Tolerance and Autoimmunity (Michels) Flashcards
What is immunological tolerance
unresponsiveness to self antigens
When does autoimmunity occur
when immune system recognizes self antigens
Where does tolerance occur for lymphocytes
central lymphoid organs- negative selection T cells and R editing for B cells
peripheral tissues- T regulatory cells, anergy and apoptosis
Central tolerance for T cells occurs where
in thymus via negative selection. Double positive at this point
Formation of T reg is from which stage of tolerance
central tolerance.
What are the functions of Tregs
prevent autimmune disease
downmodulate immune response to allergens, cancer cells and pathogens
mediate transplantation tolerance
Role of T regs falls under which category of tolerance
peripheral tolerance
What cytokine to T regs need to survive
IL-2
What must lymphocytes express to become T regs
Foxp3 and CD25
What 2 general ways to Tregs downregulate T cells
Inhibit T cell activation and inhibit the effector functions
What type of T cells are Treg
CD4+
How do Tregs inhibit T cell activation
produce IL-10 and TGF-beta
What is another term for Peripheral T cell tolerance
T cell anergy
Two mechanisms of T cell anergy
signaling block- have Ab/Ag binding thru MHC but no Co-stimulation
use of CTLA-4 inhibits the R signaling
Why is peripheral tolerance necessary
central tolerance is not absolute
What induces co-stimulatroy signals
any “danger signals” like LPS
What targets the T cell in peripheral tolerance for apoptosis
either induction of pro-apoptotic proteins or engagement of death Receptors (Fas/FasL)
Induction of pro-apoptotic proteins for peripheral tolerance is mediated by what?
Ag recognition dependent and mitochondrial mediated
Mutation of FAS
autoimmune diseases
Differences in location of Ag for tolerogenic self antigens and immunogenic Ag
tolerogenic- in generative organs that induce neg selection
immunogenic- presence in blood and peripheral tissues permits concentration in secondary lymphoid organs
Describe costimulation effects in tolerogenic Ag and immunogenic Ag
tolerogenic- deficiency may lead to T cell anergy or apoptosis, development of T reg or sensitivity to their suppression effects
immunogenic-expression of costimulators promotes lymphocyte survival and activation
Compare Ag exposure in tolerogenic and immunogenic foreign Ag
tolerogenic- long lived persistence, (prolonged TCR engagement) may induce anergy
immunogenic- short exposure to microbial Ag = effective immune response
What are the T cell independent Ag types
self-polysaccarides, lipids and nucleic acids
Describe central B cell Tolerance
Receptor editing of the light chains or NEgative selection
Describe two mech of peripheral B cell tolerance
When B cell recognize self antigen without T cell help- there is a block put in Ag R so cell becomes anergic
When B cell partially recognizes self it is excluded from lympohoid follicles(necessary to survive) therefore undergoes apoptosis
What does a B lymphocyte express in its most tolerance-senesitive stage
Immature B cell. has IgM no IgD
Stimuli for tolerance of T cells
central= high avidity recognition of self peripheral= Ag presentation by APCs lacking co-stimulators. Or repeated stimulation by self Ag
Stimuli for tolerance of B cells
central= recognition of multivalent Ag in bone marrow peripheral= Ag recognition without T cell help or second signals
Where does anergy take place
peripheral tolerance. not central
Effector mechanisms of autoimmunity
immune complexes
circulating autoAb
autoreactive T lymphocytes
Principle factors in the development of autoimmunity
inheritance of genes and environmental factors
infections also play a role
What factors hinder out understanding of autoimmune diseases
Self Ag not identified
heterogeneous and multifactorial
clinical manifestation can be prolonged and variable
What disease is a great model for prolonged manifestation of autoimmunity
Diabetes Type I where there is autoimmune destruction of pancreatic Beta cells
How can we predict whether a child will become diabetic type I
based on the amount of autoAb
What is the phase called when there is loss of first insulin response
Pre-diabetes
When does the clinical onset of diabetes begin
when body can’t keep up with the insulin demands
Describe sex distribution of autoimmune conditions
majority females
Non-HLA genes involved in Autoimmunity- SINGLE genes
AIRE
FoxP3
FAS
what is characteristic of single gene defects of non-HLA in autoimmunity
numerous autoimmune conditions EARLY in life. Widespread autoimmunity
IPEX is a mutation where
FOXP3 gene- deficient Tregs, increased IgE
Disease assoc with mutation in FAS
Autoimmune lymphoproliferative syndrome (ALPS) defective apoptosis of self-reactive T cells and B cells in the periphery
Why do IPEX kinds have increased IgE
T regs usually produce IL-10 and TGF-beta which inhibit TH2 usually. if Tregs deficient then TH2 overactive
What other mutation presents similar to a FOXP3 mutation
CD25 mutation (IL-2 R on Tregs)
What IL suppresses IgE and what inhibits its production
IL10 suppresses IgE production
TGF-beta inhibits IgE production
Hypothesis of autoimmunity caused by microbes
Induction of costimulators on APCs
molecular mimicry
What is the pathogenic component for Systemic Lupus erythematosus
T cells and the Ab
B cells are normal and present Ag to T cells
What is the pathogenic component in Diabetes
T cells. B cells are normal and the Ab is diagnostically used but not a causative component for the disease
What is the pathogenic component in Myasthenia Gravis
Ab only
T cells and Ab secretion by B cells is normal
Actual Ab blocks ACh R on mm cells
What is the pathogenic component in Multiple Sclerosis
The TH1 cells are pathogenic
B cells are fine and Ab are present but f(x) unknown
What is the postulated mech for T cell mediated autoimmunity
failure for central self tolerance and so when inflammation occurs APCS are activated and there is an influx of self-reactive T cells into tissues
What cells are found to influx in diabetes type I
T cells influx to the islets
Mechanisms of AutoAb
stimulating: Graves.
The Ab activates the TSH R causing increased thyroid hormone production
blocking: myasthenia gravis
The ab blocks ACh R on mm cells
Symptoms of MS
urinary incontinence, blindness, ataxia, muscle weakness and paralysis of limbs
Why are oligoclonal Ig found in the CNS of MS patients
the B cells have never been exposed to all of those self antigens
Why are MS patients Tx with corticosteroids, cyclophophamide and IFN-Beta
suppress immune system
If you treated a MS patient with IFN-gamma what would you expect
acceleration of disease because you are increasing TH1 response
Why feed MBP to mice to prevent EAE
show T cells to recognize as self antigen. downregulate co stimulatory molecules resulting in anergy of T cells. “peripheral tolerance”
