15 - Immunological Tolerance & Autoimmunity Flashcards
Immune tolerance
The failure to mount an immune response to an antigen
Self tolerance
The state in which the host immune system includes mature lymphocytes which have receptors that can recognise self antigens expressed on normal tissues of the body, but these lymphocytes do not function when self antigen is recognised
Autoimmunity
Breakdown or failure of self tolerance such that lymphocytes specific for self antigen are activated
Autoantibodies
Antibodies produced against self antigen
Central tolerance
Immature lymphocytes specific for self antigens may encounter these antigens in the generative lymphoid organs and are deleted, change their specificity (B cells only), or (CD4 + T cells) develop into regulatory lymphocytes (Tregs)
Peripheral tolerance
- Some self-reactive lymphocytes may mature and enter peripheral tissues
- Inactivated or deleted by an encounter with self antigens in these tissues or are suppressed by the regulatory T cells (Tregs)
Autoimmune regulator protein (AIRE)
- Part of a complex that regulates the expression of tissue restricted antigens (TRAs) in medullary thymic epithelial cells (MTECs).
- Peptides derived from these antigens are displayed on the MTEC and recognised by immature antigen-specific T cells, leading to the deletion of many self-reactive T cells.
Negative selection
Deletion
Absence of functional AIRE
- Immature self reactive T cells are not eliminated
- Leads to autoimmunity
Mechanisms of peripheral T cell tolerance
- Anergy (irreversible functional unresponsiveness)
- Suppression (block in activation)
- Deletion (apoptosis)
Costimulatory molecule present in normal T cell response that is absent in self reactive responses
B7 (binds CD28)
Mechanisms of T cell anergy
- Recognition of self antigen in absence of costimulation leads to either:
- A block in signaling from the T cell receptor (TCR) complex OR
- Engagement of inhibitory receptors
Examples of inhibitory receptors
- Cytotoxic T lymphocyte antigen 4 [CTLA-4]
- Programmed cell death protein-1 [PD-1]).
Signalling block mechanism of anergy
Result of recruitment of phosphatases to the TCR complex or the activation of ubiquitin ligases that degrade signaling proteins.
GRAIL
- Gene Related to Anergy In Lymphocytes
- Targets components of CD3 for degradation in the proteasome, thus blocking TCR signalling and subsequent proliferation
Mechanism of activation of CTLA-4
- CTLA-4 expressed on Tregs or activated T cells can inhibit the activation of responding T cells on the same APC
- OR CTLA-4 binds to B7 molecules on APCs and removes them, making the B7 costimulators unavailable to CD28 and blocking T cell activation.
When is CTLA-4 best able to remove B7 molecules
When B7 levels are low, enabling CTLA-4 to outcompete the lower affinity receptor CD28
Tregs
- Generated by self antigen recognition in the thymus and antigen recognition in peripheral lymphoid organs
- Require IL-2 and transcription factor FOXP3
- Suppress activation and effector functions of self reactive lymphocytes
Central tolerance in B cells
- High avidity self antigen recognition: B cells die by apoptosis or change specificity of their antigen receptors (receptor editing of light chains)
- Low avidity self antigen recognition: leads to anergy of B cells
Clonally ignorant B cells
- Escape central and peripheral tolerance and activated in peripheral tissues
- Basis of autoimmune disease
Peripheral tolerance in B cells
B cells that encounter self antigens in peripheral tissues become anergic, die by apoptosis, or are regulated by inhibitory receptors
Activation of clonally ignorant B cells
- Specific for unmethylated CpG DNA
- Unmethylated CpG DNA is enriched in cells undergoing apoptosis
- During infection, extensive cell death and inadequate clearance of apoptotic fragments can result in activation of previously ignorant self reactive B cell
Mechanisms of T cell mediated autoimmunity
- Various genetic loci may confer susceptibility by influencing the maintenance of self-tolerance.
- Environmental triggers (e.g. infections, inflammatory stimuli) promote the influx of lymphocytes into tissues and the activation of self-reactive T cells, resulting in tissue injury
Infection and autoimmunity
- Encounter of a mature self-reactive T cell with a self antigen presented by a costimulator-deficient APC results in peripheral tolerance by anergy
- Microbes may activate the APCs to express costimulators, therefore self-reactive T cells are activated rather than rendered tolerant.
Molecular mimicry
- Cross recognition of a pathogen antigen that has similarity to self antigen
- Strong signals from microbes may activate T cells specific for self antigens
Immunologically privileged sites
- Sites of body that do not induce immune responses
- Antigens from these sites leave and interact with T cells, inducing tolerance instead of activation that is destructive to tissue
Examples of immunologically privileged site
- Brain
- Eyes
- Testis
- Uterus (foetus)
Damage to immunologically privileged site
- Can induce autoimmune response
- Antigens expressed in IP sites can activate autoreactive lymphocytes if the encounter occurs outside of the site, in the periphery
- E.g. sympathetic opthalmia
Autoimmune colitis
- CD4+CD25+ Treg inhibit colitis by migrating to the colon and mesenteric lymph nodes, where they interact with dendritic cells and hyper-reactive effector T cells
- Depletion of CD4+CD25+ Treg exacerbates or causes disease
Example of molecular mimicry
- Rheumatic fever
- Occurs after sore throat or scarlet fever caused by streptococcus pyogenes
- Similarity of epitopes on Strep pyogenes and heart muscle leads to B and T cell responses against heart muscle
Stimulation by antigens released from damaged tissue
- Intracellular autoantigens are targets in SLE, they are released from injured/dying cells and bind to BCR of autoreactive B cells
- B cell present peptide to autoreactive T cell which activates B cell to differentiate into plasma cell
- Anti-self antibodies produced initiate an inflammatory response and causes more cell damage, thus activating mpre autoreactive B cells
Multiple sclerosis
- T cell mediated chronic neurological disease caused by destructive immune response against several brain antigens, including myelin basic protein
- Activated CD4 T cells autoreactive for brain antigens can cross the blood brain barrier and encounter their specific antigen presented by microglial cells
- Inflammation causes increased vascular permeability and the influx of T and B cells, resulting in demyelination
