Immunology Lecture Notes PDF

Lecture 7 √√ Thursday 17 October 2024 13:37 1. Why do we need immunological tolerance? Random generation of repertoire of BCR and TCR Many self-reactive specificities will be produced If no tolerance, autoreactivity would lead to serious pathology. 2. What does random TCR (alpha/ß)...

Lecture 7 √√ Thursday 17 October 2024 13:37 1. Why do we need immunological tolerance? Random generation of repertoire of BCR and TCR Many self-reactive specificities will be produced If no tolerance, autoreactivity would lead to serious pathology. 2. What does random TCR (alpha/ß) gene rearrangement lead to? T cells expressing TCR that: 1) fail to recognise self-MHC (useless) - Die by neglect (no positive selection survival signals. 2) Recognise self-MHC + peptide generated from Ag present in the thymus (potentially dangerous). - Binds self MHC too well - Expanded by positive selection - Eliminated by negative selection/ deletion 3) Recognise self-MHC + “any other” peptide not present in thymus (potentially useful) - Expanded by negative selection/ deletion. - Medium affinity for self MHC, should not give an autoimmune response - But includes cells that are capable of responding to self MHC when it contains peptides derived from Ag not present in the thymus (i.e. from Ag found in pathogens). 3. True or false? Not all self Ag are expressed In the thymus. True E.g. insulin, antibodies. 4. What is AIRE? Autoimmune regulator protein Transcription factor Key role in tolerance induction Allows the expression of many tissue-specific Ag (TSA) in the thymus Negative selection/ deletion of T cells that recognise these Ag. Patients with AIRE deficiency/ mutations have major autoimmune syndrome. 5. What does random Ig gene rearrangements lead to in B cells? Many B cells potentially express self-reactive BCRs. Autoreactive B cells are negatively selected/ deleted (in bone marrow not thymus). B cells get a second chance to rearrange self-reactive BCR. (Rearrange another light chain) - Receptor editing; new light chain may remove self-reactivity. 6. What happens to lymphocytes that recognise self Ag? Can become unresponsive I.e. anergic 7. What happens when BCR encounter Ag in bone marrow that is NOT multivalent? They down regulate BCR and leave bone marrow as unresponsive (anergic). 8. How can T cells be made anergic? 1) unstimulated macrophages do not deliver a co-stimulatory signal to T cells recognising a nonbacterial antigen —> Anergic T cells 2) Naïve T cell becomes unresponsive (anergic) 3) Anergic T cell receives signal 1 but no signal 2 as APC is not activated i.e. does not express co-stimulates. 4) Bacteria stimulate macrophages to deliver a co-stimulatory signal to T cells recognising a bacterial antigen. —> proliferation and differentiation of T cells specific for a bacterial protein Naïve T cell receives signal 1 and 2 9. What is immunological ignorance? Many Ag are not presented at sufficient levels to activate T cells. 10. What are privileged sites? Ag sequestered from immune system (suppressive cytokines also prevalent) E.g. eye, testis, CNS (barriers in place). 11. What happens if Ag-specific T cells are absent/ tolerant? No help for B cell is available -> no antibody response. 12. Describe regulatory T cells (Treg) CD4+ T cell subset that suppress immune responses Crucial for preventing autoimmune responses Arise in thymus from T cells with high affinity for TCR for self Ag - Express FoxP3 transcription factor - (nTreg) or can be induced in periphery (iTreg) 13. What does deficiency of Treg lead to? Severe autoimmune syndrome IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X linked syndrome) 14. What do cytokines (IL-10 and TGF-ß) produced by Treg do? Inhibit other self reactive T cells 15. What is the role of regulatory B cells (Breg/10)? Secrete IL-10 Crucial in preventing autoimmunity. 16. What do CD4+ T cells differentiate into following successful activation? Effector T cells CD4+ Th(1/2/17), CD4+Treg/Breg, CD4+TFH 17. What is the role of CD4+Th1? Activation of macrophages, NK cells, cytotoxic T cells. - Via secretion of cytokines e.g. IFN-y, GMCSF, TNF-alpha. - Express CD40L which binds CD40 on macrophage Can kill chronically infected macrophages - Fas ligand/ Fas induce apoptosis - Released bacteria destroyed by healthy macrophage - Other cells can then kill the pathogen 18. What is the role of IFN-y? Can inhibit development of TH17 cells Acts on TH2 cells to inhibit proliferation. 19. How do CD4+Th1 cells kill chronically infected macrophages? Fas ligand/ Fas induce apoptosis Released bacteria destroyed by healthy macrophage Other cells can then kill the pathogens. 20. What is the role of CD4+Th2? Promotes responses mediated by eosinophils and mast cells Secrete IL4 - Inhibits differentiation of TH1 cells 21. What is the role of IL-4? Inhibits the differentiation of TH1 cells Can inhibit development of TH17 cells Role in antibody responses, especially IgE. 22. What is the role of CD4+Th17? Promotes responses against fungi Subset of CD4+ T cells Secrete IL-17 Function to recruit neutrophils early in fungal infections Implicated in autoimmune disease. Evolutionarily oldest form of acquired immunity. 23. What is the role of CD4+Treg/Breg? Suppress unwanted responses 24. What is the role of CD4+Tfh? Specialised Th found in GC to help B cells - Can produce TH1,2, & 17 cytokines) 25. Describe CD4+ Treg Not a single population Mixed bag of cells - CD4+CD25 - Some CD8+T cells can have Treg activity Arise from thymus (nTreg) or from circulating T cells in peripheral tissues (iTreg) Act to suppress other T cell responses. 26. What is the role of CD4+ Treg? Secretion of suppressive cytokines - TGF-ß - IL-10 Can also involve cell-cell contact IL-10 inhibits APC function Suppress the differentiation and proliferation of TH1 and TH2 cells 27. What is the type of Th response influenced by? The cytokines that are present when T cells are activated (signal 3) IL-12 promotes differentiation into Th1 cells. IL-4 - Th2 cells IL-6 + TGF-ß - Th17 cells TGF-ß + IL-2 - Treg cells These cytokines come from APCs (dendritic cells, macrophages) 28. What are the key cytokines in naïve T cell activation by APC? IL-12 and IFN-y: Th1 differentiation (by activating transcription factors) IL-4: Th2 differentiation – activation of eosinophils, mast cells, B cells (important fr humoral and allergic response) 29. What do TH1 cytokines promote and inhibit? Promote commitment to TH1 Inhibit development of TH2, TH17 – by suppressing the cytokines & transcription factors required for differentiation 30. What do TH2 cytokines promote and inhibit? Promote commitment to TH2 – drives differentiation – enhances immune response against extracellular pathogens (especially by activating B cells) Inhibit development of TH1, TH17 – preventing shift towards cell mediated immunity and inflammatory responses. 31. What do TH17 cytokines promote and inhibit? Promote commitment to TH17 cytokines – enhances immune response to fungal and bacterial infection (& recruits neutrophils) Inhibit development of Treg – Treg would promote tolerance (counterproductive to Th17 role in inflammation (Th17 ensures strong aggressive response, Th17 suppresses immunity)) 32. What do Treg cytokines promote and inhibit? Promote nothing Inhibit TH1,TH2,TH17 responses. Inhibit Th1: prevent excessive inflammation and tissue damage Inhibit Th2: (fight extracellular pathogens) could lead to allergies if overactive. Inhibit Th17: prevent excessive inflammation. 33. How does Treg allow successful pregnancy? TGF-ß1 —> FoxP3+ Treg cell —> Suppression of activation of the immune system Successful placentation TGF-ß1 promotes FoxP3 Treg cells. FoxP3 express FoxP3 transcription factor (crucial for immune tolerance). Tregs suppress activation of immune responses around the foetus – prevents the mothers immune system from attacking foetal tissues. 34. What is the importance of polarised responses Ensures correct responses for different types of pathogens – e.g. TH1 intracellular, Th2 extracellular Can go wrong - may lead to allergy (excessive TH2) – if there is an imbalance and the immune system overreacts. Control of autoreactivity/ pregnancy – Treg controls auto reactivity - allows for successful pregnancy by tolerating foetus. 35. Why is immune tolerance required? To prevent autoimmunity caused by self-reactive B and T cells generated during random receptor rearrangement. Central tolerance - thymus and bone marrow – self-reactive immune cells are eliminated or rendered inactive (anergic) before being allowed to circulate. Peripheral - mechanisms (Treg) control any remaining self-reactive cells that escape central tolerance. 36. Clonal deletion of B cells occurs in the ____. Bone marrow 37. Clonal deletion of T cells occurs in the ____. Thymus 38. Immature B cells that recognize self antigen that are not deleted may undergo ____ or become ____ before entering the circulation. Receptor editing Anergic 39. Recently it has been described that some T cells that are not initially positively selected by self-MHC may rearrange their ____ genes TCR alpha chain 40. Negative selection of T cells in the thymus removes those expressing TCR with high for self MHC and ____. Self peptides 41. Some T cells with high affinity self-reactive TCR do not undergo negative selection but develop into ____. Regulatory T cells (Treg) 42. Why are there several subsets of CD4+ T cells? Th1 - activates macrophages for intracellular pathogens (e.g. bacteria, viruses) Th2 - promotes eosinophil and mast cell responses for parasites and allergens. Th17 - recruits neutrophils for fungi and extracellular bacteria. 43. CD4+TH1 T cells are important to activate ____. Macrophages NK cells Cytotoxic T cells 44. CD4+ TH17 T cells can be identified by the production of ____. IL-17 45. CD4+ TH2 T cells inhibit the responses of ____. Th1 cells 46. Once activated by APC, CD8+ T cells develop into ____. Cytotoxic T lymphocytes 47. How do iTreg cells differ from nTreg cells? Itreg: induced in peripheral tissues from circulating T cells. – induced by tolerogenic signals (TGF-ß and low co-stimulation) –maintain tolerance to environmental and commensal antigens (gut). Ntreg: naturally arise in thymus, high affinity self antigen recognition. – arise during central tolerance from recognition of self-antigens with intermediate affinity – presented on MHC by thymic epithelial cells or dendritic cells during negative selection. – Rather than being deleted, T cells differentiate into T cells differentiate into nTregs due to intermediate TCR signalling strength and the presence of cytokines (IL-2). 48. What factors drive the differentiation of iTreg cells in peripheral tissues? ITreg cells develop in peripheral tissues when naïve CD4+ T cells encounter antigens in a tolerogenic environment. TGF-ß: drives iTreg differentiation - promotes FoxP3 expression. IL-2: maintains Treg survival and FoxP3 expression Low pro-inflammatory cytokines: minimal IL-6 and IL-12 levels favour iTreg induction Antigen presentation without strong co-stimulation encourages tolerance over activation. 5. B cell tolerance 6. 14. Naïve T cell activation by APC 26. Th1 responses. Th2 responses CD8+ T cells