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IMM250H1 (167)

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LECTURE 8 Autoimmune diseases Ehrlich discovered Mast cells, mediators of allergic disease Called autoimmune disease called horror autoxicus Affect many ppl have some form of autoimmunity o Common and rare diseases o Often chronic diseases with debilitating complications o Many have no cure just some form of lifelong therapy o Ones in use now treat symptoms, not disease so nonspecific Many of toxic sideeffects Also not always effective More than 80 debilitating diseases Handful of common ones and some rare disease Standard of care is v. nonspecific Sterorids general suppression of immune system not specific, with sideeffects o Some temporary disease relief o Commonly used o Etiology cause is unclear Women more effected o Striking during child-bearing years A lot of funding to this area Prevalence of autoimmune disease by sex Salivary glands shigrenes syndrome Multi-systemic often kidney targeted systemic lupus They are female-biased Others have no gender bias, like diabetes Only one is biased towards men Reason is unclear as to the female bias Classified into two categories 1 organ-specific Type 1 diabetes targeting insulin secreting cells of pancreas Multiple sclerosis central nervous system Thyroid myasthenia gravis 2 systemic Rheumatoid arthritis multiple joints throughout body Scleroderma all over body, the skin Systemic lupus erythematosus lupus involvement of antibodies o Antibodies access sites as they circulate the body o So multiple sites are accessed Pathogenesis Simplified slide How T cells lose their tolerance to self Failure to maintain self-tolerance T cell becomes activated and leads to autoimmune disease Need to understand T cell tolerance and know where to intervene for each individual o Each person has different reason why T cell intolerant Four different mechanisms of tolerance simplified Many different checkpoints to keep T cells from responding to tissue V. common but not everyone has autoimmune disease Central tolerance in thymus and bone marrow as lymphocytes are developing, before circulation, must be educated when still immature Bone marrow where lymphocytes are born Thymacyte immature T-cell o They exit bone marrow and go to organ called thymus o Thymus active until puberty, when it atrophies o Where Tcells educated to what is self and what is not self Thymus v. organized Has many lobes each lobe organized like in diagram Cortex at top and medulla at bottom Blue cells are thymus candidate T-cells When in cortex, they interact with corticoepithelial cells, like scaffold cells within thymus o Corticoepithelial cells play important role in education o In medulla, called medullary-epithelial cells Out of thymus and into blood circulation How thymocytes interact with epithelial cells interact tightly dense meshwork T cell development in cortext Born in bone marrow, move to thymus via blood Go into subcapsular region into cortico region of thymus o At this stage, express CD4 and CD8 o Enter thymus as double positive o Interact with corticoepithelial cells in thymus and undergo positive selection o After that, negative selection occurs in medulla of thymus Negative selection gets rid of self-reactive thymocytes Efficient way of getting rid of autoreactive T-cells (vast majority) Have autoreactive T-cell in the first place because it is a RANDOM process Cannot influence this process VDJ recombination express functional receptor and test so its not autoreactive After negative selection, if survive, then become mature T-cell that express either CD4 or 8 Then leave thymus Positive selection A little bit of autoreactive is good; too much is BAD o Goldilocks principal Want to select in first line Tcells with little autoreactivity o Must show evidence that T-cell receptor can effectively bind MHC molecule with peptide o Corticoepithelial cells express MHC o If the immature thymocyte can see the T-cell receptor with low affinity (aka stickiness) then pass then positively selected So go to medullary region of thymus LITTLE BIT OF SELF-REACTIVITY o BUT if the thymocyte has T-cell receptor with no affinity with MHC and self peptide that T-cell is of no use in immune system If it goes out to periphery and sees real antigen, cannot respond To let this T-cell leave thymus, v. wasteful deleted Immature thymocyte interact with thymic cortico epithelial cell does not recognize
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