L13 - Autoimmunity 1 COPY Flashcards
TERMINOLOGY
i) what is auto immunity? what is it also known as?
ii) what are auto immune diseases?
iii) what is tolerance? how does autoimmunity relate to tolerance?
iv) why are some diseases such as sarcoidosis and IBD not classified as autoimmune disease?
i) immune response to self antigens
ii) adaptive immune responses to self antigens contribute to tissue damage
iii) state of immunological non reactivity to an antigen
iv) involve immune system but have not been demonstrated to involve adaptive immune response to self antigens
SELECTION OF ADAPTIVE IMMUNE LYMPHOCYTES
i) how are lymphocyte receptors produced?
ii) what is the purpose of positive selection? what is the purpose of negative selection?
iii) what numbers of cells for each antigen are seen for naive B and T cell receptors? what number of receptors are there overall?
iv) after exposure to infection - what happens to lymphocytes? what do most end up doing? what do some do?
i) by random VDJ recombination
ii) positive selection > ensures reeptors are useful and can recognise self antigen in the form of MHCII
negative selection > deletes T cells with receptors that have a very high affinity for self antigen and reduce autoreactivity
iii) naiive T and B cell receptors > small numbers of cells for each antigen but large number of receptors overall
iv) after infection exposure > expansion of best lymphocyte populations
- most ie and some stay as memory T cells
ADAPTIVE IMMUNE SYSTEM AND AUTOIMMUNITY
i) what does negative selection do?
ii) what are the consequences of neg selection is too rigorous? (3)
iii) what are the consequences if neg selection is too permissive? (3)
iv) what is inevitable?
v) which mechanisms fail if autoimmunity is produced?
i) neg selection > remove all cells with autoreactivity or bind self antigen too strongly
ii) rigourous negative selec > low risk of AI but poor repertoire of cells an increased suscep to infection
iii) permissive negative selec > broad repertoire of cells, lower risk of infection but higher risk of autoimmunity
iv) some auto reactive T cell production is inevitable
v) failure of peripheral tolerance mechanisms
PERIPHERAL TOLERANCE MECHANISMS
i) what is immunological heirarchy? what is required for CD4 activation?
ii) what is antigen segregation? give two egs of where this occurs
iii) what is peripheral anergy?
iv) what is the role of regulatory T cells? what do they express on their surface?
v) what is cytokine deviation? give an eg
vi) what is clonal exhaustion?
vii) what may failure of these peripheral tolerance mechnaisms allow for?
i) IH - lots of cells are needed for the immune response
- CD4 will not be activated unless antigen is presented in an inflam context with TLR ligation
ii) antigen segregation - physical barrier that sequester antigen
- eg in eye and CNS
iii) PA - weak signalling between APC and CD4 T cell without co stimulation can cause T cell to be non response
iv) Tregs supress immune responses by cytokine/juxtacrine signalling - express CD25 and FOXP3
v) cytokine deviation - change in T cell phenotype eg Th1 to Th2 to reduce inflam
vi) clonal exhaustion - apoptosis post activation due to activation induced cell death
vii) fail of peripheral tolerance may allow activation of auto reactive T cells > AI disease
CLASSIFICATION OF AUTOIMMUNE DISEASE
i) what is organ specific AI disease? give three examples
ii) what is multi system AI disease? give three examples
i) organ specific - antigen and target of damage is in one organ
- T1DM, pephigus, graves, hashimoto, AI cytopenias
ii) multi sys - antigen is distributed
- SLE, RA, sjogrens syndrome
AUTOANTIBODIES IN AI DISEASE
i) which type of hypersensitivity reaction involves production of auto antibods?
ii) how does the antibody act in this situation? what does it cause?
iii) what are the three criteria for an antibody to be pathogenic?
i) type II hypersensitivity
ii) antibody is clearly pathogenic > causes disease/tissue damage directly
iii) 1) disease can be transferred between experimental animals by infusion of serum or during gestation (mum to baby)
2) removal of antibod by plasmapheresis is beneficial
3) a pathogenic antibody can be identified and characterised
AUTOIMMUNE CYTOPENIAS
i) what happens in autoimmune haemolytic anaemia? give two symptoms of this
ii) what other type of AI cytopenias can develop?
iii) which is characterised by peticiae and bruises?
i) RBC are recog by pathogenic antibodies > phago or activate complement > autoimmune haemolysis
- anaemia and mild jaundice
ii) can affect any part of blood compartment
iii) rash and bruises = AT thrombocytopenia (low plats)
GRAVES DISEASE
i) what type of autoimmune disease is this? which hormone is targeted?
ii) give four symptoms
iii) what may be seen in the neck? what is seen in the eyes?
iv) give three reasons it is classfied as this type of AI disease?
v) what does production of the antibody cause in relation to thyroid hormone production? what is the end result?
i) antibody mediated disease - antibodies to TSH
ii) tachycardia, palpitations, tremor, heat intol, anxiety
iii) goitre in neck
- eyes = graves ophalmopathy = proptosis and eyelid retrac
iv) baby gets hyperthyroid if mother affected
- serum transfers disease between animals
- antibod can be detected and charac
v) auto immune B cell makes antibodies against TSH receptor which ACTIVATE the receptor
- stimulation of thyroid hormone production
- hormones neg feedback to TSH but no effect on antibody action so lots of thyroid hormone continues to be produced
MYASTHENIA GRAVIS
i) name two symptoms
ii) which five things are most often affected? what can make ptosis more marked?
iii) what is an antibody produced against to cause disease? what does this lead to?
i) muscle weakness and fatigability
ii) eyelids, facial muscles, chewing, talking and swallowing
- ptosis more marked after asking pt to open and close eyes repeatedly
iii) antibod against Ach receptor at the NMJ
- AchRs are internalise and degraded
- no Na+ influx and therefore no muscle contraction
SPONTANEOUS URTICARIA
i) what type of rash does it produce?
ii) what causes it?
iii) what happens in relation to mast cells? how does this manifest clinically?
iv) is there an allergen trigger present?
v) what happens if it occurs in a deeper skin layer?
i) raised and itchy rash
ii) antibody is produced against IgE receptor or IgE itself
iii) IgG FceR1 antibody cross links the mast cells receptor
- causes degranulation > histamine
- manifests as hives and swelling
iv) no allergen trigger present
v) swelling and angioedema
ANTIBODIES AND AI DISEASE
i) what does an antibody have to be to be defined to cause AI disease?
ii) how else may antibodies be produced? what are these useful for?
iii) give two examples of where the above occurs?
i) auto antibody has to be pathogenic and directly lead to disease
ii) antibods can also be produced as a by product of inflamm process > dont fulfil criteria to be ‘pathogenic’
- useful in diagnosis
iii) tissue transglutaminase antibod - coeliac disease
- islet cell antibody - diabetes
T CELL MECHANISMS IN AI DISEASE
i) what type of hypersensitivity reaction is mediated by T cells?
ii) give two ways in which this can occur?
iii) how easy is it to demonstrate this in vitro? what do experimental models rely on?
i) type IV hypersensitivity reaction
ii) T cells can be activated by macrophages/other elements of innate immunity
or CD8 T cells damage tissue directly
iii) hard to demonstrate autoreactive T cells invitro
- experimental models rely on genetically susceptible animals that are sensitised (by exposure to self antigen with an adjuvant)
HASHIMOTOS THYROIDITIS
i) what is this mediated by?
ii) what is it the most common cause of? which sex/age are most affected?
iii) what is there autoimmune destruction of? which cells infiltrate? what do they react against?
i) mediated by T cells
ii) most common cause of hypothyroidism in industrialised countries > women 30yrs+
iii) autoimm destruction of thyroid
- organ becomes infiltrated by CD4 and CD8 T cells
- T cells react against thyroid antigens
GENETICS AND AUTOIMMUNITY
i) what type of genetic disorders can be associated with autoimmune diseases?
ii) what is enrichment of AI disease in families most attributable to?
iii) in groups of NOD mice with identical genetic background and similar enviro > what is seen in dev of T1DM? what does this indicate?
i) rare monogenic disorders
ii) enrichment in families > HLA associations
iii) NOD mice > variable dev of T1DM
- shows there is more than just genetics at play as they are all genetically identical
MONOGENIC DISORDERS - APACED
i) what is APACED?
ii) which gene regulates ectopic expression of tissue specific antigens in the thymus? what does this allow?
iii) what do mutations in this gene result in? what is this strongly associated with?
iv) antibodies to which interleukin make candidis a key feature of this disease?
i) autoimm polyglandular syndrome, candidadis and ectodermal dystrophy
ii) AIRE gene reg ectopic express of antigens in thymus which allows T cell exposure to lots of antigens
iii) mutations in AIRE > failure of negative selection
- strong assoc with organ specific AI disease
iv) antibodies to IL-17 = reduced defence to fungi at mucosal surfaces