L#3 & #4: Immune Cells, Organs, and Innate Immunity
L#3 & #4: Immune Cells, Organs, and Innate Immunity 0530
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This 5 page Class Notes was uploaded by Denise Croote on Wednesday January 20, 2016. The Class Notes belongs to 0530 at Brown University taught by Dr. Richard Bungiro in Fall 2013. Since its upload, it has received 20 views. For similar materials see Principles of Immunology in Biology at Brown University.
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Date Created: 01/20/16
Lecture Three: Cells and Organs Immune cells develop in the primary lymphoid organs and they are activated in the secondary lymphoid organs The WBCs that mediate the immune response are called leukocytes. Leukocytes are continuously generated by hematopoiesis in the bone marrow Lymphocytes are a subset of leukocytes that mediate the adaptive immune response. They circulate through the body and enter the secondary lymphoid organs to await their pathogen. Blood is made up of plasma and of cells. The plasma is made up of mostly water, but also electrolytes, hormones, and proteins. The blood is made up of Erythrocytes (RBC) – Platelets – Leukocytes (WBC) Hematopoiesis: o Making new blood cells from self renewing stem cells o HSCs only make up about 0.05% of the bone marrow cells but can proliferate in times of stress, sickness, blood loss, or need o HSCs require help from stromal cells in the bone marrow – these cells provide a correct microenvironment o HSCs make progenitor cells, these are committed to a given cell lineage and cannot self renew. o These progenitor cells terminally differentiate into a population How do we sort out a population? o As cells develop they present differ clusters of differentiation (CD) antigens, these markers are targeted with monoclonal antibodies. Monoclonal antibodies bind to a particular surface molecule o For example.) CD3 CD antigens are found on Helper and Cytotoxic T cells. CD4 are nly found on T helper and CD8 are only found on cytotoxic T cells How can you enrich a cell population with HSCs? 1. Use antibodies to attach to differentiation antigens on cells that have already differentiated and then kill these cells (Negative selection) 2. Treat the remaining cells with antibodies designed to bind to antigens that are specifically on HSC cells (Positive selection) o You only need 30 to 100 HSCs to recover a completely irradiated mouse. Regulation of Hematopoiesis: The bone marrow contains osetoblasts, endothelial cells of blood vessels, reticular cells, and sympathetic neurons – each of these produce soluble factors that promote differentiation of HSCs. o There are also microenvironments in the bone marrow designed to compartmentalize the common developing HSCs. You can regularly donate blood because your HSC population replaces lost cells Bone marrow transplants are used for those who have a defective HSC because they can provide a new way to generate the immune system Lymphocytes: these B cells, T cells, and Natural Killer cells have different antigen recognition molecules (like Igs and TCRs) that mark pathogens o B cells produce immunoglobulin 1. Their cycle is: naïve B lymphocyte, antigen activation induces cell cycle entry G1 gene activation phase lymphoblast DNA synthesis cell division into a.) effector (plasma) cells or b.) memory cells o T cells have special TCRs o Natural Killers lack the Ig and TCR but they are involved in a cytotoxic response against tumors and infected cells o NKT Cells – express the typical NK receptors but also express some TCRs and can interact with MHCI Monocytes and Macrophages: present in the blood as monocytes and as macrophages in the tissues. They are involved in phagocytosis, tissue repair, antimicrobial activity, tissue repair, and antigen presentation. The can also secrete mediators to cue inflammation. o What is the difference? o Macrophages are formed from monocytes, bigger, have more lysosomes and other organelles, have increased phagocytic ability, and are activated by cytokines and microbial products During phagocytosis …… bacteria attach to the membrane called pseudopodia, are ingested forming phagosomes, fuse with lysosomes, digested by enzymes, and degraded products are released from the cell Granulocytes: 1. Neutrophils – these are phagocytic, short lived cells involved in the inflammatory response and antimicrobial activity. They can cause direct harm to pathogens and remodel damaged tissue. 2. Eosinophils – phagocytic, involved in anti-parasite defense, induce the formation of ROS and have some antiviral activity 3. Basophils/Mast Cells- non-phagocytic, bind the IgE but do not produce it, release mediators involved in allergy, mast cells are tissue dwelling basophilic cells Dendritic Cells: These are professional antigen presenting cells and have high levels of MHCII. The function in activating naïve T cells. They are present in several tissues. Follicular Dendritic Cells: These are DIFFERENT than dendritic cells. They are important in antigen retention and formation of germinal centers in lymph nodes. They do NOT come from the bone marrow or have MHCII. They bind antigen-antibody complexes and function in B cell development Primary Lymphoid Organs: o These are sites of FOREIGN antigen independent and SELF dependent growth Bone Marrow: proB cells preB cells mature naïve B cells o The major event B cells go through is the gene rearrangement and expression of antibodies, as well as positive and negative selection to eliminate potentially damaging antibodies Thymus: pro T cells pre T cells Mature naïve T cells o proT cells migrate from the bone marrow to the cortex o The major event is when the TCR undergo gene rearrangement and positive and negative selection o Thymus degrades with age Secondary Lymphoid Organs o These are sites of foreign Antigen DEPENDENT growth o Lymph Nodes: Drain and filter antigens from tissue fluids via the lymphatic vessels, upon exposure to an antigen these guys form lymphoid follicles Has a Follicle zone for B cells and a Paracortex zone for T cells Also has lymph vessels and blood vessels for transport o Spleen: Filters antigens from the blood, contains red and white pulp, it also forms lymphoid follicles and germinal centers. The periarterial lymphatic sheath (PALS) is populated by T cells and B cell follicles waiting to encounter an antigen All of the antigens enter through the splenic artery of the blood o Mucosal-Associated Lymphoid Tissue: located in the epitheliam mucosa of the gut and respiratory tract, there are more antibody secreting plasma cells in the malt than in the spleen, lymph nodes, and bone marrow combined Immune responses in the gut involve antigen transporting M cells and organized lymphoid structures called Peyer’s patches REVIEW of CELL LINEAGES Lymphoid • Natural killers Progenitor • B cells Cells • T cells HSC (Self renewing) • Macrophages and Myeloid Dendritic Cells Progenitor • Granulocytes (Neu, Cells Eos, Baso, Mast) • RBCs and Platelets BONE MARROW HSC proB preB B Lymph Or HCS proT BLOOD Nodes Spleen Thymus proT prêt T Malt Lecture Four: Innate Immune System Innate Immunity: includes anatomical barriers, phagocytosis, induced cellular innate responses, inflammatory responses, and natural killer cells. All vertebrate animals and multicellular organisms (including plants and insects) have an innate immune system Some key features of the innate immune response are that it: requires no prior exposure to the pathogen, it is independent of B and T cells, and it does not adapt or improve with exposure. The innate systems recognizes generic patters on pathogens and launches a response in minutes to hours It can nearly eliminate a pathogen but signals for the adaptive response to kick in and completely finish off the pathogen Once a pathogen enters the body the innate response can address it and the adaptive response can finish it off. Or the innate response can finish it off if it is weak. Or if there is no innate response than the innate response can address it but not be able to finish it off so it will exponentially grow. Or there will be no innate response and the infection will exponentially grow from the beginning. Some of the tricks of the anatomical barriers are….. o Their surfaces contain antimicrobial proteins and enzymes to degrade the pathogen o They have a low pH (acidic environment (stomach)) o They have sweeping motions of fluid flow to wash pathogens off the surface, like tears or like the intestines and throat that have mucus to prevent pathogens from latching on. For example.) psoriasin is an antimicrobial protein of the skin. It prevents the colonization by E.coli. You can test this in the lab by putting E.coli on one finger and another bacterium on another finger. After a little while if you press your fingers to the slides you will see that nothing comes off your E.Coli finger (because it has all been killed) but bacteria does come off of your other bacteria finger. Inflammation: 5 characteristic signs: redness, swelling, heat, pain, loss of function. o When the response is initiated, vasodilation increases blood flow so that more cells can come to the site of the injury and the vessels become permeable (because of the actions of the protin TNF alpha) so that the cells can leave them and surround the site. o Phagocytes usually come and engulf the bacteria, and neutrophils are among the first to arrive. o There is an accumulation of extra fluid and the release of mediators that will cue the adaptive response. The mediators are commonly cytokines and chemoattractants. Phagocytosis: pseudopodia are membrane extensions that attach to the bacteria to initiate the engulfing process, and lysosomes degrade shortly after Innate cells (like phagocytes) pick up on pathogens either by binding directly with pattern recognition receptors, or by binding with opsonin receptors. Opsonin receptors bind to opsonins which have bound to the host protein. Antimicrobial Proteins: there are over 800 but the most effective in humans are defensins. These kill species of bacteria by disrupting their microbial membranes. They can be produced by neutrophils, intestine cells, and epithelial cells of the pancreas and kidney Pattern Recognition Receptors: these are activated by the presence of PAMPS on pathogens- Pamps are necessary for the pathogens to survive, therefore most have them. o PRRs once bound are very good at activating the complement system, inducing the innate response, and inducing opsonization (which describes the process where something (like an antibody) binds to an antigen to enhance its visibility as a pathogen.) o Our own body has a PAMP like equivalent – this is a DAMP and they are released by dead or dying cells to initiate a clearing response even in the absence of infection o Dendritic cells and macrophages use PRR to bind to PAMP and DAMPS and from there they may increase their phagocytosis, release some cytokines, or start some antigen processing and presentation The Complement System aids in innate and adaptive immunity, the complement system is comprised of serum proteins and these serum proteins can phagocytosis, lyse, and trigger the activation of the inflammatory response with some of their byproducts. PAMPS LPS and pepidoglycan are important PAMPS found on bacteria cell walls PRR TYPES: o Toll Like Receptors (TLRs) – these are named after the receptors found in flies known to protect against fungal infection. It was found that there were similar receptors in humans. Mice who have mutant TLRs are not affected by the introduction of LPS, a PAMP that would normally initiate a response. TLRs can recognize a variety of microbial proteins beyond LPS The cascade once a TLR is activated is as follows: the microbial protein binds to the LRR domain, the adaptor proteins on the TIR domain are activated, some sort of phosphorylation that results in the initiation of an enzyme cascade that results in the activation of immune genes o CLRs these are plasma membrane receptors that recognize carbohydrates o RLRs soluble PRR that recognize viral RNA o NLRs cytosolic receptors for intracellular PAMPS, these can cluster together to form a inflammasome and an inflammasome can trigger a procytokine to turn into an active cytokine MAJOR LEUKOCYTES OF INNATE IMMUNITY o 1.) neurtrophils – they phagocytosis, and produce ROS and antimicrobial proteins o 2.) Macrophages- same as above in addition to producing inflammatory mediators, antigen present, and activating complement proteins o 3.) Dendritic Cells – they produce ROS and antimicrobial proteins, they antigen present, and they release cytokines o 4.) NK cells – they lyse viral infected cells and activate interferons (interferons are just cytokines that induce and antiviral state) All of these cytokines that are released by the innate immune system can activate the adaptive response. Common cytokines that do this are IL1, IL6, TNF alpha Pathogens can mutate so that they are not recognized by TLRS, they can block PRR signaling pathways, preventing the activation of the adaptive immune response, and can prevent themselves from being killed or inhibited. *** this is why we need an adaptive system – we need to be able to change with the changing pathogens
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