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Lecture

IMM250H1 Lecture Notes - Rodent, Autoimmune Polyendocrine Syndrome Type 1, Nuclear Material


Department
Immunology
Course Code
IMM250H1
Professor
J.Gommerman

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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
oCommon and rare diseases
oOften chronic diseases with debilitating complications
oMany have no cure just some form of lifelong therapy
oOnes 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
oSome temporary disease relief
oCommonly used
oEtiology cause is unclear
Women more effected
oStriking 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
oAntibodies access sites as they circulate the body
oSo multiple sites are accessed
Pathogenesis
Simplified slide
How T cells lose their tolerance to self
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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
oEach 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
oThey exit bone marrow and go to organ called thymus
oThymus active until puberty, when it atrophies
oWhere 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
oCorticoepithelial cells play important role in education
oIn 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
oAt this stage, express CD4 and CD8
oEnter thymus as double positive
oInteract with corticoepithelial cells in thymus and undergo positive
selection
oAfter 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
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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
oGoldilocks principal
Want to select in first line Tcells with little autoreactivity
oMust show evidence that T-cell receptor can effectively bind MHC
molecule with peptide
oCorticoepithelial cells express MHC
oIf 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
oBUT 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 self peptide no signal DEATH
Fails positive selection
Negative selection
Positive selection test T-cell receptor to make sure it works
Negative selection test T-cell if self reactive or not
Double positive thymocyte enter medulla interact with medullary
oMedullary epithelial cells also express MHC and peptide
If HIGH AFFINITY for self antigen in context of MHC, that thymocyte
DELETED by apoptosis
o90% of incoming thymocytes from bone marrow die
oLymph node not a lot of cell death
Second positively selected thymocyte
oInteract with thymic medullary epithelial cell NO AFFINITY
graduates and becomes single positive T-cell either CD4 (helper)
or CD8 (cytotoxic killer) T-cell
Avoided negative selection
Apoptosis
Programmed cell death
Nuclear material starting to condense
Membranes collapse and cell dies
Common mediator
oFAS membrane protein expressed on thymocytes and mature T
oDeath receptor
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