Immune tolerance Flashcards
What are the three main reasons for immune tolerance?
1) To avoid excessive lymphocyte activation and tissue damage, during normal protective responses against infections.
2) To prevent inappropriate reactions against self-antigens (tolerance)
3) Failure of control mechanisms is the underlying cause of immune-mediated inflammatory diseases. Immune regulation is the control of immune response to prevent inappropriate reactions
What is autoimmunity?
The stimulated immune response against self-antigens, pathologic .
Disorders are classified under immune-mediated inflammatory diseases
What are the general principles in the pathogenesis of autoimmunity?
Susceptibility genes + environmental triggers; systemic or organ-specific (autoimmunity against specific antigenic. proteins presented by discrete cells)
B and T cell receptor repertoires and MHC genes are genetically distinct, self-antigens may be compatible with TCR to predispose for susceptibility infection activates an autoimmune response.
Why do immune-mediated inflammatory diseases occur?
Chronic disease with prominent inflammation, caused by a failure of tolerance or regulation. The inflammatory disease may be attributed n response to self-antigens (autoimmunity), however, others concerned with microbial antigens
Main causes: T cells and autoantibodies
Systemic or organ-specific
What is Crohns disease?
An inflammatory bowel disease, enhanced recruitment, and retention of effector macrophages, neutrophils, and T cells into the inflamed intestine whereby they are activated, releasing proinflammatory cytokines.
Microbiota of gut flora can activate immune response via PAMPs.
Which antibodies are responsible for allergic reactions?
IgE
How is an anaphylactic shock stimulated?
Deleterious immune response to non-infectious antigens that cause tissue damage and disease.
Mediated by antibody (IgE), and mast cells
B cell-driven
How is sepsis stimulated?
Pathogens stimulate excessive immune response through a positive-feedback loop. Triggered by pathogens, entering the wrong compartment.
This activates non-specific cytokines leads to systemic response; or a failure to regulate response to correct level Hypercytoinemia
What are the 3 phases in the 3-signal model?
Antigen recognition
Co-stimulation
Cytokine release
What happens during antigen recognition in the 3-signal model?
T/B cells activation occurs when presented with cognate antigen bound to complementary TCR/BCRs binding to MHC-II APCs.
What happens during co-stimulation?
Cell-cell communication is required through dendritic and antigen-presenting cells, by engaging CD38 with B7 on APC. This adopts a spatial mechanism as activating molecules provides an immune synapse on the T cell- results in converges of TCRs to enable interaction and activation of signaling cascade.
TCR includes 1/2 signaling molecules (2 required)
Co stimulation molecules clear space in cell surface membrane to traffic TCRs
The signal from APC to the T cell informs the T cell to express CD28 on the surface to have interacted with B7
Activates T cell
Which molecules form an immune synapse?
CD28-B7 interacting molecules
What happens during the cytokine release phase of the 3-signal model?
The interaction produces a series of downstream signals which promote the target T cells survival and activation
What is a self-limiting response?
The Cardinal feature of all immune responses is self-limitation, manifested by the decline of immune responses. The principal mechanisms involve elimination of antigen that initiated the response
First signal for lymphocyte activation is eliminated
Autoimmune disease occurs considering the inhibition of antigen removal
What is the induction phase of immunity?
Antigen-presenting cells (dendritic cells) phagocytose antigen, internalization, and fragmentation at the endoplasmic reticulum results in peptide epitope being resented at the cell surface membrane at MHC molecules
T-cell activation due to peptide-TCR interaction, facilitated by b7-cd28 as costimulatory signals - specific antigen recognize, inducing a response, releasing cytokines
What happens during the effector stage of immunity?
Naive T-cells specializes in an effector: Autocrine communication with cytokines (Interleukin-2) causes cellular proliferation.
Effector T-cells recognize further MHC: peptide complexes on infected cells and performs the function
What happens during the memory phase of immunity?
Effector pool contracts to memory
What are the four main stages of cell immunity?
Induction phase
Effector stage
Memory phase
Resolution and repair
What happens during the resolution and repair phase?
Resolution: No tissue damage, returns to normal. Phagocytosis of debris by macrophages
Repair: Healing with scar tissue and regeneration. Fibroblasts and collagen synthesis
Chronic inflammation: Active inflammation and attempt to repair damage ongoing.
How are lymphocytes removed once a pathogenic threat has been eliminated?
Responses against pathogens decline as the infection is eliminated, therefore resulting in reduced presenting antigens.
Apoptosis of lymphocytes is stimulated due to a reduction in survival signals (Absence of antigen-stimulated signaling)
Specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen (Tolerogen v immunogen)
What is the role performed by costimulatory factors in immunological tolerance?
PDL-1 synthesized by T-cells and presented on cell surface membrane become inert to activation
Active control mechanisms may function to limit response to persistent antigen, adopting inhibitory signals.
What is the significance of immunological tolerance?
Individuals are tolerant of their own antigens (self-tolerance), breakdown of self-tolerance results in autoimmunity
Inducing tolerance exploited to prevent graft rejections treat autoimmune and allergic disease
What is central tolerance?
Destroys self-reactive T/B cells before they enter circulation. Lymphocytes that recognize self-antigens before maturation in the generative organs are eliminated (apoptosis) - concept of negative selection.
Receptor binding editing, B-cells to reduce receptor affinity
What is peripheral tolerance?
Destroy or control self-reactive t/b cells that enter circulation. B cells may alter their specificity and T cells may develop into regulatory (suppressive) T lymphocytes
Where does BCR development occur?
Bone marrow
Which enzymes are responsible for BCR development?
VDJ recombinase enzymes
Which immunoglobulin that interacts with the BCR to a stromal cognate antigen causes apoptosis during negative selection?
IgM
Where does TCR selection occur?
Thymus gland
How does TCR selection work?
T-cells recognize cognate antigen associated with the MHC molecules
The inability to recognize self-MHC triggers apoptosis.
Binds to self-MHC adherently - negative selection causes apoptosis
How do T cells undergo positive selection?
Appropriate binding strength to self-MHC, signal to survive (positive selection)
What is the autoimmune regulator (AIRE)?
Developing T cells encounter MHC bearing proteins that are expressed in other bodily regions through the autoimmune regulator.
Transcription factor binds onto promoter region, activating repertoire of genes ex[ressed in peripheral tissues, removing epigenetic modifications.
Promotes self-tolerance by allowing the thymic expression from other tissues. TCRs can be bound to self-specific proteins, identifying their respective binding strengths, t cells are selected
What is the consequence of AIRE mutations?
AIRE mutations result in multi-organ autoimmunity (Autoimmune polyendocrinopathy syndrome type 1). Pathogens express proteins resembling human proteins, enhanced immunity
What is anergy in terms of peripheral tolerance?
Naive T cells require costimulatory signals in order to become activated (CD28-B7) interactions. The majority of cells **lack costimulatory proteins and MHC class II molecules.** Recognition of MHC peptide/ligands without appropriate costimulatory proteins, the T-cell becomes anergic - Less likely to be stimulated in future, despite presented co-stimulation
What is ignorance in peripheral tolerance?
The antigen may be present in insufficient concentrations to reach the threshold for T-cell receptor triggering immunologically privileged sites (eye an brain)
T cells cannot pass the blood-brain barrier
Compartmentalization of cells and antigens controls interactions
What is antigen-induced cell death?
Activation through the T cell receptor can result in apoptosis; influenced by the nature of the initial T-cell activation events
Peripheral T cell apoptosis caused by the induction of expression of the death ligand, FAS-ligand (CD95, fasL); antigen-presenting cells. FAS protein is a transmembrane receptor, upon activation promotes apoptosis
Which ligand induces apoptosis?
FAS ligand
Which Th cells produce IFN-y?
Th1, boosts intracellular immune response
Which Th cells produces the canonical cytokines?
Th2
What are canonical cytokines?
IL-4, IL-5, IL-13, associated with specific T-helper states
Which Th subset resides within B cell follicles (Germinal centers)?
Follicular helper T cells
Which interleukin is secreted by follicular helper T cells?
Il-21
What is the purpose of follicular helper t cells?
Essential for generation of isotype switched antibodies
Which t helper cells are proinflammatory?
Th17
What is the role performed by th17 cells?
Important for pathogenic control, through activation of neutrophils and macrophages. Secretion of IL-17 in autoimmune disease (arthritis)
What are t regulatory cells?
Regulate activation or effector functions of T cells and induced regulatory t cells, necessary to maintain tolerance to self-antigens
What are the main transcription factor classes for th differentiation?
STAT & GATA/BCl
What is cross-regulation?
Cross regulation between T cells is required in order to ensure that secreted cytokines do not express antagonistic effects that may hinder the immune response. Cytokines inhibit other pathways
What inflammatory properties are expressed by Treg cells?
Anti-inflammatory
Which anti-inflammatory cytokines are released from Treg cells?
IL-10, and TGF-beta
Which transcription factors develop TRegs to secrete specific anti-inflammatory cytokines?
FOXP3
Which is the main mechanism of action exhibited by Treg cells?
Secretion of immune-suppressive cytokines inactivation of dendritic cells of responding lymphocytes
A mutation in FOXP3 leads to which autoimmune disorder?
IPEX syndrome
What are natural regulatory T-cells?
Development in the thymus requires recognition of self-antigen during T cell maturation, nTregs reside in peripheral tissues to prevent deleterious reactions against self
What are inducible regulatory T cells?
Develop from mature CD4 t cells that are exposed to antigen in the periphery, no role for thymus. Generated in all immune responses to reduce collateral damage.
What is the role performed by IL10?
Cardinal anti-inflammatory pleiotropic cytokine, expressing influential effects on a range of cells and blocking pro-inflammatory cytokine synthesis including tnf, il6/8, ifn-y.
IL-10 downregulates macrophages reducing antigen-presentation
What does uterine pregnancy behave as?
Parasitic infection
How is a uterine pregnancy tolerated?
Foreign antigens are expressed in the body. Exposure to foreign novel antigens through expressing foreign MHC-1 molecules can result in rejected pregnancy.
Tregs limit and regulate the immune response to prevent this
Which bacterial antibodies most commonly break tolerance and reacts with cardiac muscle?
Anti-streptococcus pyogenes antibodies can cross-react with cardiac muscle (antigenic resemblance)
What is isotype antibody class switching?
T-cell secreted cytokines influence alterations in the constant region (variable region stays the same), to change immunoglobulins type of b cell.
Why is it important to keep selecting T/B cells in blood?
T cells can transform into Treg cells and B cells can change antibody type produced, so constant selection is required to make sure they don’t become self-reactive
AIRE function?
To allow thymus to express peripheral tissues in the thymus, so T cells can be positively selected effectively
Fates of T cells
**Is T cell useless? **
Doesn’t bind to any self-MHC at all
Death by neglect (apoptosis)
Is T cell dangerous?
Binds self MHC too strongly
Apoptosis triggered – negative selection
Is T cell useful?
Binds self MHC weakly
Signal to survive – positive selection
How are B cells selected?
B cell down-selection of self reactive in immature cells relatively simple
If immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM, apoptosis is triggered.
-No thymus so not many peripheral tissues
