Flashcards in Models of AI disease Deck (47)
What can happen to self-reactive cells in self tolerance?
may merely become anergic
What are the pros of in vitro research models?
simple; inexpensive; answers about olecular/cellular interactions; immortalised cells; ethical
What are the cons of in vitro research models?
cannot stidy systemic interactions; growing cells; hayflick number-limited number of cell divisions; need to make assumptions about disease
What are the pros of using mice models?
mammalian; very well characterised; inbred strains-reliable, consistent and reproducible; genetic modification easy; many similarities; inexpensive; lots of reagents
What are the cons of mice?
incred strains (humans arent inbred!); essentially naive immunologically; many differences
What is the key initiating event in an autoimmune repsonse?
recognition of a peptide from self tissue bound to an MHC and then presented to an autoreactive T cells which becomes activated
Give examples of cellular autoimmunity?
What mediates cellular autoimmunity?
CD4 and CD8 T cells; macrophages
What mouse model is used to mimic T1DM?
non-obese diabetic mouse (NOD)
What are the features of the NOD model?
spontaneous disease phenotype affecting AI infiltration of the islets; thyroid and salivary glands and with many genetic immunological and pathological similarities to human T1DM
What is seen in Tregs in NOD diabetes?
reduced numbers and function of Tregs in the periphery
What happens if you transfer small numbers of Tregs to NOD mice?
reverses even ongoing disease
Why if many individuals carry AI T cells does the clinical disease only sometimes develop?
failure to regulate the immune repsonse properly; contributory role of multiple predisposing genes; role of infectious disease
What is central tolerance?
deleting cells found during differentiation in the thymus to be self reactive
what is peripheral tolerance?
regulating any self-reactive cells that have entered the immune repetoire
If negative selectin of self-reactive T cells depends on engagement of self antigens during passaage through teh thymus, how can this work for proteins specifically expressed at other sites?
autoimmune regulatory protein gives T cells a chance to see proteins across body whilst in thymus by expressing different proteins
What disease is caused by mutation in AIRE?
APECED: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
What is the function of natural Tregs?
curb autoreactive T cells by subduing their function wtihout killing them
What happens to CTLA-4 and FoxP3 knockout mice?
fatal aroudn 3 weeks of AI lymphoproliferative disease
What happens in TGFb knockout mice?
wasting syndrome; multifocal, mixed inflammatory cell response and tissue necrosis leading to organ failure and death
Waht happens to Cbl-b knockout mice?
auto-antibody production, infiltration of activated T and B cells into multiple organs and parenchymal damage
Why is PTPN22 involved in so many AI disease?
sets threshold for T cell activation vs tolerance
What is epitope spread?
autoimmunity starts with reactivity to one epitope then in inflammatory environemnt, start responding to other epitopes
How does microbiome modulate susceptibility to autoimmunity?
shapes T cell subset responses
Where is AIRE mainly expressed?
in lymphoid organs especially the thymus
Which cells express AIRE in the thymus?
meduallry epithelial cells and to a small extent DCs
What is the function of medullary epithelial cells?
involved in the negative selection of self-reactive thymocytes
What is a special feature of medullary epithelail cells?
transcripts enocding peripheral tissue antiegns are extopically expressed by MECs
What is the function of clonal deviation of PTA-reactive thymocytes?
allows them to survive whil acquiring protective characteristics eg. as FOXP3 Treg cells