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204 theme 1 > 12. autoimmune diseases > Flashcards

12. autoimmune diseases Flashcards

1
Q

autoimmunity definition

A

immune responses to self antigens

a failure of tolerance

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2
Q

autoimmune diseases definition

A

adaptive immune responses to self-antigens contribute to tissue damage

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3
Q

tolerance definition

A

state of immunological non-reactivity to an antigen

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4
Q

peripheral tolerance mechanisms

A 
immunological hierarchy 
antigen segregation 
peripheral anergy 
regulatory T cells 
cytokine deviation 
clonal exhaustion
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5
Q

immunological hierarchy

A

peripheral tolerance mechanism

CD4 T cell will not be activated unless antigen is presented in an ‘inflammatory’ context, with TLR ligation

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6
Q

antigen segregation

A

peripheral tolerance mechanism

physical barriers to sequestered antigens

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7
Q

peripheral anergy

A

peripheral tolerance mechanism
weak signalling between APC/CD4 T cell without co-stimulation
causes T cells to be non-responsiveness

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8
Q

regulatory T cells

A

peripheral tolerance mechanism
CD25+FoxP3 positive T cells and other types of regulatory T cells actively suppress immune responses by cytokine and juxtacrine signalling

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9
Q

cytokine deviation

A

peripheral tolerance mechanism
change in T cell phenotype
eg, Th1 to Th2 may reduce inflammation

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10
Q

clonal exhaustion

A

peripheral tolerance mechanism

apoptosis post-activation by activation-induced cell death

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11
Q

classification of autoimmune disease (AID)

A

organ specific

non-organ specific

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12
Q

organ specific AID

A 
type 1 diabetes mellitus
pemphigus, pemphigoid
Graves disease 
Hashimotos thyroiditis 
autoimmune cytopenias, anemia, thrombocytopenia
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13
Q

non organ-specific AID

A

systemic lupus erythematosis

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14
Q

autoantibodies

A

type II hypersensitivity - according to Gell and Coombes

refers to diseases where an antibody is pathogenic - directly damages tissue

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15
Q

criteria for autoantibody disease

A

disease can be transferred between experimental animals by infusion of serum or during gestation
removal of antibody by plasmapheresis is beneficial
pathogenic antibody can be identified and characterised

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16
Q

examples of autoantibody disease

A

autoimmune haemolytic anaemia
autoimmune thrombocytopenia
autoimmune hyperthyroidism
myasthenia gravis

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17
Q

autoimmune hyperthyroidism

A

symptoms of hyperthyroidism disease (tachycardia, palpitations, tremor, anxiety, heart tolerance
goitre
grave’s opthalmopathy
has all characteristics of antibody mediated disease

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18
Q

how does Grave’s disease meet criteria for type II hypersensitivity?

A

neonatal hyperthyroidism is mother affected
serum transfers disease between experimental animals
antibody detected and characterised

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19
Q

myasthenia gravis

A

muscle weakness and fatiguability
eyelids, facial muscles, chewing, swallowing and talking most often affected
ptosis at rest

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20
Q

spontaneous urticaria

A

IgG receptor antibody cross-links mast receptor - causing degranulation
manifests with hives and swelling

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21
Q

antibodies and autoimmune disease

A

autoantibody is pathogenic
autoantibodies found in many other autoimmune diseases - seem to be byproduct of inflammatory process
useful for diagnosis

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22
Q

T cell mediated autoimmunity

A

type IV hypersensitivity
tissue damage is directly mediated by by T cell dependent mechanisms - activate macrophages and other elements of innate immunity
experimental models rely on genetically susceptible animals that are sensitised = often by exposure to self antigen with an adjuvant

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23
Q

autoimmune hypothyroidism

A

t cell mediated autoimmunity
Hashimoto’s thyroiditis
most common cause of hypothyroidism in industrialised countries
particularly women over 30
autoimmune destruction of thyroid - infiltration by CD4 and CD8 T cells

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24
Q

t cell mediated autoimmune disease examples

A

hashimoto’s thyroiditis
coeliac
type 1 diabetes mellitus

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25
Q

genetics and autoimmunity

A

rare monogenic disorders of immune system associated with autoimmune diseases
mouse models rely on genetically susceptible strains
enrichment in families, mostly attributable to HLA
environment also important

26
Q

monogenic disorders

A

APACED
DiGeorge syndrome
IPEX

27
Q

APACED

A

AIRE gene regulates ectopic expression of tissue specific antigens in thymus
mutations result in failures of negative selection
strongly associated with organ specific autoimmune diseases
key feature = candidiasis

28
Q

DiGeorge syndrome

A

failure of migration of 3rd/4th brachial arches
absent parathyroids, cleft palate, congenital heart defects, thymus aplasia
variable presentation - may affect any features in isolation
huge spectrum of immunodeficiency - mild to SCID-like
microdeletions on chromosome 22

29
Q

IPEX

A

exceedingly rare X linked mutation affecting FoxP3
abrogates production of CD4+CD25+FoxP3 regulatory T cells
IBD, dermatitis, organ-specific autoimmunity

30
Q

classical complement deficiency

A

immune complexes cleared by phagocytes
process enhanced by phagocyte Fc and C3b receptors
deficiency of C1q/C2/C4 predisposes to lupus
presumable because immune complexes cannot be cleared effectively
some patients may suffer from recurrent bacterial infections

31
Q

HLA system

A

APCs present processed peptide to T cells in combination with highly polymorphic MHC (HLA) molecules
enclosed by HLA system on chromosome 6
strong association between HLA molecules expression and some autoimmune diseases

32
Q

coeliac disease

A

common inflammatory disease of small bowel with gastrointestinal and extra-gastrointestinal features
most common in women, majority undiagnosed
characteristics of autoimmune disease, but triggered by exogenous antigen (gluten)

33
Q

coeliac disease manifestations

A 
loose stool 
weight loss 
vitamin deficiency 
anaemia 
poor growth in children
34
Q

advanced coeliac disease

A

total villous atrophy
crypt hyperplasia
lymphocyte infiltration

35
Q

coeliac sufferers express (usually)

A

HLA-DQ2
HLA-DQ8
or both

36
Q

HLA and coeliac disease

A

dietary gliadin degraded by tissue trans glutamine 2 enzyme during digestion
produces gliadin peptides
HLA DQ2/8 can present gliadin peptides to T cells if appropriate T cell receptors are present

37
Q

coeliac pathogenesis

A

damage mediated by T cells - antibodies produced but do not contribute to tissue damage
inflammation resolves with strict gluten avoidance
30-50% express HLA DQ2 and/or HLA DQ8
not clear which genetic/environmental factors are important

38
Q

infection - non-genetic factors immunity

A

some infections have been linked to subsequent development of autoimmune disease
immunological explanation = molecular mimicry
epitopes relevant to pathogen are shared with host antigens

39
Q

molecular mimicry

A

viral infection: presentation of viral peptides to CD4 T cells, via MHC 2
viral peptides happen to be similar to host derived peptide
activated T cell reacts strongly to self-peptide and initiates inflammation
process depends on having correct MHC molecules to present epitope which is common to virus and host
also depends on having T cell to recognise it

40
Q

examples of molecular mimicry

A

autoimmune haemolysis
rheumatic fever
target antigens not well defined

41
Q

autoimmune haemolysis

A

after Mycoplasma pneumoniae
mycoplasma antigen has homology to ‘I’ antigen on red blood cells
IgM antibody to mycoplasma may cause transient haemolysis

42
Q

rheumatic fever

A

inflammatory disease occurring after streptococcal infection
affects heart, joints, skin and brain
anti-streptococcal antibodies believed to cross-react with connective tissue

43
Q

type 1 diabetes

A

lack of insulin impairs cellular uptake of glucose

important to differentiate from monogenic diabetes and type 2 diabetes

44
Q

immunology of type 1 diabetes

A

islet cell antibodies detectable for month to years before onset of clinical disease
HLA associations
mouse model
early pancreatic biopsy show infiltration with CD4/8 T cells
by time diabetes is established, generally no active inflammation in pancreatic biopsy

45
Q

genetics and type 1 diabetes

A 
genetic background is important - concordance in twins close to 100%
HLA class II alleles are major defined risk factor 
like coeliac, molecules believed to be required to present relevant islet cell antigens to CD4 T cells 
autoimmune response may occur if appropriate T cell receptors are present in combination with genetic and environmental factors
46
Q

precipitating events to type 1 diabetes

A

autoantibodies to islet cell antigens for months/years before onset of clinical disease
gap between initiation of disease and presentation makes identification of triggers difficult
some evidence for Coxsackie virus

47
Q

effect of Coxsackie virus

A

stronger immune response in diabetes cases compared to controls
viral infection can cause pancreatitis in humans and precipitate autoimmune diabetes in mice
protein 2c - homology with islet cell antigen - glutamic acid decarboxylase

48
Q

autoimmune serology

A

indirect immunofluorescence
solid-phase immunoassay
direct immunofluorescence

49
Q

indirect immunofluorescence

A

patient serum added to glass slide with tissue of interest and incubated
detection antibody with fluorescent marker added
under microscope look for fluorescence

50
Q

immunoassay = ELISA

A

antigen coated well
desired antibody binds to antigen
washed to remove other antibodies
enzyme linked antibody added - binds to desired antibody
washed to remove excess enzyme linked antibody
substrate for enzyme added (changes to coloured product) - rate at which this happens is proportional to amount of specific antibody

51
Q

particle bead suspension

A

replacing ELISA

more automated

52
Q

direct immunofluorescence

A

biopsy of affected tissue
if damage is antibody mediated, antibody will be stuck to antigen in tissue
add detection antibody marked with fluorescent marker
look for fluorescence under microscope

53
Q

bullous skin diseases

A

pemphigoid

pemphigus

54
Q

pemphigoid

A

thick walled bullae
rarely on mucus membranes
target = antigen derma-epidermal junction
linear deposition of antibody, activates complement
produces skin dehiscence and blister

55
Q

pemphigus

A

thin walled bullae
on skin and mucus membranes
rupture easily
target = intercellular cement protein desmoglein 3 in superficial skin layers

56
Q

coeliac disease diagnosis

A

antibody binding to edomysium of smooth muscle fibres
target antigen = tissue transglutaminase (tTG)
hLA typing also utilised (absence of HLA DQ-2/8 makes coeliac unlikely

57
Q

pernicious anaemia

A

B12 absorbed in terminal ileum
requires cofactor = intrincsic factor (Secreted by gastric parietal cells)
liver stores ~2 years B12 supply
clinical manifestations: anaemia, neurological, sub fertility

58
Q

AID treatment managing the consequences - why?

A

often preferable to treating immunology
immunosuppressive drugs are toxic
by time disease is overt, damage is already done

59
Q

treatment for consequences - examples

A

thyroxine for underachieve thyroid
carbimazole, surgery or other drugs fro thyrotoxicosis
insulin for diabetes
b12 for pernicious anaemia

60
Q

drugs used for immuoodulation

A

particularly for multi-system autoimmune diseases
systemic corticosteroids
small molecule immunosuppressive drugs (methotrexate, ciclosporin)
high dose intravenous immunoglobulin
increasing interest in biologics

61
Q

plasmapharesis

A

removes antibodies from blood stream

may be useful in antibody mediated disease

204 theme 1 (12 decks)

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