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12. autoimmune diseases Flashcards

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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
genetics and autoimmunity
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
monogenic disorders
APACED DiGeorge syndrome IPEX
27
APACED
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
DiGeorge syndrome
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
IPEX
exceedingly rare X linked mutation affecting FoxP3 abrogates production of CD4+CD25+FoxP3 regulatory T cells IBD, dermatitis, organ-specific autoimmunity
30
classical complement deficiency
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
HLA system
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
coeliac disease
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
coeliac disease manifestations
``` loose stool weight loss vitamin deficiency anaemia poor growth in children ```
34
advanced coeliac disease
total villous atrophy crypt hyperplasia lymphocyte infiltration
35
coeliac sufferers express (usually)
HLA-DQ2 HLA-DQ8 or both
36
HLA and coeliac disease
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
coeliac pathogenesis
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
infection - non-genetic factors immunity
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
molecular mimicry
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
examples of molecular mimicry
autoimmune haemolysis rheumatic fever target antigens not well defined
41
autoimmune haemolysis
after Mycoplasma pneumoniae mycoplasma antigen has homology to 'I' antigen on red blood cells IgM antibody to mycoplasma may cause transient haemolysis
42
rheumatic fever
inflammatory disease occurring after streptococcal infection affects heart, joints, skin and brain anti-streptococcal antibodies believed to cross-react with connective tissue
43
type 1 diabetes
lack of insulin impairs cellular uptake of glucose | important to differentiate from monogenic diabetes and type 2 diabetes
44
immunology of type 1 diabetes
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
genetics and type 1 diabetes
``` 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
precipitating events to type 1 diabetes
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
effect of Coxsackie virus
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
autoimmune serology
indirect immunofluorescence solid-phase immunoassay direct immunofluorescence
49
indirect immunofluorescence
patient serum added to glass slide with tissue of interest and incubated detection antibody with fluorescent marker added under microscope look for fluorescence
50
immunoassay = ELISA
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
particle bead suspension
replacing ELISA | more automated
52
direct immunofluorescence
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
bullous skin diseases
pemphigoid | pemphigus
54
pemphigoid
thick walled bullae rarely on mucus membranes target = antigen derma-epidermal junction linear deposition of antibody, activates complement produces skin dehiscence and blister
55
pemphigus
thin walled bullae on skin and mucus membranes rupture easily target = intercellular cement protein desmoglein 3 in superficial skin layers
56
coeliac disease diagnosis
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
pernicious anaemia
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
AID treatment managing the consequences - why?
often preferable to treating immunology immunosuppressive drugs are toxic by time disease is overt, damage is already done
59
treatment for consequences - examples
thyroxine for underachieve thyroid carbimazole, surgery or other drugs fro thyrotoxicosis insulin for diabetes b12 for pernicious anaemia
60
drugs used for immuoodulation
particularly for multi-system autoimmune diseases systemic corticosteroids small molecule immunosuppressive drugs (methotrexate, ciclosporin) high dose intravenous immunoglobulin increasing interest in biologics
61
plasmapharesis
removes antibodies from blood stream | may be useful in antibody mediated disease

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