Tolerance and Autoimmunity (Michels) Flashcards by Amanda Beach

What is immunological tolerance

unresponsiveness to self antigens

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When does autoimmunity occur

when immune system recognizes self antigens

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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

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Central tolerance for T cells occurs where

in thymus via negative selection. Double positive at this point

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Formation of T reg is from which stage of tolerance

central tolerance.

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What are the functions of Tregs

prevent autimmune disease
downmodulate immune response to allergens, cancer cells and pathogens
mediate transplantation tolerance

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Role of T regs falls under which category of tolerance

peripheral tolerance

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What cytokine to T regs need to survive

IL-2

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What must lymphocytes express to become T regs

Foxp3 and CD25

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What 2 general ways to Tregs downregulate T cells

Inhibit T cell activation and inhibit the effector functions

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What type of T cells are Treg

CD4+

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How do Tregs inhibit T cell activation

produce IL-10 and TGF-beta

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What is another term for Peripheral T cell tolerance

T cell anergy

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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

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Why is peripheral tolerance necessary

central tolerance is not absolute

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What induces co-stimulatroy signals

any “danger signals” like LPS

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What targets the T cell in peripheral tolerance for apoptosis

either induction of pro-apoptotic proteins or engagement of death Receptors (Fas/FasL)

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Induction of pro-apoptotic proteins for peripheral tolerance is mediated by what?

Ag recognition dependent and mitochondrial mediated

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Mutation of FAS

autoimmune diseases

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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

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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

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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

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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"