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
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
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
