lymph nodes

Auto-immune disease - commonly auto-immune cytopenias

Lymphoma

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24
Q

what does ALPS stand for

A

Auto-immune lymphoproliferative syndrome

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25
Q

what are the polygenic autoinflammatory diseases

A

Crohns disease
Ulcerative colitis
Osteoarthritis
Giant cell arteritis
Takayasu’s arteritis

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26
Q

summarise Polygenic Auto-inflammatory Diseases

A

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)

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27
Q

is there a genetic predisposition to IBD

A

yes - very strong
15% of people with it have affected family
more concordance inn monozygotic twins

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28
Q

genetics of crohn’s disease

A

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

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29
Q

factors leading to crohn’s

A

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

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30
Q

clinical features of crohn’s

A

Abdominal pain and tenderness
Diarrhoea (blood, pus, mucous)
Fevers, malaise

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31
Q

treatment of crohn’s

A

Corticosteroid
Anti-TNF alpha antibody

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32
Q

what are the mixed pattern diseases

A

Axial spondyloarthritis
Psoriatic arthritis
Behcet’s syndrome

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33
Q

summarise mixed pattern diseases

A

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

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34
Q

summarise ankylosing spondylitis mutations

A

Highly heritable - 90% of the risk of developing disease is genetic

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35
Q

features of axial spondyloarthritis

A

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

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36
Q

treatment of ankylosing spondylitis

A

NSAIDs
immunosuppression - anti-TNFa, anti-IL17

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37
Q

what are the polygenic autoimmune diseases

A

Rheumatoid arthritis
Myaesthenia Gravis
Pernicious anaemia
Addison disease
Systemic lupus erythematosus
Primary biliary cholangitis

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38
Q

summarise polygenic auto-immune disease

A

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

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39
Q

HLA associations with the following diseases

A
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40
Q

mutations in polygenic auto-immune disease

A

Abnormal allele in PTPN 22 means less functional – predispose to these things

Mutation in CTLA4 – don’t reg T cells as well = diseease

41
Q

what are the Gel and Coombs classification for effector mechanisms of immunopathology

A

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
Q

summarise type 2 hypersensitivity

A

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
Q

what are the type 2 hypersensitivity autoimmune conditions - their antigens and pathology/sx

A
44
Q

summarise type 3 hypersensitivity reactions

A

Ab bind to soluble ag = circ immune complex
= deposit
Local damage to blood vessels

45
Q

type 3 hypersensitivity autoimmune condition - their antigens and pathology/sx

A
46
Q

summarise type 4 hypersensitivity - HLA class1

A

T cell response
Can be CD8 T cell response

Cytotoxic – kill

47
Q

summarise class 4 hypersensitivity - HLA class 2

A

CD4 -> inf-y -> activate macrophage, inflammation -> cell damage

48
Q

example of class 4 hypersensitivity autoimmune condition - ag and pathology

A

CD8 kill pancreatic B cells

49
Q

classify the polygenic autoimmune conditions into organ specific diseases and multisystem diseases

A
50
Q

summarise grave’s disease and the evidence for the path

A

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
Q

pathophysiology of graves

A

autoAb stim the TSH receptor
-> uncontrolled over prodyction of thyroid hormones

-ve feedback can’t override Ab

52
Q

summarise hishimoto thyroiditis

A

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
Q

should we test for anti thyroid peroxidase and anti-thyroglobulin ab

A

no just do thyroid biochem
a lot of normal people have these ab

54
Q

pathology of T1dm

A

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
Q

summarise pernicious anaemia

A

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
Q

features of B12 deficiency

A

Neurological features with subacute combined degeneration of cord (posterior and lateral columns),
peripheral neuropathy,
optic neuropathy

57
Q

disease with the following auto ab

A
58
Q

mx of pernicious anaemia

A

B12 injection

59
Q

disease with

A
60
Q

summarise myaesthenia gravis

A

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
Q
A
62
Q

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?

A

anti-glomerular basement membrane disease (Goodpasture’s disease)

Antibodies specific for glomerular basement membrane disease underpin the pathology and are useful in diagnosis

63
Q

ix for goodpasture disease

A

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
Q
A
65
Q

genetic predisposition to rheumatoid

A

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
Q

pathogenesis of rheumatoid arthritis

A

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
Q

ab in RA

A

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
Q

what are antinuclear antibodies and how do you test for them

A

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
Q

pathophysiology of SLE

A
  • 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
Q

pathophysiology of SLE

A
  • 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
Q

how are lupus nephritis and goodpastures nephropathy different

A

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
Q

immunological investigations for lupus

A

quantification of Ab levels - Measured by titre (the minimal dilution at which the antibody can be detected) or by concentration in standardised units

73
Q

what are the specific ANA

A

dsDNA
Ro, La, Sm, U1RNP - Ribonucleoproteins
SCL70 - Topoisomerase
Centromere

74
Q

how do you determine which ANA ab is present

A

Pattern of staining helps

Homogenous – usually because Ab is directed at dsDNA

Then do elisa for Ab for dsDNA

75
Q

summarise anti-dsDNA ab

A

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
Q

speckled ANA

A

Associated with antibodies to extractable nuclear antigens
Specificity is for some ribonucleoproteins (Ro, La, Sm, U1RNP) – confirm with ELISA/EliA

77
Q

summarise anti-ENA ab

A

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
Q

what are the pathways of complement activation and how it relates to SLE

A

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
Q

complement profiles in SLE

A
80
Q

crp and esr in SLE

A

ESR high
CRP can be normal - if high, think infection

81
Q

sx of antiphospholipid syndrome

A

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
Q

when should you test for anti-phospholipid ab

A

sx of APS
anyone with SLE

83
Q

test for antiphospholipid ab

A

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
Q

what is sjogren’s

A

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

Focus of lymphocytic sialadenitis in lip biopsy (B cell infiltration)
85
Q

ab in sjogren

A

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
Q

what is Limited Cutaneous Systemic Sclerosis (CREST)

A
  • Calcinosis
  • Raynauds
  • Oesophageal dysmotility
  • Sclerodactyly
  • Telangectasia

Association with Primary pulmonary hypertension
skin involvement doesnt go past forearms, can be perioral

87
Q

what is Diffuse Cutaneous Systemic Sclerosis

A

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
Q

difference in ANA staining between limited and diffuse systemic sclerosis

A

it is an important px factor

89
Q

what is dermatomyositis

A

Within muscle – perivascular CD4 T cells and B cells
Immune complex mediated vasculitis

heliotrope rash

90
Q

what is polymyositis

A

Within muscle – CD8 T cells surround HLA Class I expressing myofibres
CD8 T cells kill myofibres via perforin / granzymes

91
Q

ab for myositis

A

+ve ANA in some pts - need extended myositis panel

92
Q

differentiation of connective tissue disease by ANA

A
93
Q
A
94
Q

what ab do ANCA associated vasculitis have

A

Anti-neutrophil cytoplasmic antibody
Most vasculitis don’t have Ab – some do

95
Q

what are the vascilitides

A
96
Q

summarise ANCA

A

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
Q

what are cANCA

A

Cytoplasmic fluorescence - Stain throughout cytoplasm
Associated with antibodies to enzyme proteinase 3 – important if specific for this.
Occurs in > 90% of patients with granulomatous polyangiitis with renal involvement
Immunosuppress and steroids

98
Q

what are pANCA

A

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
Q
A

PATHOLOGY (94 decks)

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