2024 Advanced Immunology Unit 1 PDF

Birgit Reipert IMC FH Krems – Oct 30th, 2024 1  Advanced Immunology unit 1 source: public domain Birgit Reipert, Hon.Prof.(FH) Priv.Doz.Dr. Birgit Reipert IMC FH Krems – Oct 30th, 2024...

Birgit Reipert IMC FH Krems – Oct 30th, 2024 1  Advanced Immunology unit 1 source: public domain Birgit Reipert, Hon.Prof.(FH) Priv.Doz.Dr. Birgit Reipert IMC FH Krems – Oct 30th, 2024 2 Short CV – Birgit Reipert 1976-1981: Diploma at Ernst-Moritz-Arndt-University Greifswald, Germany subject: Pharmacy / Experimental Pharmacology and Toxicology 1981-1984: PhD at Ernst-Moritz-Arndt University Greifswald, Germany subject: Pharmacology/Immunology 2005: Habilitation/Vena docendi at the Medical University of Vienna 1985-1990: Post-doc at the Institute for Cancer Research, Berlin and at the Institute for Medical Immunology at the Charitè, Berlin 1991-1994: Post-doc at the Paterson Institute for Cancer Research, Manchester, UK 1995-2020: Immuno AG/Baxter AG/Baxalta Innovation/Shire/Takeda in Vienna, Austria 2000-2020: Head Department of Immunology, Research Division, Baxter AG/ Baxalta Innovation/Shire/Takeda in Vienna, Austria 2020-2021: Project Management IMC FH Krems since 2022: Owner of freelance consultancy Translational Immunology since 2000: Teaching activities at several universities and FHs (lectures; seminars; supervision of Master- and PhD students) since 2016: Honorary Professorship IMC FH Krems Birgit Reipert IMC FH Krems – Oct 30th, 2024 3  Lectures in Advanced Immunology 2024-10-30 (3h): 10:30 – 13:15 (G.E.12) Unit 1 (1h): Introduction Basic principles of immune recognition in innate- and adaptive immune system Unit 2 (1h): Innate immune receptors Unit 3 (1h): Autoinflammatory diseases 2024-11-04 (2h): 9:00 – 10:45 (TEAMS VC) Unit 4 (2h): Mucosal Immune system and Microbiota 2024-11-05 (2h): 15:00 – 16:45 (TEAMS VC) Unit 5 (2h): Immune Oncology (guest speaker: Christina Baumgartner, PhD, Immuno-Oncology Discovery AbbVie, Chicago, US) 2024-11-13 (4h): 09:00 12:45 (TEAMS VC) Unit 6 (1h): Immunological tolerance Unit 7 (1h): Autoimmune diseases and selection of topic for team work Unit 8 (2h): Hypersensitivity Disorders and Allergies 2024-11-18 (2h): 11:00 – 12:45 (TEAMS VC) Unit 9 (1h) Present results of team work selected in Unit 7 Unit 10 (1h):Immunogenicity of Protein Therapeutics (guest speaker: Helmut Schweiger, Octapharma) Birgit Reipert IMC FH Krems – Oct 30th, 2024 4 References and Further Reading Birgit Reipert IMC FH Krems – Oct 30th, 2024 5 Why do we need an immune system ? Birgit Reipert IMC FH Krems – Oct 30th, 2024 6 The immune system protects us Birgit Reipert IMC FH Krems – Oct 30th, 2024 7 How can the immune system protect us ? Birgit Reipert IMC FH Krems – Oct 30th, 2024 8 How can the immune system protect us ? 1. It must be able to recognize pathogens and toxins 2. It must be able to differentiate between pathogens/toxins and self-proteins/self-structures 3. It must be able to differentiate between non-dangerous and dangerous microbes 4. It must be able to destroy or neutralize pathogens and toxins These processes must be fast, efficient and specific antibodys are important Birgit Reipert IMC FH Krems – Oct 30th, 2024 9 The immune system needs to express major functions in order to protect us Immune recognition Immune effector functions Immune regulation Immunological memory Birgit Reipert IMC FH Krems – Oct 30th, 2024 10 Basic principles of immune effector functions pathogens, toxins Epithelial barriers, mucous membranes, 1st line of defence: proteins, micro flora, skin, mucous membranes and micro flora, stop invadors from growing and getting in Innate Immune Innate immune cells, e.g. macrophages, neutrophils, 2nd line of defence: Sytem natrual killer cells, innate lymphoid cells Kill invaders mainly by engulfing them and destroying them with proteolytic enzymes Adaptive B- and T Immune lympho- 3rd line of defence: System cytes antigen-specific defence, e.g. antibodies, T cells, results in specific immune memory, e.g. memory B cells and memory T cells Birgit Reipert IMC FH Krems – Oct 30th, 2024 11 Cells and soluble proteins of the Innate – and the Adaptive immune system Szekanecz Z. Nat Rev Rheumatol 2021 Birgit Reipert IMC FH Krems – Oct 30th, 2024 12 Basic principles of immune recognition Recognition of patterns which are common to a group of compounds, e.g. proteins, nucleid acids, glycans or lipids Innate immune A) Pathogen-associated molecular patterns (PAMPs) recognition B) Damage-associated molecular patterns (DAMPs) C) Homeostasis-altering molecular patterns (HAMPS) Molecular patterns are recognised by germline encoded innate immune receptors Recognition of very specific epitopes Adaptive immune recognition A) B-cell receptors: B cells express receptors that recognize specific parts (epitopes) of whole molecules, e.g. proteins, lipids or carbohydrates B) T-cell receptors: T cells express receptors that recognize peptides presented by MHC-class I (CD8 T cells) or MHC-class II (CD4 T cells Birgit Reipert IMC FH Krems – Oct 30th, 2024 13 Innate Immune recognition (A) Pathogen-associated molecular patterns (PAMPs) Small molecular motifs that are conserved within a class of microbes. Christmas, P. Nature Education 2010 Birgit Reipert IMC FH Krems – Oct 30th, 2024 14 Innate Immune recognition B) Damage-associated molecular patterns (DAMPs), also known as alarmins, are molecules released by stressed cells undergoing necrosis that act as endogenous danger signals to promote and exacerbate the inflammatory response. Comish P. J Immunol 2020 Birgit Reipert IMC FH Krems – Oct 30th, 2024 15 Innate Immune recognition C) Homeostasis-altering molecular patterns (HAMPs) indicate the loss of cellular homeostasis, for example, as initiated by infection. HAMPs reflect functional consequences of pathogens on cellular processes, rather than simple molecular patterns generated by pathogens Liston A_Nat Rev Immunol 2017 Birgit Reipert IMC FH Krems – Oct 30th, 2024 16 Adaptive Immune Recognition A) B-cell receptor expressed by B-cells B-cell receptor (BCR) B-cell receptor F(ab`)2 Fc Immunoglobulin (Ig) diversity is generated by Naive B cell rearrangement of Ig genes [V(D)J recombination and junctional diversity] total potential repertoire: 5x1013 different B cell clones estimate from experiments: 107 different clones in each individual Birgit Reipert IMC FH Krems – Oct 30th, 2024 17 Rearrangement of Ig genes [V(D)J recombination] Birgit Reipert IMC FH Krems – Oct 30th, 2024 18 Adaptive Immune Recognition A) B-cell receptor expressed by B-cells B-cell receptor (BCR) B-cell receptor F(ab`)2 Fc Immunoglobulin (Ig) Receptor undergoes affinity Naive B cell maturation after contact with antigen to obtain optimal binding to the antigen (somatic mutations in Ig genes) Receptor undergoes class switch recombination to generate different Fc parts (IgM, IgG, IgA, IgE) Birgit Reipert IMC FH Krems – Oct 30th, 2024 19 Somatic Hypermutation and Class Switch V(D)J recombination is fixed but can become Class switch recombination changes out mutated by somatic hypermutations in the genes heavy chain constant regions (C) replacing of heavy-chain and light chain to generate IgM with a switched isotype (IgG1-4; IgA, IgE) high-affinity antibodies Low-affinity High-affinity antibody antibody Figure 10.13 Janeway`s Immunobiology, 10th ed. (2022) Birgit Reipert IMC FH Krems – Oct 30th, 2024 20 Lymphocytes derive from hematopoietic stem cells in the bone marrow Birgit Reipert IMC FH Krems – Oct 30th, 2024 21 B cell development and differentiation Birgit Reipert IMC FH Krems – Oct 30th, 2024 22 B cell development and differentiation Birgit Reipert IMC FH Krems – Oct 30th, 2024 23 Immature B cells are tested for self-reactivity before they leave the bone marrow Birgit Reipert IMC FH Krems – Oct 30th, 2024 24 Peripheral B cells that recognize self antigens undergo peripheral control for self-reactivity Birgit Reipert IMC FH Krems – Oct 30th, 2024 25 There are three major subsets of mature B cells Birgit Reipert IMC FH Krems – Oct 30th, 2024 26 There are three major subsets of mature B cells Birgit Reipert IMC FH Krems – Oct 30th, 2024 27 Adaptive Immune Recognition B) T-cell receptors expressed by T-cells T cells recognize peptides presented by MHC-class I and II CD8+ T cell CD4+ T cell T cell receptor T cell receptor (TCR) (TCR)     Peptide Peptide CD8 CD4 MHC-class I MHC-class II Virus infected cell Antigen-presenting cell Birgit Reipert IMC FH Krems – Oct 30th, 2024 28 Adaptive Immune Recognition B) T-cell receptors expressed by T-cells T-cell receptor (TCR) α β γ δ TCR CD8 CD4 TCRαβ TCRγδ diversity is generated by rearrangement of TCR genes [VDJ recombination and junctional diversity] total potential repertoire: 1018 different T cell clones estimate from experiments: 107 different clones in each individual Birgit Reipert IMC FH Krems – Oct 30th, 2024 29 Stages of gene rearangement of the T-cell receptor Birgit Reipert IMC FH Krems – Oct 30th, 2024 30 Stages of gene rearangement of the T-cell receptor Birgit Reipert IMC FH Krems – Oct 30th, 2024 31 Adaptive Immune Recognition B) T-cell receptors expressed by T-cells T-cell receptor (TCR) α β γ δ TCR CD8 CD4 TCRαβ TCRγδ no affinity maturation no class switch recombination no production of secreted forms Birgit Reipert IMC FH Krems – Oct 30th, 2024 32 T-cell development and differentiation Birgit Reipert IMC FH Krems – Oct 30th, 2024 33 T-cell development and differentiation Birgit Reipert IMC FH Krems – Oct 30th, 2024 34 T-cell progenitors originate in the bone marrow, but all the important events in their development occur in the thymus The cellular organization of the human thymus Birgit Reipert IMC FH Krems – Oct 30th, 2024 35 Thymic education through positive and negative selection of T cells in distinct thymic microenvironments Positive selection: Immature T cells that bind to self-MHC (MHC class I or II) expressed on cortical epithelial cells with a high enough affinity receive survival signals Negative selection: T cells that bind strongly to self-peptides presented by MHC class I or II expressed on macrophages and dendritic cells receive an apoptosis signal and are removed from the repertoire Birgit Reipert IMC FH Krems – Oct 30th, 2024 36 The affinity model of positive and negative selection of T-cells in the thymus Birgit Reipert IMC FH Krems – Oct 30th, 2024 37 Summary: Cells and soluble proteins of the innate – and the adaptive immune system Szekanecz Z. Nat Rev Rheumatol 2021 Birgit Reipert IMC FH Krems – Oct 30th, 2024 38 Summary - Basic principles of immune effector functions pathogens, toxins Epithelial barriers, mucous membranes, 1st line of defence: proteins, micro flora, skin, mucous membranes and micro flora, stop invadors from growing and getting in Innate Immune Innate immune cells, e.g. macrophages, neutrophils, 2nd line of defence: Sytem natrual killer cells, innate lymphoid cells Kill invaders mainly by engulfing them and destroying them with proteolytic enzymes Adaptive B- and T Immune lympho- 3rd line of defence: Sysytem cytes antigen-specific defence, e.g. antibodies, T cells, results in specific immune memory, e.g. memory B cells and memory T cells Birgit Reipert IMC FH Krems – Oct 30th, 2024 39 Summary - Basic principles of immune recognition Recognition of patterns which are common to a group of compounds, e.g. proteins, nucleid acids, glycans or lipids Innate immune A) Pathogen-associated molecular patterns (PAMPs) recognition B) Damage-associated molecular patterns (DAMPs) C) Homeostasis-altering molecular patterns (HAMPS) Molecular patterns are recognised by germline encoded innate immune receptors Adaptive immune Recognition of very specific epitopes recognition A) B-cell receptors: B cells express receptors that recognize specific parts (epitopes) of whole molecules, e.g. proteins, lipids or carbohydrates B) T-cell receptors: T cells express receptors that recognize peptides presented by MHC-class I (CD8 T cells) or MHC-class II (CD4 T cells Birgit Reipert IMC FH Krems – Oct 30th, 2024 40 Summary - B-cell development and differentiation Birgit Reipert IMC FH Krems – Oct 30th, 2024 41 Summary - T-cell development and differentiation Birgit Reipert IMC FH Krems – Oct 30th, 2024 42  Thank you for your attention Birgit Reipert IMC FH Krems – Oct 30th, 2024 43