13 - Tolerance and Autoimmunity Flashcards
Central Vs Peripheral
Tolerance
Central Tolerance
T + B Cell development = negative selection
restricted to Thymus + Bone Marrow = Maturation Sites
Majority of mature cells react ONLY w/ FOREIGN Ag
Peripheral Tolerance
Mature T + B-cell event in PERIPHERY
Restricted to
Spleen / Lymph Node / Non-lymphoid Tissue
T-Cell
Central Tolerance Mechanism
CLONAL DELETION
Occurs during EARLY development in THYMUS
Positive Selection then –> Negative Selection
Thymic Epithelial Cells
Express AIRE (autoimmune regulator) gene that regulates expression of 100s of tissue secific Self-ag
Ex. Pre-inulin / Thyroglobulin
Thymic Dendritic Cells
BOTH express low level of:
COSTIMULATORY + ADHESION molecules
that ultimately FAIL to fully activate cell
Express HIGH level of FASL
signals cell death in the setting of the Semi-response
What is
AIRE?
AIRE = Autoimmune Regulator Gene
Expressed by
Thymic Epithelial Cells
Regulates Expression of 100s of Tissue-Specific self-Ag
ex = Pre-insulin + Thyroglobulin
- *CENTRAL TOLERANCE MECHANISM**
- *CLONAL DELETION for T-Cells**
Positive Selection
Central Tolerance Mechanism
Clonal Deletion - T-Cell
in the CORTEX of the thymus
T-cell learns to:
- *recognize SELF-MHC** bound to AG-peptide
- *THE COMPLEX**
- not just free Ag*
Weakly interacting cells –> SURVIVE
Negative Selection
Central Tolerance Mechanism
Clonal Deletion - T-Cell
Occurs in the MEDULLA of the thymus
T-Cell must learn to:
NOT recognize peptides derived from SELF-Ag
T-cell that recognizes SELF-ag –> ELIMINATED
STRONG INTERACTON = DIE OFF
B-Cell’s 3
Central Tolerance Mechanisms
Clonal Deletion
Imature B-cell that reacts to SELF-AG –> clonal deletion in bone marrow
Anergy
exposure to soluble-self-AG results in:
incomplete activation –> unresponsiveness to self-AG
Receptor Editing
Self-Ag triggers SECONDARY Light Chain Gene Rearrangements
that alter receptor specificity
What occurs during RECEPTOR EDITING?
B-Cell
Central Tolerance Mechanism
Self-Ag Recognition
VVVV
Triggers a SECONDARY
LIGHT CHAIN GENE REARRANGEMENT
that will alter receptor specificity
B-Cell with HIGH AVIDITY
What happens?
DELETION
or
RECEPTOR EDITING
B-Cell with Moderate Avidity
What happens?
ANERGY
B-cell just hangs out
B-Cell with low avidity
What happens?
CLONAL IGNORANCE
- No threat*
- B-cells just hang out*
- *CLONAL DIVERSION**
- *Central Tolerance Mechanism**
- *High-Affinity, Self-Ag specific CD4+ Tcell**
- *DIVERTED** to become a
- *T-REGULATORY** cell
10% of CD4+ T-cells are TREGS:
Made in Thymus -> Lymph node migration
Control over Self-Ag reactive T-cells in periphery
Attenuate Immune response to NON-Self-Ag
T-regs express the transcription factor:
FOXP3
which is the master regulator of T-cell development & function
What is FOXP3?
and what are its functions?
Transcription Factor expressed by T-REGS (Cd4+ Th)
Master Regulator of Th development & Function
UPREGULATES
expression of CD25 & other treg associated cell-surface olecules
like CTLA-s / TNF receptor molecules
SUPPRESSES
expression of IL2 / INF-y / IL-4
What type of TOLERANCE?
Occurs in
Generative Lymphid Organs = THYMUS + BONE MARROW
Apoptosis = Deletion
Receptor Editing
Development of T-Regs from CD4+t-cells
CENTRAL TOLERANCE
What type of TOLERANCE?
Occurs in
Spleen / Lymph Node / Non-lymphoid Tissue
Anergy
Apoptosis
Supression
PERIPHERAL TOLERANCE
peripheral tissues
Peripheral Tolerance
in Mature T-Cells
some Mature cells will:
have TCR that can respond to SELF-AG NOT encountered in the thymus
encounter HIGH Self-Ag that OVERWHELMS TCR
and will result in REACTION (despite low affinity)
encounter strong secondary signals in response to infection
(despite low affinity)
What is the PROTECTIVE EFFECT?
Occurs after an interaction between:
Autoimmune T-cell + Self-AG
on a cell that is:
NOT COMPETENT to DELIVER A COSTIMULATORY SIGNAL
Resulting in functional inactivation
of self-reactive lymphocytes through lack of costim signal
ANERGY
4 Peripheral Tolerance Mechanisms
Anergy
state of unstable metabolic arrest –> apoptosis
protective effect = l**ack of costim signal
Deletion
Trigger Apoptosis by
Mitochondrial (INTRINSIC) or Death (EXTRINSIC) pathway
Regulatory T-Cell
Dominant control -> able to inactivate lymphocytes specific for SAME AG
Immune Privilege Sites
Certain tissue DEVOID of immune response
brain / eye / ovary / placenta / testes
B7 of the APC
VVV
CTLA-4 of T-cells
Causes what?
INHIBITION OF THE ACTIVITY OF T-CELLS
Peripheral Tolerance: ANERGY
What is the MITOCHONDRIAL PATHWAY?
Peripheral Tolerance Mechanism = DELETION
INTRINSIC
BCL2/BimmediatedApoptosis
Imbalanced expression of pro-apoptotic proteins
VVVV
Destabilizes MITOCHONDRIAL membrane
VVV
apoptosis
What is the DEATH RECEPTOR pathway?
Peripheral Tolerance Mechanism = DELETION
EXTRINSIC
Uses FAS/FASL from the outside
VVV
Triggers intracellular “DEATH-INDUCING SIgnaling Comlex”
VVVV
CASPASE producing APOPTOSIS
What is Dominant Control?
Regulatory T-Cell
Treg specific for self-ag is able to INACTIVATE
other lymphocytes specific for SAME SELF-AG
(Peripheral Tolerance Mechanism)
Development & Survival
of T-REGS
Regulatory T-Cell
(Peripheral Tolerance Mechanism)
Generated after Clonal Diversion after High-Affinity SELF-AG
specific CD4+ Tcell in THYMUS
Require
IL-2** & **FOXp3
to develop & survive
T-REG
FUNCTION
In PERIPHERAL TISSUE:
T-regs suppress the activation & effector fxns of other self-reactive & potentially pathogenic lymphocytes
T-REG DEFICIENCY
in periphery is sufficient to evoke chronic T-cell Mediated autoimmunity & immunopathology
TREG ENRICHMENT in MICE –> Graft Acceptance
T-Reg Mediated Suppression
MECHANISMS
Active Tregs OUT-COMPETE Ag-specific Naive Th Cells
for MHC2/APC binding because of high expression of
Adhesion Molecules = LFA-1
Tregs MODULATE DENDRITIC cell-function
downregulate B7-Expression
Tregs -> further differentiatte to KILL / Inactivate responder T-cells
by Secreting Granzyme/perforin or Immunosupressive Cytokines
IL-10
How are INDUCIBLE T-Regs Cells
GENERATED?
from
Th0 cell in the presense of immunomodulatory cytokines:
TGF-B / IFN-y / IL-10
or
Repetitive stimulation of NON-PRO APCs
Inducible T-reg
FUNCTIONS
Unlike regular Tregs
(source = thymus & require DIRECT cell-contact)
Inducible T-reg Supression is
NOT contact dependent / NOT Ag-Specific
Functions:
Help TURN OFF the immune response once over
Produce Inhibitory Cytokines = TGF-B / IL-10
Have high concentration of CTLA4 on surface
IMMUNE PRIVILEGE
Peripheral Tolerance Mechanism
Certain tissues devoid of immune response:
Brain / Eye lens / Ovary / Placenta / Testes
FASL is constitutively expressed @ PRIVELEGED SITES
binding of active lymphocytes to FasL when entering priv area
–> CELL DEATH
These cells secrete TGF-B that:
SUPPRESS infiltrating T-cells
Ex.
Cells in EYE always express FASL
–> kills any rogue T-cell that might gain entry
When is TOLERANCE INDUCTION
Desirable / Undesireble
Desirable when tolerance to:
- *Self-Ag** // Environmental Ag
- *Transpantation // FETUS**
UNDESIRABLE WHEN:
Tolerance to TUMORS
we want or body to not have tolerance to tumors –> Fight them off
State of INDUCED TOLERANCE:
Duration & Extent
Does NOT last indefinitely, wanes with time –> dissapears
Depends on:
- *Molecular Characteristic** of Ag
- *Dose & Route** of Ag
Competence of immune system:
Young fetus –> makes IgM but NOT IgG until late
takes months & exposure to develop IMMUNE Maturity
Term babies are immunocompetent but immature
- *Old** = IMMUNE SENESCENE
- good MEMORY response** but *POOR primary response
Peripheral Tolerance in
B-CELLS
B-cell encounters self-Ag in peripheral tissues:
Anergy
Functional Inactivation
Deletion
die by apoptosis
Regulation by INHIBITATORY RECEPTORS
prevent B-cell activation
Mechanisms of AutoImmunity
Genetic Susceptibility
genetic failure of self-tolerance -> self-reactive lymphocytes
Reaction to ENVIRONMENTAL stimuli
Tissue injury / inflammation -> activates self-reactive lymphocytes
ALSO SOME OVERLAP!
Multifactoral:
Genes + Immune Regulation + environment
Autoimmunity:
GENE DEFECTS
Clear association between Genetics & Autoimmune Disease:
MONOzygotic Twins > DIzygotic Twins
> Family Members > gen pop
Typically a result of:
MULTIPLE GENE DEFECTS
Single gene defect EXCEPTIONS:
Fas/FasL // AIRE // FOXp3 expression
sufficient for disease
What are SINGLE GENE DEFECT exceptions to the rule?
Defects in these SINGLE GENES are sufficient for a disease:
FAS/FASL
APS-1
AIRE
IPEX
FOXp3 expression
ALPS
APS-1
Caused by what Single Gene Defect?
AIRE
auto immune regulator
Decreased expression of self-ag in the thymus
VVV
defect in NEGATIVE SELECTION
IPEX
Caused by what Single Gene Defect?
FOXp3
Decreased generation of
T-Regs
ALPS
Caused by what Single Gene Defect?
FAS / FASL
Failure of
APOPTOTIC DEATH
of
Self-Reactive T/B-cells
SEQUESTERED AG
Autoimmunity:
Reaction to ENVIRONMENT
Inducing the release of sequestered self-Ag
normally HIDDEN from immunity:
Sites of Privilege
&
Sudden EXPOSURE to HIGH self-ag due to Trauma / Infxn
may lead to an Autoimmune Response
INFECTION / TISSUE Injury
Autoimmunity:
Reaction to ENVIRONMENT
Inducing the release of SEQUESTERED self-Ag
normally hiddden from immunity (sites of privelge)
Induction of Co-stimulatory molecules on APC due to infection
MOLECULAR MIMICRY
structurally simular microbial Ag –> self-ag can CROSS-REACT
Molecular Mimicry
Autoimmunity:
Reaction to ENVIRONMENT
Sharing of epitopes between microbe & host
VVVV
AB’s detected against infectious agent begins to
react with NORMAL Self-Ag
VVV
AUTOIMMUNITY
Ex.
RHEUMATIC FEVER
Multiple Sclerosis / Myasthenia Gravis
Guillain Barre/T1DM
- *ORGAN SPECIFIC**
- *Autoimmune Diseases**
- *T1 DM**
- *MS / Myasthenia Gravis**
- *Graves / Hashimotos**
Goodpasture’s Syndrome
Autoiimmune Hemolytic Anemia
Ways for Antibodies to produce DISEASE
B-CELL AUTIMMUNE DISEASE
Complement fixing IgM
Opsonization
hemolytic Anemias
Formation of Immune Complexes
Blockade of Cell-Surface Receptors
MG / Pernicious Anemia
Stimulation of Cell-Surface Receptors
Graves
Maternal Transfer
What Classification of AUTOIMMUNE DISEASE?
Myasthenia Gravis
GRAVES
SLE
Goodpasture Syndrome
Effector Mechanism
B-CELLS = autoANTIBODY
What Classification of AUTOIMMUNE DISEASE?
RA
Hashimotos
T1DM
MS
Effector Mechanism
ALL ARE CD4+ Tcells
RA / Hashimotos / T1DM = autoantibody also
RA / T1DM = CTLs - B-cells also
Selectives IMMUNOTHERAPIES
for Autoimmne Disease
GOAL IS TO:
Reduce SYMPTOMS
&
Preserve Organ Function
Monoclonal AB** or **Blocking Antagonists
Against: Cytokines / Cytokine Receptors / Chemokine Receptors
T-cell Synapse
CTLA4
downregulates active T-cells
Regulatory Cytokines
Restoration of Tolerance
