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Cellular Components of the Immune Response: Stem Cells and Stem Cell Transplantation Folder Title: Cells Updated: October 21, 2013 Filename: Cells.ppt 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. Rank 17% 17% 17% 17% 5 17% 4 I distributed a one-page copy of a Science note at the last class on Thursday the 17th. What was the Science note about or what was its title? (If you were not in class last Thursday please state that in your response.) 17% Responses 1 2 3 4 5 6 Response Other 6 3 2 1 Counter Rank 17% 17% 17% 17% 5 17% 4 If a pharmaceutical agent has a name that ends in “mab”, what does that tell you about the agent? 17% Responses 1 2 3 4 5 6 Response Other 6 3 2 1 Counter Immune System Make-up From 447Intro, Slides 54 and 55 Morphology & Staining of Blood Cells Kuby, 3rd Ed. Figure 3-1 ImmCells 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 normal? Blood Counts “RBC” “WBC” 5x109/ml blood 7.3x106/ml blood Ratio RBC to WBC = 685:1 “WBC” = White Blood Cells (Leucocytes) See Table 2-4, p. 30, Kuby 6th Edition Mouse Whole Blood with Human Leukemia Cells Added at ~0.5% Diluted 1:500 for Counting 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) 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. 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 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) Replacing Cells at the Correct Time with the Correct Cell Type Where Do the Blood Cells Come From? Stem Cells and Partially Differentiated Progenitor Cells Stem Cell Therapy in Medicine 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. It takes 200,000 cells to restore viability in the lethally irradiated mouse at the top, but only 1,000 cells are required for the mouse at the bottom? Why is that? Isolation of CD34+ Pluripotent Stem Cells from Mixed Bone Marrow Mononuclear Cells Using Monoclonal Antibody to CD34 Marker on Stem Cells CD34 Purification of Stem Cells See Figure 3-9 Kuby, 3rd Ed. Antibody conjugated to Biotin. Avidin coats insoluble beads Biotin Sticks Strongly to Avidin Stem Cell Transplantation in Medicine: In Immune deficiency diseases In immuno-suppressed states Autologous Transplants Syngeneic Donors Allogeneic Donors Autologous Transplant See p.38 Kuby, 4th Ed. Pluripotent Stem Cell and Lymphoid and Myeloid Lineages (Fig 2-1, Kuby 4th Ed. p. 28 StemCell Myeloid Stem Cell Hematopoiesis (formation of blood cells) Fig 2-1, Kuby 4th Ed. p. 28 HematoAll Lymphoid Lineage Fig 2-1 Kuby 4th Ed p. 28 Lymphoid 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) Differentiation Antigen Markers (CD Antigens) on Lymphocytes p. 34 Used to identify sub-populations of lymphocytes and to isolate them Appendix 1: Pages A1 to A26 339 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. 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 Hematopoiesis Hematopoiesis (formation of blood cells) Fig 2-1, Kuby 4th Ed. p. 28 HematoAll 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 Denedritic Cells Similar functions as for macrophages (Note “Follicular Dendritic Cells, p. 40) Different from bone-marrow derived dendritic cells Erythrocytes: Red Blood Cells, carrying oxygen Megacaryocytes: Produce platelets for blood clotting Myeloid Lineage Myeloid Lineage (Kuby, Fig 2-1, 4th Ed., p. 28. See Figure 2-2 Hematopoiesis 6th Edition p. 25) Differentiation in the Monocyte Macrophage Lineage Myeloid to Monocyte Tissue Macrophages BloodCells1 BloodCells2 Histiocyte (Connective Tissue) Mesangial Cell (Kidney) Osteoclast (Bone) 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 MPhMake Dendritic Cells from Sci Am Dendritic and T-Cell Dendritic Cell micrograph Types of Antigen-Presenting Dendritic Cells. Rank 1 2 3 4 5 6 Responses 17% 17% 17% 17% 3 4 17% 17% Other 1 2 5 6 Differentiation and Function in the Granulocyte Lineage Neutrophils: Eosinophils: Basophils and Mast Cells BloodCells2 Histiocyte (Connective Tissue) Mesangial Cell (Kidney) Osteoclast (Bone) 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. Macrophage and PMN Killing Kuby, 4th Edition, p. 43 Agents MPhKill 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 A leukemia in the monocyte-macrophage lineage would be a(n) ______________ leukemia Erythro Myeloid NK Lymphocytic T-Cell Innate Stem Cell Ce ll 0% St em at e 0% In n TC m ph 0% ell 0% oc yt ic K 0% N Response Counter 0% Er yt hr o M ye lo id 0% Ly 1. 2. 3. 4. 5. 6. 7. Cytokine Signaling and Cytokine Receptors in Normal Hematopoiesis and in Leukemia Myeloid Leukemia See Figure 3-6 Kuby, 3rd Ed. Kuby, 4th Edition, p. 44 Macrophage Factors MPhMake 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. TH1 and TH2 Appendix II, Pages A27 to A31 52 Cytokines from Interleukin 1 to Tumor Necrosis Factor Beta (TNF-B) If a potentially dividing cell with a cell division growth factor receptor in its membrane also produces the growth factor itself, the cell is likely to 2. 3. 4. 5. 0% 0% 0% 0% 0% 0% D Response Counter iff er en tia te a nd 6. Differentiate and enter a resting state Secrete antibodies Generate an auto-immune response Degranulate Proliferate without outside control Enter apoptosis and die en Se te G ra cr en et ... er ea at n ea tib n od au ie to s -im Pr m ol un ife D ... eg ra ra te nu wi th la En te ou te t ra ou po ts id pt ... os is an d di e 1. 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 An Exercise in the Unification of the Human Family in the Digital Age…. Search Maria Sophia and Violanda To Get to Molecular Visualizations Produced for Kuby Immunology http://bcs.whfreeman.com/immunology6e/ Or search “Kuby Immunology”, Click on “Kuby Immunology 6e” , go to Student Resources (This question is set to anonymous. Your name will not be linked to your answer) Are You Registered to Vote? 1. 2. 3. 4. Yes No None of your business Not eligible to vote in the United States I am here! 1. Yes 2. No Also try message to leader o N Y Response Counter es The next slide is a time to respond slide. This is designed in response to complaints about students consulting their notes or each other. We’ll try it out to see how it works, but I think this puts students for whom English is not their primary language at a disadvantage. 0% 0% An Exercise In Cytokine Signaling and Cytokine Receptors