- Briefly describe immunological tolerance
- Immunological tolerance is unresponsiveness to self antigens. If the mechanisms that allow for discrimination of self from non-self fail, autoimmune reactions occur, as the immune system attacks own antigens. T-cell tolerance plays the primary role. Remember that B-cell function relies on T-cells i.e. Thymus dependent response
- Two outcomes can occur when lymphocytes encounter antigens:
- Productive immune response (immunogenic): proliferation and differentiation into effector and memory cells
- Tolerance (tolerogenic): inactivation OR apoptosis of the lymphocyte
- The choice between activation and tolerance depends on
- The antigens and signals present (self-antigens are usually tolerated)
- Structure of the antigen
- Dose of the antigen
- What are the types of tolerance
- Central tolerance
- Peripheral tolerance
- Briefly describe T-cell central tolerance
- Central tolerance ****occurs with in the thymus and bone marrow as developing lymphocytes encounter self-antigens
- Death of immature T-cells (Negative selection):
- Immature lymphocytes that interact strongly to self MHC or T-cell receptors that bind to self-antigens with high affinity receive signals that trigger apoptosis.
- Antigens: plasma proteins and common cellular proteins present in high concentration
- Generation of CD4+ regulatory T cells:
- Immature CD4+ T cells that recognize self antigens with high affinity in the thymus do not undergo apoptosis but develop into Treg and enter peripheral tissue. Mechanism unknown. Treg modulate immune system, maintain tolerance, and prevent autoimmune disease. They suppress and downregulate induction and proliferation of T-cells. Important self-check built into the immune system to prevent excessive reaction.
- Briefly describe T-cell peripheral tolerance
- Peripheral tolerance ****occurs in secondary lymphoid organs and peripheral tissue as mature lymphocytes encounter self-antigens. Prevents T cell response to antigens not present in the thymus and back-up for preventing autoimmunity in situations where central tolerance is incomplete
- Functional inactivation (anergy)
- Antigen recognition without adequate co-stimulation results in anergy. Anergic cells survive but are incapable of responding to the antigen.
- Abnormal signalling by TCR complex without co-stimulation,
- Expression of CTLA-4 which terminates activation of T cells and mediates Treg suppression (CTLA-4 removes B7 from APCs),
- Programmed cell death-1 (PD-1) expression by CD4+ and CD8+ after antigen recognition. Interacts with its ligand PDL-1 on APCS thus inhibiting the immune response
- Antigen recognition without adequate co-stimulation results in anergy. Anergic cells survive but are incapable of responding to the antigen.
- Suppression (Block in Activation):
- Treg develop in thymus or peripheral tissue on recognition of self antigens. CD4+ express high levels of CD25, a-chain of IL-2 receptor, FOXP3 transcription factor required for their development and function. Survival and functions of Treg depend on **IL-2 (**Promotes immune response by stimulating T cell proliferation and maintaining Treg), and **TGF-B (**Stimulates expression of FOXP3 transcription factor). Mechanism:
- Production of IL-10 and TGF-B that inhibit lymphocyte, macrophage and dendritic cell activation
- Express CTLA-4 which blocks or removes B7 on APCs making them incapable of co-stimulating and activating T-cells via CD28
- Express IL-2 receptor, binding and consumes IL-2 thus reducing its availability for responding T cells
- Treg develop in thymus or peripheral tissue on recognition of self antigens. CD4+ express high levels of CD25, a-chain of IL-2 receptor, FOXP3 transcription factor required for their development and function. Survival and functions of Treg depend on **IL-2 (**Promotes immune response by stimulating T cell proliferation and maintaining Treg), and **TGF-B (**Stimulates expression of FOXP3 transcription factor). Mechanism:
- Deletion (Apoptosis):
- Recognition of self-antigens triggers apoptosis that deletes self-reactive proteins. Mechanism:
- Production of pro-apoptotic proteins to induce apoptosis due when antigen is recognized without co-stimulation
- Co-expression of death receptors and death receptor ligands (FASDR CD95 and FASL), engagement and death
- Recognition of self-antigens triggers apoptosis that deletes self-reactive proteins. Mechanism:
- Briefly describe B-cell central tolerance
- Self-proteins may not elicit autoantibody response because of T-cell tolerance. Self-polysaccharides, Lipids and nucleic acids are TI antigens and tolerance must be developed against them. Mechanism:
- Receptor editing:
- Re-expression of RAG genes: resuming Ig light chain gene recombination and expression of new Ig light chains. Reduces chances of potentially harmful self-reactive B cells leaving the bone marrow. 25-50% of mature B cells in a normal individual may have undergone receptor editing
- Apoptosis:
- B cells with high affinity receptors for cell membrane and soluble cell antigens are eliminated by receiving apoptotic signals
- Anergy
- Self antigens such as soluble proteins recognized in the bone marrow with low avidity cause reduced expression of receptors
- Briefly describe B-cell peripheral tolerance
- Anergy:
- B-cells that recognize an antigen but do not receive help from T cells (which have been eliminated or are tolerant) become anergic as the signalling from the antigen receptor becomes blocked
- Apoptosis:
- Die because there are no follicular helper T cells, Express FASDR which interact with T-cells containing FASL
- Engagement of inhibitory receptors on B-cells
- Treg function (CTLA4, etc.): reduces co-stimulation
- Anergy:
