Autoimmunity, Immune Tolerance Flashcards
2 hallmarks of autoimmune disease? (IMPT!!!)
1) Loss of immune tolerance to self antigens
2) Tissue damage or physiological dysfunction due to autoimmunity
Define autoimmunity
Adaptive immune response specific for self antigens
What are 2 rare single gene defects associated with autoimmunity?
AIRE: Autoimmune regulator
Foxp3: for Treg dvp, multi-organ autoimmunity
Do we know the exact cause of autoimmune diseases?
No, we do not. However, it is likely due to:
1) Cumulative effect of multiple minor genetic variants
+
2) Environmental factors
Why are women more prone to autoimmune conditions?
Systemic Lupus Erythematosus (SLE) an example.
related to female sex hormones.
Relationship to ovarian hormonogenesis?
-Incidence highest during reproductive years
-Declines around the menopause
Relationship to pregnancy?
-May relapse during pregnancy
-Symptoms may improve postpartum
How does infection trigger autoimmunity?
Infections activate self-reactive lymphocytes
Define immune tolerance
Mec that prevent autoimmunity, prevent adaptive immune response against specific self antigens
What are 2 types of immune tolerance?
- Central tolerance: immature lymphocytes undergo selection in Primary Lymphoid organs
- Peripheral tolerance: mature lymphocytes under selection in Periphery
What are 3 fates of T cells in Central Tolerance?
Useless TCR: lost
Useful TCR: preserved
Dangerous TCR: eliminated
What is MHC restriction?
Both TCR-peptide and TCR-MHC contacts are required to stabilise interaction
TCRs without some ability to bind to self MHC would not be useful.
What is neglect?
Immature T cells that fail to bind any self peptide-MHC complex in thymus will not receive enough signal to survive –> apoptosis
rationale: Non-functional T cells removed to avoid wasting resources & immune inefficiency.
What is positive selection?
Select for lymphocytes that express TCRs with some reactivity for self peptide-self MHC, thus exhibit MHC restriction.
T cells expressing TCRs that bind with low to moderate affinity survive.
T cells expressing TCRs that fail to bind will not survive (neglect)
What is negative selection?
T cells with receptors that bind to self peptide-self MHC complexes with high affinity will die by apoptosis
What is the role of Autoimmune Regulator?
Causes transient expression in the thymus of extra-thymic tissue-specific antigens
Allows for negative selection of TCRs specific for self antigens that are normally not expressed in the thymus
Mutations in AIRE associated with autoimmune disease
Role of thymus?
T cell precursors migrate to the thymus from the bone marrow. Within the thymus, immature T cells undergo further development, and are subject to positive and negative selection. Subsequently, the T cells that survive this process exit the thymus as mature but naïve T cells.
How does dendritic cells mature?
recognition of Pathogen-Associated Molecular Patterns (PAMPs) by Pathogen Recognition Receptor (PRR) triggers maturation of dendritic cells
What are 3 signals required by naive T cell activation?
1) Specific antigen signal (TCR:antigen-MHC complex)
2) Co-stimulation signal (B7:CD28)
3) Cytokines signal (IL2, etc)
What happens in costimulation?
CD28 (T cell) bind to B7 (APC) –> upregulate IL-2, autocrine growth factor for T cell proliferation and differentiation
What happens in signal 3 Cytokines?
IL-12 and IFN-γ → Th1 → more IFN-γ to activate M1 macrophage + cytotoxic T (intracellular pathogen, cell-mediated immunity).
IL-4 → Th2 → IL-4, IL-5, IL-13 to activate B cell (extracellular pathogen, humoral immunity).
4 Mechanisms of Peripheral Tolerance
- Ignorance: insuff signal 1
- Anergy: signal 1 but no signal 2
- Deletion
- Regulation
What is Ignorance in peripheral tolerance
Interaction bw TCR and MHC: self-peptide is too weak to cause activation of mature T cells in the periphery
What is Anergy in peripheral tolerance
Naive T cell bind MHC: peptide receive signal 1 but not costimulation signal 2.
reasons:
1. immature DC (PAMP not triggered) –> exp low level of costimulation.
- Non-APC: present MHC Class I but no costimulation.
- Anergised T cells remain unresponsive, even if they reencounter peptide-MHC & appropriate costimulatory later.
Suggest 3 mec of anergy
Active process requiring transcription of anergy genes
- Some suggested mechanisms:
-Failure to activate IL-2 autocrine loop
-Abnormal signalling by TCR complex (modification / degradation of intracellular signalling proteins impedes activating signals)
-Ligation of inhibitory receptors
What is deletion in peripheral tolerance?
Mature T cells that recognise self antigens can undergo apoptosis and so are deleted from the T cell repertoire
2 mecs of T cell deletion
Mitochondrial pathway regulated by members of the bcl-2 family
Death receptor pathway mediated by Fas – Fas ligand signalling.
px with genetic defects in Fas, FasL dvp autoimmunity
Best examples of Tregs? And what is their transcription factor?
CD4+ CD25+ T cells. Transcription factor: Foxp3
How does Regulation happen?
Via Regulatory T cells inhibiting immune response
How does Treg act out its function?
Possess strong TCRs that recognises SP-SMHC strongly, and act on self-reactive immune cells to suppress their activity
Several possible mechanisms of action:
* Cell-cell contact: Constitutive expression of CTLA4 on Tregs blocks and removes B7 from APCs
* Soluble factors: Secrete inhibitory cytokines, e.g. TGF-β
Mutation in foxp3 is associated with?
Multi-organ autoimmune disease
Similarities and differences between CTLA-4 and CD28? (IMPT)
Similarities:
- Both expressed on T cells
- Both binds to B7
Differences:
- CTLA4 not constitutive, comes up a few days after T cell activation, only constitutive in Treg
- CTLA4 binds more strongly to B7 than CD28
- Interaction between CTLA4:B7 delivers negative signal while that between CD28:B7 delivers positive signal
CTLA-4 on Tregs may inhibit T cell activation by:
-Sequestration of B7 on APC (by CTLA-4 higher affinity binding)
-Downregulation of B7 on APC
With respect to CTLA4 and PD1, how can cancer evade immunity?
-Upreg CTLA4 or PD1 on tumour specific T cells
-Expression of PDL1 (LIGAND!) on tumour cells
-recruit Tregs to inhibit
How can we enhance T cell function with respect to CTLA4?
We can have Anti-CTLA4 antibody
Depletes Tregs and block inhibitory effect of CTLA4 on effector t cell
When is Programmed Cell Death Protein 1 expressed
induced after T cell activation, exp strongly in chronically activated T cells
What is the role of PD-1 in immune checkpoint
- limit T cell mediated tissue damage during chronic infection
- inhibit autoreactive T
via mec of inhibiting TCR & CD28
In what type of cells do we see Programmed Death-1 (PD-1). What are the effects?
In chronically activated T cells.
Inhibits activation signalling from TCR complex (signal 1) and CD28 (signal 2)
With ref to immune checkpoint, how do we enhance anti-tumour T cell response?
In immune checkpoint blockade: use Ab against CTLA-4, or PD-1, inhibit Treg & reduce inhibitory signals for T cell –>boost T cell response –> tumour regression
