12. autoimmune diseases Flashcards
autoimmunity definition
immune responses to self antigens
a failure of tolerance
autoimmune diseases definition
adaptive immune responses to self-antigens contribute to tissue damage
tolerance definition
state of immunological non-reactivity to an antigen
peripheral tolerance mechanisms
immunological hierarchy antigen segregation peripheral anergy regulatory T cells cytokine deviation clonal exhaustion
immunological hierarchy
peripheral tolerance mechanism
CD4 T cell will not be activated unless antigen is presented in an ‘inflammatory’ context, with TLR ligation
antigen segregation
peripheral tolerance mechanism
physical barriers to sequestered antigens
peripheral anergy
peripheral tolerance mechanism
weak signalling between APC/CD4 T cell without co-stimulation
causes T cells to be non-responsiveness
regulatory T cells
peripheral tolerance mechanism
CD25+FoxP3 positive T cells and other types of regulatory T cells actively suppress immune responses by cytokine and juxtacrine signalling
cytokine deviation
peripheral tolerance mechanism
change in T cell phenotype
eg, Th1 to Th2 may reduce inflammation
clonal exhaustion
peripheral tolerance mechanism
apoptosis post-activation by activation-induced cell death
classification of autoimmune disease (AID)
organ specific
non-organ specific
organ specific AID
type 1 diabetes mellitus pemphigus, pemphigoid Graves disease Hashimotos thyroiditis autoimmune cytopenias, anemia, thrombocytopenia
non organ-specific AID
systemic lupus erythematosis
autoantibodies
type II hypersensitivity - according to Gell and Coombes
refers to diseases where an antibody is pathogenic - directly damages tissue
criteria for autoantibody disease
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
examples of autoantibody disease
autoimmune haemolytic anaemia
autoimmune thrombocytopenia
autoimmune hyperthyroidism
myasthenia gravis
autoimmune hyperthyroidism
symptoms of hyperthyroidism disease (tachycardia, palpitations, tremor, anxiety, heart tolerance
goitre
grave’s opthalmopathy
has all characteristics of antibody mediated disease
how does Grave’s disease meet criteria for type II hypersensitivity?
neonatal hyperthyroidism is mother affected
serum transfers disease between experimental animals
antibody detected and characterised
myasthenia gravis
muscle weakness and fatiguability
eyelids, facial muscles, chewing, swallowing and talking most often affected
ptosis at rest
spontaneous urticaria
IgG receptor antibody cross-links mast receptor - causing degranulation
manifests with hives and swelling
antibodies and autoimmune disease
autoantibody is pathogenic
autoantibodies found in many other autoimmune diseases - seem to be byproduct of inflammatory process
useful for diagnosis
T cell mediated autoimmunity
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
autoimmune hypothyroidism
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
t cell mediated autoimmune disease examples
hashimoto’s thyroiditis
coeliac
type 1 diabetes mellitus
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
monogenic disorders
APACED
DiGeorge syndrome
IPEX
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
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
IPEX
exceedingly rare X linked mutation affecting FoxP3
abrogates production of CD4+CD25+FoxP3 regulatory T cells
IBD, dermatitis, organ-specific autoimmunity
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
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
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)
coeliac disease manifestations
loose stool weight loss vitamin deficiency anaemia poor growth in children
advanced coeliac disease
total villous atrophy
crypt hyperplasia
lymphocyte infiltration
coeliac sufferers express (usually)
HLA-DQ2
HLA-DQ8
or both
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
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
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
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
examples of molecular mimicry
autoimmune haemolysis
rheumatic fever
target antigens not well defined
autoimmune haemolysis
after Mycoplasma pneumoniae
mycoplasma antigen has homology to ‘I’ antigen on red blood cells
IgM antibody to mycoplasma may cause transient haemolysis
rheumatic fever
inflammatory disease occurring after streptococcal infection
affects heart, joints, skin and brain
anti-streptococcal antibodies believed to cross-react with connective tissue
type 1 diabetes
lack of insulin impairs cellular uptake of glucose
important to differentiate from monogenic diabetes and type 2 diabetes
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
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
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
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
autoimmune serology
indirect immunofluorescence
solid-phase immunoassay
direct immunofluorescence
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
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
particle bead suspension
replacing ELISA
more automated
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
bullous skin diseases
pemphigoid
pemphigus
pemphigoid
thick walled bullae
rarely on mucus membranes
target = antigen derma-epidermal junction
linear deposition of antibody, activates complement
produces skin dehiscence and blister
pemphigus
thin walled bullae
on skin and mucus membranes
rupture easily
target = intercellular cement protein desmoglein 3 in superficial skin layers
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
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
AID treatment managing the consequences - why?
often preferable to treating immunology
immunosuppressive drugs are toxic
by time disease is overt, damage is already done
treatment for consequences - examples
thyroxine for underachieve thyroid
carbimazole, surgery or other drugs fro thyrotoxicosis
insulin for diabetes
b12 for pernicious anaemia
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
plasmapharesis
removes antibodies from blood stream
may be useful in antibody mediated disease
