L15 - Tolerance and immunoregulation Flashcards
Innate Immunity: what receptors are involved with its activation, what does it recognise, and how is it encoded?
Pattern Recognition Receptors
Recognise MAMPs/PAMPS & DAMPS
Encoded in the germline
Adaptive Immunity: what receptors are involved with its activation, how is it generated, and how diverse is the repertoire of the antibodies produced?
BCRs (Antibodies) & TCRs
Somatically generated after TCR activation - Rearrangement of multiple gene segments in developing B and T cells
Highly diverse random repertoire (polyclonal)
Does self-reactivity always lead to an autoimmune disease?
Autoimmunity is normal within a healthy immune system - restrained by mechanisms of tolerance
Self-tolerance: what is it and how is it obtained?
Failure to respond to intrinsic self-antigens and response to harmless non-self antigens (ie healthy bacteria)
Acquired not inherited - Non-identical twin calves sharing a common placenta become tolerant of each other
Is tolerance always useful?
Can be useless in some instances:
* Self-tolerance - failure to respond to intrinsic self-antigens
* Harmless non-self antigen - commensal bacteria, etc
* therapeutically relevant antigens - allergens, transplantation antigens, etc
Autoimmunity: what mechanisms prevent it?
Immature or developing lymphocytes whose antigen receptor binds self-antigen are mechanised to die
Mechanisms contributing to tolerance
- Inactivation of potentially self-reactive clones - Death, Editing or Anergy
- Immune regulation - Suppression, Functional Deviation
- Self-epitopes not available for recognition - Ignorance, Sequestration, Immune Privilege
Tolerance checkpoints
1 - Central Tolerance:
* Primary lymphoid organs (bone marrow, thymus) - removal of highly self-reactive clones during lymphocyte development (deletion, editing, anergy; functional skewing to tTreg)
2 - Peripheral Tolerance:
* Peripheral organs & tissues, secondary lymphoid organs (LNs, spleen) - Multiple mechanisms limit reactivity against self and harmless antigens in the periphery (eg lack of T cell help for B cells; T cells - ignorance, anergy, deletion, functional skewing, regulation….)
B-cell tolerance process
B Cell Fate is Determined by Interaction with Self-Antigen in the Bone Marrow
The strength of interaction with self-antigen is influenced by:
* The concentration of antigen
* It’s ability to cross-link surface receptors
If B-cells pass the central tolerance check what happens?
They move to the periphery
RAG genes stay on - further recombination at the light chain locus
Self-reactive clones are deleted or rescued by editing
Self-reactive clones: what do they do?
Self-reactive clones are ANERGIC (unresponsive) – die rapidly
T-cells: where do they develop and what forms are there?
Thymus
- Alpha - most abundant along with β T-cell (~95%)
- Beta - most abundant along with α T-cell (~95%)
- Gamma - roles in epithelial surface immune responses (innate?)
- Delta - roles in epithelial surface immune responses (innate?)
T-cells: what are their stages of development and what are they named by?
- Early thymocyte
- Double negative (DN) thymocyte
- Double positive (DP) thymocyte
- Single positive (SP) thymocytes (CD4/CD8 cells)
Stages named according to the expression of CD4 and/or CD8
T-cells: what antigens do they react to?
MHC class I - 8-10 peptide, presents intracellular antigens (ie viral antigens) to CD8+ T cells
MHC class II - 12-20+ peptide, presents extracellular, engulfed antigens to CD4+ T cells
T-cell receptors bind to both the MHC and the antigen peptide
T-cell tolerance process
TCR gene rearrangements occur and give rise to various forms
* TCRs that fail to make a surface receptor
* TCRs that fail to recognise self-antigens
* TCRs that recognise self-antigens too strongly
* TCRs that recognise self-antigens but don’t bind them too strongly
The latter is the ideal and only ~2% fit that objective and enter the periphery from the Thymus
Checkpoints during TCR development
1 - Quality Check - Failure to receive a survival signal -> USELESS cell deleted by apoptosis (subcapsular region)
2 - Positive selection - Recognition of self-antigen (cortex)
3 - Negative selection - Strength of recognition tested (medulla)
Positive selection of T-cells during development: what is the point, where does it occur, what cells do they interact with, what happens if positive selection fails, and what happens to cells if positive selection succeeds?
Check if TCRs recognise self-antigen
Cortex
Cortical epithelial cells
Receptor editing of the alpha chain occurs, attempting to recover the TCR but if this fails, death by apoptosis occurs after 3-4 days
~10-30 cells pass positive selection and move into the medulla as SP CD4/8+ cells
Negative selection of T-cells during development: what is the point, where does it occur, what cells do they interact with, ????
Detect if TCRs recognise self-antigen too strongly
Medulla
DCs & medullary epithelial cells (?)
MEC/AIRE - what on earth is this watch leccy
Thymic emigrants: what are they and what further differentiated forms do they make up?
- CD8+ (CDLₙₐᵢᵥₑ)
- CD4+ (Thₙₐᵢᵥₑ) - Th1, Th2, Th17, ThFH, Foxp3⁺iTreg, Foxp3⁻iTreg (Tr1,Th3)
- CD4+ (Foxp3⁺tTreg)
T-cells: what three signallings are required for activation to occur?
- Antigen-specific activation signal (TCR/MHC:pep)
- Co-stimulation
- Cytokines
Peripheral Tolerance in B cells
Mainly due to Lack of T Cell Help
Is dendritic signalling always activating?
Dendritic cells signal to TCRs but this may not always be activating - presentation in the absence of danger (no co-stimualation) is tolerogenic and leads to anergy
Tolerogenic
Anergy - incapable of producing immunological tolerance
When T-cells are tolerogenic, they are unreactive and unresponsive
Clonal Anergy: Turning T Cells Off
When only signal 1 is presented, T-cells are inactivated
Regulation: peripheral induced Treg (pTreg)
Antigen along with immunosuppressive signals may turn T cells off
Thymic derived Treg (tTreg) and induced peripheral Treg (pTreg)
Antigen along with immunosuppressive signals may turn T cells off
Thymic Tregs regulate immunity against self-antigen
Peripheral Tregs regulate immunity against self-antigen and harmless antigens
Tregs: what are they, what do they do, and how do they do their function?
T-regulatory cells
Inhibit harmful T-cells (still not completely understood)
- Production of anti-inflammatory, pro-regulatory cytokines; TGFβ, IL10, IL35 (dependent on signals driving differentiation of the Treg)
- Modulation of dendritic cells
- Outcompete effector T cells for resources; IL2 (Treg commonly express IL2R)
- Direct killing of T cells
- Exosome transfer of miRNAs
Are all tissues are immunologically equivalent?
No - ie gut
Immune privileged sites: what are they, why do they exist, and how does the body work with them?
Antigens in immune privilege sites do not induce immune attack
Enclosed by a physical barrier - limited lymphatic drainage; selective entry
- Low MHC I
- Rich in suppressive cytokines, eg TGFβ
- Express FasL
Breaking Immune Privilege - Sympathetic Ophthalmia
Eye infection may cause both eyes to be damaged as T-cells ‘see’ eye antigens and destroy them
They were unseen due to the physical barrier of the eye to the rest of the body causing a lack of tolerance checks due to no reference point
Recruitment of immune suppression can allow tumors to attain immune privilege
ITC type stuff
Cancerous cells can secrete immune suppressive cytokines and facilitate T-cell destruction
Examples of Self-Tolerance: whar are they and what are their mechanisms of tolerance?
- Central Tolerance - Deletion/Editing
- Antigen segregation - Physical barrier to self-antigen access to lymphoid system
- Peripheral anergy - Cellular inactivation by weak signalling without co-stimulus
- Tregs - Suppression by cytokines, intercellular signals
- Functional deviation - Differentiation of Tregs that limit inflammatory cytokines
- Activation-induced cell death - Apoptosis
Healing peripheral tolerance
Can slowly desensitise yourself
Ie small amounts of peanuts may lead to reducing allergies
