Lecture 32: Immunopathology - Autoimmunity Flashcards
What is type IV hypersensitivity mediated by and what do they secrete?
CD4+ T helper 1 cells which secrete IFNg
What does IFNg activate?
tissue macrophages which secrete inflammatory mediators
How long until type I hypersensitivity reactions are detectable after exposure to allergen?
5-10 minutes
What are the three components of autoimmunity?
genetic susceptibility, environmental and loss of self-tolerance
Why are circulating auto-reactive lymphocytes not always activated?
antigen is not available, absence of signal 2, auto-reactive B cells do not have auto-reactive CD4+ T cells
What are dendritic cells activated by?
danger signals
What do mature, naive B cells require to be activated and differentiate into antibody secreting cells?
two signals
cognate antigen and activation signal
How do autoimmune diseases develop?
autoimmune responses do not always result in autoimmune diseases but all autoimmune diseases involve autoimmune responses
What does autoimmunity result from?
a chronic (ongoing) autoimmune response with ongoing tissue damage
How do macrophages respond to self antigens?
secrete nitric oxide, proteases and oxidative radicals
How do CD4 and CD8 T cells respond to self antigens?
delayed type hypersensitivity responses, CTL killing of stromal cells and provision of B cell help
What are delayed type hypersensitivity responses?
Th1 activation of macrophages, cytokine production, pro-inflammatory mediator release
How do B cells respond to self antigens?
type II hypersensitivity (including ligand mediated reactions)
type III hypersensitivity (immune complex deposition)
What are organ-specific autoimmune diseases?
diseases confined to particular organs or cell types and the antigens recognized are organ specific
What are systemic autoimmune diseases?
diseases in which multiple tissues of the body are targeted and the antigens recognized are more ubiquitous
What is the thyroid gland essential for?
regulating metabolism through the production of thyroid hormones
Why does the pituitary gland secrete TSH?
acts on the thyroid to induce the release of thyroid hormones
How do thyroid hormones act on the pituitary?
they shut down production of TSH, suppressing further thyroid hormone synthesis (feedback suppression)
What is Graves disease?
autoantibodies bind to the TSH receptor on thyroid cells which stimulates the receptor, thus encouraging enhanced production of thyroid hormones -> hyperthyroidism
What is Graves disease an example of?
type II hypersensitivity
What is myasthenia gravis?
production of autoantibodies which inhibit acetylcholine receptor function (in the neuromuscular junction) -> no Na+ influx and no muscle contraction
What are the three mechanisms by which myasthenia gravis inhibits transmission at the neuromuscular junction?
complement binding and activation at the NMJ, antigenic modulation and functional AChR block
Which autoantigens are involved in systemic lupus erythematosus?
numerous autoantigens are involved and these are widely expressed
What is observed in systemic lupus erythematosus?
B cell hyper-reactivity and presence of anti-DNA autoantibodies and immune complex deposition in kidney
What causes systemic lupus erythematosus?
immune complex deposition on basement membranes of kidney -> activation of the complement cascade -> tissue injury caused by leukocyte activation and inflammation
What is celiac disease?
type IV hypersensitivity which is not a true autoimmune disease
What are people with celiac disease hypersensitive to?
wheat, barley and rye (gliadins, gliadin like molecules)
How is the jejunum affected in celiac disease?
there is villous atrophy
Why are people with celiac disease hypersensitive to gluten?
modified gluten peptides (gliadins) can bind with high affinity to HLA-DQ2 and HLA-DQ8 resulting in T cell activation
production of IL-15, activation of IELs
What is gluten made up of?
is a complex mix of glutamine and proline rich poly- peptides (proline content provides stability in intestine)
What is the role of tissue transglutaminase?
converts glutamine into glutamic acid (negative charge)
What type of autoimmune disease is type 1 insulin dependent diabetes mellitus?
organ specific, T cell mediated (both CD4 and CD8)
What occurs in type 1 insulin dependent diabetes mellitus?
autoimmune destruction of pancreatic beta-cells (insulin producing)
What is type 1 insulin dependent diabetes mellitus characterised by?
infiltration of lymphocytes, weak autoantibody response, T cell reactivity to islet proteins
gradual loss of insulin secretion, and resultant insulin dependence
In which people does type 1 insulin dependent diabetes mellitus occur more frequently?
in people with HLA DR3-DQ2 and DR4-DQ8
What initiates the killing of beta cells in insulin-dependent diabetes?
an effector T cell recognises peptides from a beta cell-specific protein and kills the beta cell
What is multiple sclerosis?
polygenic degenerative disorder of the CNS that results in episodes of paralysis during formative disease, with chronic paralysis in the latter stages
What is MS caused by?
CD4 T cells specific for myelin antigens promote an inflammatory response and degrade the myelin sheaths covering nerve axons
What initiates inflammation which induces recognition of self antigen?
infection with microorganism
exposure of self antigen due to dying cells
