Immune Regulation and Tolerance Flashcards
Immunologic tolerance
The specific unresponsiveness of the normal adaptive immune system to an individuals own SELF antigens
Difference between T cell tolerance and B cell tolerance
T cell tolerance is long lived
B cell tolerance is short lived, less complete than in T cells, and is quiescent in the absence of T cell help
Activation: Immunogenic antigens
Elicit the functional ACTIVATION of lymphocytes bearing specific receptors (require co-stimulation) of T-cells by activated APCs
Tolerance: Tolerogenic antigens
Elicit functional INACTIVATION or KILLING of lymphocytes bearing specific receptors for those antigens (without co-stimulation or T cell help) - deletion of lymphocytes that recognize SELF antigens
Ignorance: Non Immunogenic
Antigens that are ignored by lymphocytes bearing specific receptors for those antigens
Whether an antigen will induce tolerance is largely determined by
1) Immunologic maturity
2) Antigenic structure and dose
3) Immunosuppressive therapy
Significance of immunologic toleranc
Abnormal immune responses to self-antigens can lead to autoimmune and other diseases
Central tolerance
Tolerance obtained by immature cells in the generative lymphoid organs - the B-cells or T-cells encounter SELF antigen
Peripheral tolerance
Tolerance obtained by mature cells in peripheral lymphoid tissues
3rd checkpoint in lymphocyte maturation
Positive and Negative selection: Does the antigen receptor recognize SELF - the strength of this interaction is called avidity
Thymocytes
Immature T-cells before expression of TCRβ and TCRα chains
Positive selection
Occurs in the thymic cortex - selection of T cells expressing functional T cell receptors that can recognize either Class I MHC or Class II MHC molecules
Negative Selection
Occurs in the thymic medulla - Cells that recgonize high avidity self antigens presented on MHCs are killed through apoptosis
- Exception is T-regulatory cells
Death by neglect
No recognition of MHC + self-peptide by TCR and co-receptor
Double positive thymocytes
Thymocytes that express both CD8+ and CD4+
Aire Transcription factor gene
Drives expression of numerous tissue-specific self-peptides of peripheral organs - T-cells that respond to these are eliminated
Avidity and Selection
Positive Selection = Low avidity
Negative selection = High avidity
Loss of Aire
Results in lack of NEGATIVE SELECETION OF SELF-REACTIVE T CELLS in thymus
APECED
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy: Patients make auto-antibodies to immune proteins important in the control of fungal infections
Treg
T-regulatory cell: Some self reactive CD4+ cells are not deleted but become regulatory Treg
Express Foxp3
When activated in the periphery these cells suppress immune responses
Peripheral tolerance mechanisms
Anergy, Suppression, Deletion
Treg development
Develop in the thymus following recognition of self-antigen by immature double positive thymocytes - activated in periphery by self antigen and IL-2
Anergy: Unresponsiveness
APCs lack costimulatory molecules (B7)
T cells express the CTLA-4 molecule which sends an inhibition to the T cells upon binding APC B7
CD28 vs. CTLA-4
T cells express CD28 (ITAM - Activating - high levels of B7) or CTLA-4 (ITIM - Inhibiting - low levels of B7)
Supression Mechanisms
Contact dependent: Tregs directly bind to mature T cells to induce inhibitory signaling via CTLA-r surface bound TGFβ killing of targets thorugh perforin
Contact independent: Treg cells secrete high levels of TGFβ and IL-10 that inhibit T-cell activation
CTLA-4-IG biologic immunotherapy
Binding domain of CTLA-4 molecule works by binding CD80 and CD86 on antigen presenting cells - prevents those co-stimulatory molecules from binding to CD28 expresed on T cells - Removes 2nd signal, limits T cell activation
IPEX syndrome
Due to mutation in Foxp3 and loss of T regulatory cells
Affects boys in infance
Broad regional hyper-inflammatory responses in the mucosa, skin, pancreas and thyroid
T-cell deletion
1) Cell death caused by deficiency of survival genes
2) Cell death caused by engagement of death receptors
The _______, _______ and ________ of self-antigen recognition may contribute to tolerance or breakdown in tolerance
location, abundance, persistance
Central B tolerance: Strong avidity and Low avidity
Strong avidity:
- Receptor editing - rearrangement of IgL chains
- Deletion - negative selection by apoptosis
Low avidity
- Anergy
Receptor editing
Generation of new light chains after additional VJ recombination events
Re-expression of BCR - non-self
Peripheral B cell tolerance mechanisms
1) Occurs in germinal centers during immune response
2) Differ from normal Naive B cells
- Short lifespan
- Reversible
3) Constitute 1-4% of B cells in blood
Autoimmunity (1-2% of individuals)
An immune response against self antigens; failure of tolerance
Principle factors in the development of autoimmune disease
1) Inheritance of susceptibility genes which may contribute to FAILURE of SELF-TOLERANCE
2) Environmental triggers which may activate self-reactive lymphocytes
Autoimmunity is a mixture of…
Genetic susceptibility
Environmental Triggers
Uncontrolled immune response
Mutations in MHC may contribute to autoimmune disease through:
Defect in Central Tolerance - Inefficient display of self-antigens
Defect in Peripheral Tolerance - Mutant MHC may not stimulate Tregs
Autoimmunity: Environment (Mechanisms)
1) Microbes induce co-stimulatory molecule expression - self reactive T cells become activated
2) Molecular mimcry - microbial peptide is similar to self peptide
