Self-tolerance Flashcards
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Briefly describe the layers of tolerance, their mechanisms and site of action
- Central tolerance:
- Deletion
- Editing
- Site of Action
- Thymus
- Bone marrow- Antigen segregation
- Physical barrier to self-antigen access to lymphoid system
- Site of action: Peripheral organs (e.g., thyroid, pancreas)
- Peripheral anergy
- Cellular inactivation by weak signaling without co-stimulus
- Secondary lymphoid organ - Regulatory T cells
- Suppression by cytokines, intercellular signals
- Secondary lymphoid tissue and sites of inflammation - Functional deviation
- Differentiation of regulatory T cells that limit inflammatory cytokine secretion
- Secondary lymphoid tissue and sites of inflammation
- Antigen segregation
- Activation- induced cell death
- apoptosis
- secondary lymphoid tissue and sites of inflammation
TRUE OR FALSE: microbial pathogens are the only source of antigens in the body
FALSE
- Microbial pathogens are not the only source of antigens.
- Host tissues also comprise a range of antigens.
- Mechanisms in place to limit immune responses to host tissue.
- These are termed self-tolerance.
Define self-tolerance
Microbial pathogens are not the only source of antigens.
- Host tissues also comprise a range of antigens.
- Mechanisms in place to limit immune responses to host tissue.
- This implies that the immune system is able to distinguish between self and non-self antigen
Define autoimmunity
Mechanisms in place to limit immune responses to host tissue.
Autoimmunity occurs where mechanisms fail and this an immune response is mounted to host cells or tissues.
B1
Review clonal selection
- Each lymphoid progenitor results in the generation of a large number of lymphocytes.
- Each lymphocyte recognizes antigen with a receptor with unique specificity.
- Potentially self-reactive immature lymphocytes are eliminated before maturation can occur.
- Following interaction with a foreign antigen with a specific receptor on a mature naive lymphocyte, activation results in the generation of lymphocytes recognizing a specific antigenic sequence and expansion of a specific clone of effector cells.
- Following elimination of the antigen, the response ceases.
- Some lymphocytes are retained, providing immunological memory.
Define immunological tolerance
Lack of response when lymphocytes recognizing a specific antigen are exposed to that antigen.
List and define the types of immunological tolerance
- Central tolerance. ^[compare and contrast question]
- Developing lymphocytes encounter antigen in the primary/central lymphoid organs.
- Peripheral tolerance.
- Mature lymphocytes encounter antigen in secondary lymphoid organs.
List the types of central and peripheral tolerance
- Mechanisms of central tolerance: apoptosis, change in B cell receptors (gene rearrangement and receptor editing), and development of regulatory T lymphocytes (a small number, CD4+ T cells only, which can contribute to suppression)
- Mechanisms of peripheral tolerance: anergy, apoptosis or deletion, and suppression
Describe mechanisms of central T cell tolerance and mechanisms of cell tolerance in the thymus
Central T Cell Tolerance
- Negative selection results in death of immature T cells: apoptosis.
- strong recognition of specific antigen by immature T cells
- 90% will die
- Production of CD4+ regulatory T cells.
- undeleted immature T cells specific for self antigen, migrate to the periphery
Central Tolerance (Thymus)
- Immature T cells migrate to the thymus.
- Encounter antigen presented by thymic epithelial cells.
T cells arise in the thymus that are capable of recognising tissue-specific antigens.
Under control of AIRE, thymic medullary cells expressing tissue-specific proteins deleting tissue-reactive T cells.
Without AIRE, cells reactive tissue-specific antigens mature and leave the thymus.
A lack of AIRE results in a wide range of symptoms.
A deficiency in immune regulation.
- The AIRE gene is mutated in the rare autoimmune syndrome autoimmune polyendocrinopathy syndrome type 1 (APS-1), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).
- Disruption of AIRE results in the development of a range of autoimmune diseases, the most common clinical conditions in the syndrome are hypoparathyroidism, primary adrenocortical failure and chronic mucocutaneous candidiasis
Describe mechanisms of peripheral T cell tolerance
- Mature T cells recognize self-antigen in the peripheral tissues.
- Several mechanisms including:
- Anergy (functional inactivation).
- Suppression by regulatory T cells (block activation).
- Absence of correct activation signals.
- Signal 1 (antigen) - relies on TCR
- Signal 2 (co-stimulation from antigen-presenting cells/cytokines) - other receptors
- T cell may become refractory to activation.
- Blocks clonal expansion.
Describe anergy
Anergy (Peripheral T Cell Tolerance Mechanisms)
- Induction of functional unresponsiveness when a T cell is exposed to and recognizes self-antigen.
- Long-lived response.
- Recognition of antigen in the absence of adequate co-stimulation results in the downregulation of activating signal transmission.
- e.g. due to lack of receptor on APC
- Recognition of antigen may lead to upregulation of inhibitory signals (CTLA-4 or PD-1). -> leads to suppression and blocking of secondary signal
Describe the role of CTLA-4
- site of action: secondary lymphoid organs
- induction or priming is inhibited
- CD4+ is more than or same as CD8+
- leads to cellular expression of Tregs and activated T cells
- binds to B7 with high affinity and removing B7 from APCs by competitively inhibiting CD28
- A role of Treg mediated suppression of immune responses
Describe the role of PD-1
- site of action: peripheral tissues
- effector phase is inhibited
- CD8+ more than CD4+
- leads to cellular expression of activated T cells
- Signalling inhibitor of CD28 and TCR, inhibiting kinase-depending signals by activating phosphatase
- NOT involved in Treg-mediated suppression of immune responses
Describe regulatory T cells
- Production of cytokines that inhibit activation of lymphocytes, dendritic cells, and macrophages (IL-10, TGF-beta).
- TGF-b promotes proliferation and T cell effector function
- inflammation
- Expression of CTLA-4.
- Antigen-presenting cells unable to provide co-stimulation via CD28 and thus activation of T cells.fector function- inflammatory response
- Expression of IL-2R.
- Reduces availability for other T cells recognizing a specific antigenic stimuli.
- IL-2 promotes proliferation of T cells, blocking the receptor reduces IL-2 availability
Describe apoptosis
- Activation of pathways that result in deletion of the self-reactive lymphocytes.
There are two pathways for apoptosis:- deficiency of survival signals e.g. reduction of IL-2 and balance shifts between pro- and anti-apoptotic proteins, release of pro-apoptotic proteins from the mitochondria
- engagement of death receptors (expression of death receptors (Fas) and ligand (FasL))
