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Vinnie Maugeri Biology, Senior At Life’s first dawn, God chose for us, This magic blessed place. That we might together share, The joys of Time’s embrace Cellular Components, Cytokines and Growth Factors of the Immune Response. Stem Cells and Stem Cell Transplantation Folder Title: Cells(NoTP) Updated: November 1, 2016 Questions About Cellular Components of the Immune Response How many different cell types are there? What are the numbers of the various cell types? What do these different cell lineages do? Where do they come from? How Long do they last? What becomes of them at the end of their functional life span? What controls their replacement? (How does the hematopoietic system know what needs to be replaced?) What happens if they aren’t replaced correctly? If they are deficient in number? If they are produced in excess to what is needed? If they are not structurally or functionally normal? How We Learn Things: Memorization vs Gradual Familiarity Immune System Make-up From 447Intro Morphology & Staining of Blood Cells Kuby, 3rd Ed. Figure 3-1 About 6 u diameter About 20 u diameter 700 RBC to one leucocyte Leukemic Leucocytes: About 20u diameter Red Blood Cells: 4 to 6 u diameter. Diluted 1:1000 from whole blood In this photo: 33 RBC:1 Leukemic Leucocyte Replacing Cells at the Correct Time with the Correct Cell Type Hematopoiesis Where Do the Blood Cells Come From? Stem Cells and Partially Differentiated Progenitor Cells How Can We get Our Hands on Stem Cells for Treatments? Stem Cell Therapy in Medicine See Figure 2-1 p. 28, 7th Editon Hematopoiesis (formation of blood cells) Fig 2-1, Kuby 4th Ed. p. 28 Right to Left View Note Cytokine Signalling: IL2, IL3, IL4, IL6, IL7, IL8,IL11,EPO, GMCSF Hematopoiesis What the cells look like as colonies growing in soft agar Where Hematopoietic Cells Come From: Separating Different Kinds of Hematopoietic Cells Antibodies to differentiated end-product blood cells Separating Out Stem Cells (S) and Pluripotent progenitor cells (P) Removes progenitor (P) Cells Isolation of CD34+ Pluripotent Stem Cells from Mixed Bone Marrow Mononuclear Cells Using Monoclonal Antibody to CD34 Marker on Stem Cells Biotin attached To Antibody Fc Region These are the Pluripotent Stem Cells that can make all of the other blood cells Antibody conjugated to Biotin. Avidin coats insoluble beads Biotin Sticks Strongly to Avidin 200,000 peripheral blood cells restore viability 1,000 mixed stem cells and progenitor cells restore viability Pure Stem Cells 30 to 100 Stem cells restore viability See Figure 2-5 Kuby, 6th Ed. Please put away all notes and any devices except for your Turning Point NXT Transmitter. No papers or computers on your desk please. No communication between or among students. Response Counter Rank 1 2 3 Responses 4 5 6 Non-Response Response Counter Rank Responses 1 2 3 4 5 6 Non-Response Myeloid Lineage Differentiation and Function Among “Granulocytes”, Polymorpho-nuclear Leucocytes (PMN’s) : Neutrophils, Eosinophils, Basophils/Mast Cells, Monocytes Monocytes/Macrophages, Dendritic Cells Erythrocytes Magakaryocytes/Platelets Cells of Myeloid Lineage Polymorphonuclear leukocytes: (Granulocytes) Neutrophils, Eosinophils, Basophils, Mast Cells Antimicrobial, allergic reactions, ADCC Monocyte Macrophages: Mononuclear phagocytes Antimicrobial, attack virally infected cells, Phagocytosis, Endocytosis, & Pinocytosis Degrade and present processed antigens Dendritic Cells Similar functions as for macrophages See Slides 49 - 53 Erythrocytes: Red Blood Cells, carrying oxygen Megacaryocytes: Produce platelets for blood clotting Myeloid Lineage Myeloid Lineage (Kuby, See Figure 2-2 Hematopoiesis 6th Edition p. 25) Note roles of cytokines, Activated T-Helper Cells, And Activated Macrophages BloodCells1 BloodCells2 Histiocyte (Connective Tissue) Mesangial Cell (Kidney) Osteoclast (Bone) Myeloid to Monocyte Differentiation in the Myeloid Series to Monocyte Macrophage Lineage Tissue Macrophages Differentiation and Function in the Granulocyte Lineage Neutrophils: Eosinophils: Basophils and Mast Cells Differentiation and Function in the Granulocyte Lineage Neutrophils: Multi-lobed Nucleus (PMN) Polymorphonuclear Leucocyte 50% of circulating leukocytes. Short-lived (Hours or Days). Phagocytic Circulates, extravasates out of vasculature into tissue. Responds to chemotactic factors released by infection and inflammation (e.g. from complement or blood-clotting reactions or cytokines released by T-cells or macrophages). Granules release peroxidase, lysozyme, hydrolases, proteases, collagenase. Antimicrobial agents released. Part of innate natural immune response. Differentiation and Function in the Granulocyte Lineage Eosinophils: Acidic Granules Anti-parasitic immunity 1% of circulating leukocytes Phagocytic Basophils: Less than 1% of circulating leukocytes Non-phagocytic Degranulate to release substances supporting allergic attack Mast Cells: Similar to Basophils, but in tissue sites Secrete histamine in allergic attacks Erythropoetin ROS = Reactive Oxygen Species MIP-1a = Macrophage Inflammatory protein See Appendix III, p. C-1, 7th Edition Note Name Changes & Complexity See Slide Following from Science, 2015, 349, Nov. 2015 Neutrophils trails guide virus-specific CD8+ T cell migration. (CXCL12 is a chemokine: chemical agent attracting cell movement) Virus-specific Cytotoxic T-Cell Blebs containing CXCL12 from Uropod (Trailing membrane region) of Neutrophil “Bread-crumb” trail Kihong Lim et al. Science 2015;349:aaa4352 Cytotoxic T-Cell migration through trachea to virus-infected cells Published by AAAS Differentiation and Function in Monocyte/Macrophage Dendritic Cell Lineage Monocyte to Macrophage Macrophage (MPH or MO) Monocyte Monocyte to Macrophage Kuby, Immunology. 6th Edition Figure 2-7 MC&MPH Macrophage Ingesting and Degrading Bacterial Targets Kuby, Immunology, 6th Edition, Figure 2-8 Macrophage bacteria Antigen presentation MPHIngest Kuby, 4th Edition, p. 44 Macrophage Factors Cytokines Cytokine Cytokine Growth Factors MPhMake Macrophage and PMN Killing Kuby, 4th Edition, p. 43 Agents MPhKill Types of Antigen-Presenting Dendritic Cells. (Shown in Lymphoid Series in Slide 53) Dendritic Cells from Sci Am Dendritic and T-Cell Dendritic Cell micrograph Megakaryocyte – Platelet Lineage: Blood-Clotting Function Please put away all notes and any devices except for your Turning Point NXT Transmitter. No papers or computers on your desk please. No communication between or among students. Response Counter Ce1l 1 Response Counter Rank 1 2 3 4 5 6 Responses Response Counter To Here: Thursday October 27, 2016 Differentiation and Function in the Lymphocyte Series Cells of Lymphocyte Lineage B-Lymphocytes: Antibody receptors and antibody production T-Lymphocytes (Thymus-derived lymphocytes): T-Cell Receptors Helper T-Cells “CD4 positive” Cytotoxic T-Cells “CD8 Positive” Natural Killer Cells (“Non-B-Cell, Non-T-Cell Lymphocytes) Recognize virally infected or transformed cells Bind to antibody labelled cells as part of antibodydependent, cell mediated cytotoxicity (ADCC) Lymphoid Lineage Fig 2-1 Kuby 4th Ed p. 28 Natural Killer Cell (Non-B, Non-T Cell) Bone-marrow-derived lymphocyte (Makes Antibodies) Helper T-Cell (Helps B-Cell Differentiation) Promotes Cellmediated Immunity Committed Lymphocyte Progenitor Lymphocytes “Educated” in Thymus Cytotoxic T- Cell Promotes Humoral Immunity (Helps BCells make Ab’s & Itself Makes Cytokines) TH1 and TH2 RBC? Note size differences RBC???? Antigen-activated B- Cells Differentiated B-Cell; Makes Antibodies Natural Killer Cells • • • • Large Granular Lymphoctyes Part of innate natural immune response Usually without T-Cell Receptor or Membrane Antibody Recognize patterns of surface molecules or unusual expression of self-molecules (Class I MHC) • Have anti-tumor and anti-viral activity • CD16 Membrane Receptor for specific antibody regions gives Antibody-dependent cell-mediated cytotoxic activity • NKT Cells have TCR, – Bind to MHC-like molecules CD1 – Secrete cytokines See Appendix 1; Pages A1 to A29, Edition 7 350 CD Antigens on Leucocytes. What Cell Express Them What they do/ Differentiation Antigen Markers (CD Antigens) on Lymphocytes p. 34 Unique TCell Marker Unique TCell Marker Distinguishes Tc from TH Unique NK-Cell Marker Unique BCell Marker Unique TCell Marker Unique BCell Markers Unique NK-Cell Marker Used to identify sub-populations of lymphocytes and to isolate them Blood Cell Replacement Problems At the correct time: When cells are damaged, aged, or no longer functional or necessary. Replace with the correct cell type. In the correct number. Do not propagate errors arising during cell division. Blood Cell Survival Times and Turn-Over Erythrocytes (Red Blood Cells) ~ 4 Months Neutrophils 1 Day Lymphocytes Years White Blood Cell Generation 3.7 x 1011/day (50 x World Human Population per Day) Replacing Cells at the Correct time Getting Rid of Aged or Damaged Cells Without generating inflammation: Genetically Programmed Cells Death (Apoptosis) vs Inflammatory Lysis and Necrosis Genetically Programmed Cell Death: Apoptosis Cysteine – aspartate protease Bcl-2 gene: B-cell Leukemia associated gene Hematopoeisis and Leukemogenesis (Leukemia) What happens if damaged cells are not destroyed? What happens if Apoptosis is not invoked? Bcl-2 gene up-regulation in leucocytes leads to leukemia. (Strong inhibition of Apoptosis) FAS Gene or Caspase Genes down-regulated or lost in cells leads to leukemia and other cancer. (Failure to initiate or promote Apoptosis) “Caspase” = cysteine-aspartate proteaase Increasing this leads to failure of cell death and to leukemia Cysteine – aspartate protease Shutting these down leads to failure of cell death and to leukemia Bcl-2 gene: B-cell Leukemia associated gene Cytokines, Cytokine Receptors, and Normal and Pathological Cell Signaling How do the multiplicity of hematopoietic cells at distant sites in the host “talk” to one another? How do the cells “know” where to go and what to do? Cytokine Signaling and Cytokine Receptors in Normal Hematopoiesis and in Leukemia An Exercise In Cytokine Signaling and Cytokine Receptors Need persons who speak: Spanish Chinese Japanese (or Other?) Key Hematopoietic Growth Factors and Their Targets Relatively Multi-Specific: Granulocyte-Macrophage Colony-Stimulating Factor GMCSF Interleukin III - IL3 Relatively Mono-Specific: Granulocyte Colony Stimulating Factor - GCSF Macrophage Colony Stimulating Factor - MCSF Erythropoietin - EPO GrowFact Cytokine Table See Table 3-1 Kuby 3rd Ed. Autocrine stimulation (Self-Signaling) and the Generation of Leukemias and other Cancers See Figure 3-6 Kuby, 3rd Ed. Appendix II, Pages B1 to B6, 7th Edition 58 Cytokines from Interleukin 1 to Tumor Necrosis Factor Beta (TNF-B) Autologous Cells in Transplantation Medicine Stem Cell Therapy in Medicine Autologous Transplant Step 2 Step 1 Step 3 Stem Cell Transplantation in Medicine: (See pages 42-43, 7th Edition) Treatments with Stem Cells In Immune deficiency diseases In immuno-suppressed states Autologous Transplants Non-Self Donors Syngeneic Donors Allogeneic Donors Please put away all notes and any devices except for your Turning Point NXT Transmitter. No papers or computers on your desk please. No communication between or among students. 1. l Response Counter 0% 0% 0% 0% 0% 0% 0% 1. 2. 3. 4. 5. 6. 7. Response Counter 0% 0% 0% 0% 0% 0% 0% 1. 2. 3. 4. 5. 6. 7. 17% Response Counter 1. 17% 2. 17% 17% 17% 3. 4. 5. 17% 6. To Get to Animations & Molecular Visualizations Produced for Kuby Immunology http://bcs.whfreeman.com/immunology6e/ (Or search “Kuby Immunology”, Click on “Kuby Immunology 6e” , go to Student Resources) Animations Chapter 2: Cells; Cell Death Chapter 10: Cell Death Chapter 11: Signal Transducton Chapter 13: Leucocyte Extravasation Molecular Visualization Chapter 2: Cells and Organs Chose Other Chapters for Other Molecular Visualization Edition 6 (2007) :Appendix 1: Pages A1 to A26 339 CD Antigens on Leucocytes Edition 7 (2013): Apendix 1: Pages A1 to A29 350 CD Antigens on Leucocytes What cells types express them What they do e.g. CD4 is a co-receptor on helper T-cells. Confirms binding of T-Cell with its T-Cell Receptor to an antigen-presenting cell. Please put away all notes and any devices except for your Turning Point NXT Transmitter. These responses are set at anonymous so we won’t know what any student says How Well Are You Following What is Being Presented so Far in theCourse? (This will be set to anonymous so you will not be identified and your response will not be graded) 1. 2. 3. 4. 5. I’m totally lost. I’m having hard time, but I follow some of it. I’m OK. I can figure most of it out later. I’m following very well. There is no problem with the level of the course. This isn’t pitched at a level appropriate for an upper division undergraduate course. Please move to a higher level of challenge. Response Counter What is your evaluation of the course so far? (This will be set to anonymous so you will not be identified and your response will not be graded) 1. 2. 3. This course is below average for a Biology Department course at the 400 level. It needs to be improved in presentation and content. This course is about average for a Biology Department course at the 400 level. This course is actually pretty good for a Biology Department course at the 400 level. Response Counter