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Immunology Cancer and Medical Treatments Autoimmune Disease www.kind.med.tu-muenchen.de Hypersensitivity Infectious Diseases www.lytnyc.com Immunology Bach J. N Engl J Med 2002;347:911-920. Immunity Immunity: from immunis = exempt -> individuals who had recovered from certain infectious diseases will not contract the disease again Vaccine: from vacca (= cow), term coined by Pasteur in honor of Jenner’s cowpox/chicken pox studies Herd immunity: When a critical mass is immune to an infection, this infection is less likely to spread to individuals who are not immune Bendall et al., Science 2011 Cells and Organs innate PRRs: pattern recognition receptors; detect PAMPs: Pathogen-associated molecular patterns adaptive Rearranged and edited receptors: Incredibly high diversity Adapts to better recognize, eliminate, and remember Physical and chemical barriers Dranoff, Nat. Reviews Cancer 2004 Communication through cytokines Hematopoiesis www.dentalarticles.com The Adaptive Immune System Cellular immune responses: T cells Antigen presentation CD4 T cell help Humoral immune responses B cells T cells Adaptive Immune Cells http://cancerlabtechperspective.blogspot.dk/ Lymphocyte receptors Adaptive Immune Cells http://www.sbs.utexas.edu/sanders/Bio347/Lectures/2006 T cells Adaptive Immune Cells Recognize peptides of a specific length presented by antigen-presenting cells on MHC molecules T helper cells and cytotoxic T cells (CD4 and CD8), ratio ~ 2:1 CTL: eliminates cells that display foreign antigens complexed with MHC class I TH1: help the immune response against intracellular pathogens TH2: help the immune response against extracellular pathogens TH17: help cell-mediated immunity and the immune response towards fungi TFH: help humoral immunity Treg: inhibit immune responses All these subsets fulfill their functions to a large extent by secreting specific sets of cytokines that drive special arms of the immune system T cells Adaptive Immune Cells O'Shea and Paul. 2010. Science B cells Adaptive Immune Cells http://cancerlabtechperspective.blogspot.dk/ B cells Adaptive Immune Cells • B cells can recognize soluble or particulate antigen • Plasma cells secrete 100s – more than 1000 immunoglobulin molecules per second! • Can undergo somatic hypermutation and class switching (affinity maturation) Georgio et al., Nat Biotechnology 2014 B cells Adaptive Immune Cells Georgio et al., Nat Biotechnology 2014 Tan et al., JCI 2014 B cells Adaptive Immune Cells Hematopoiesis www.dentalarticles.com NK and NKT cells NK cells • 5-10% of all lymphocytes • Efficient cell killers by releasing cytotoxic granules • Recognize the absence of MHC class I on target cells • Express antibody receptors -> leads to decoration of antibodies: when those bind to target, the NK cells is triggered to release its cytotoxic contents NKT cells • Carry TCRs and sometimes CD4 • Recognize specific lipids and glycolipids presented by CD1 • Carry antibody receptors • Can release granules and many cytokines (stimulatory as well as inhibitory) • Apparently involved in asthma, but inhibitory in cases of autoimmunity and cancer Vivier et al., Science 2011 Hematopoiesis www.dentalarticles.com Innate Immune Cells - Granulocytes Neutrophils: • Frontline attackers during an immune response • Multi-lobed nuclei • Carrying tons of granules containing proteins such as cytokines and antimicrobial peptides • • • • • 50-70% of circulating leukocytes Leukocytosis due to transient increase of neutrophils -> indication of infection Phagocytose pathogens Secrete cytokine, antimicrobial and tissue-remodeling inducing peptides, and others Dominant first responders and main cellular component of pus Eosinophils: Neutrophil Basophil • • • • 1-3% of circulating leukocytes Phagocytic, but not to the same extent as neutrophils Mostly important in worm defense, role in asthma and allergy Secrete cytokines, incl. Chemokines, and proteases Basophils: • • • • • <1 % of circulating leukocytes Nonphagocytic Release basophilic protein in response to antibody-binding Histamine: increases blood vessel permeability and smooth muscle activity Critical in the defense towards parasites (helminthes) and drivers of allergic reactions Mast cells: Mast cell Eosinophil • • • • • <1% of circulating leukocytes Mature in the tissues Histamines and other pharmacologically active compounds Involved in allergies Relationship to basophils not fully clear Hematopoiesis Dendritic cell www.dentalarticles.com Innate Immune Cells – professional antigen-presenting cells Monocytes and Macrophages, Dendritic Cells • Can recognize and respond to pathogens • Secrete proteins that attract and stimulate other immune cells • Phagocytose and digest pathogens to present peptide on their surface to lymphocytes • Express co-stimulatory molecules From: animatedhealthcare.com Innate Immune Cells – Activation Kaufmann, Nat. Reviews Microbiology 2007 Innate Immune Cells – Monocytes and Macrophages Monocytes • 5-10% of white blood cells • Heterogenous: migrate to tissues and give rise to multiple phagocytic cells, such as macrophages and dendritic cells • Inflammatory monocytes and patrolling monocytes Macrophages • Inflammatory macrophages with dual role: phagocytosis and antigen presentation • Other macrophages are long-term residents in tissues and help repair and regeneration • Osteoclasts: bones, Microglial Cells: brain, Alveolar macrophages: lung, Kupffer cells: liver • Opsonization From: www.vet.uga.edu Dendritic Cells DCs are key sentinel cells that possess distinct “stellate” morphology and unparalleled ability to stimulate naïve T cells (Steinman 2007) • Arise from myeloid and lymphoid progenitors • Can take up antigen in one location and present it in another • Phagocytosis, receptor-mediated endocytosis, pinocytosis • Activation leads to loss of phagocytic activity and gain of antigen presentation capability, as well as migration From: amaltherapeutics.com Antigen presentation Signal 1: TCR stimulation Signal 2: Costimulation Signal 3: Cytokines Antigen presentation Harding and Boom, Nat. Reviews Microbiology, 2010 Subramanian and Tabas, Nat. Imm. News and Views, 2014 Hansen and Bouvier, Nat. Reviews Imm., 2009 Networks in Immunology Primary lymphoid organs – Bone Marrow Supports stem cell self-renewal and differentiation into all myeloid and erythroid cells and B cells Is a pool for fully mature memory cells, such as plasma cells Osteoblasts: generate bone and control the differentiation of HSCs Endothelial Cells: line the blood vessels, regulate HSC differentiation Reticular Cells: send processes connecting cells to bone and blood vessels Sympathetic neurons: control the release of hematopoietic cells from the BM Lymphoid and myeloid cells mature in environmental micro-niches Endosteal niche: Occupied by quiescent HSC in close association with osteoblasts Vascular niche: Occupied by HSCs that have been mobilized to differentiate or circulate Primary lymphoid organs - Thymus Supports T cell development, place of T cell selection Immature T cells: thymocytes Corticomedullary junction: T cell precursors enter the thymus and mature single-positive T cells exit the thymus Subcapsular Cortex: double-negative T cell precursors proliferate and begin to assemble TCR Cortex: contains double-positive T cell precursors with functional TCR and CD4 and CD8 contains cortical thymic epithelial cells to test MHC-peptide complex binding Positive selection: Survival, maturation and migration to the medulla of T cells that recognize self MHC-peptides with intermediate affinity Medulla: T cell maturation Contains medullary thymic epithelial cells for negative selection of potentially dangerous T cell clones Negative selection: cell-death of T cells that bind self-MHC complexes too high Secondary lymphoid organs (SLOs) • Spleen, lymph nodes, mucosa-associated lymphoid tissues (tonsils, peyer’s patches, appendix,…) • Contain anatomically distinct regions of B- and T-cell activity • Contain follicles for B-cell development and selection • Most cells enter SLOs from the blood through high endothelial venules and leave them through the lymphatics • Antigen and antigen presenting cells enter SLOs through the lymphatics (except spleen – only served by blood!) • Cell movement in the lymph is directed by chemokines Secondary lymphoid organs – spleen • Specialized in filtering blood and trapping blood-borne antigens • Not supplied by lymphatic vessels • Red pulp: Red blood cell graveyard • White pulp: lymphocyte rich • Marginal zone: populated by a unique set of macrophages and B cells -> first line of defense galleryhip.com 1. Antigens and lymphocytes come in through the splenic artery and interact first with the marginal zone 2. Antigens get processed by dendritic cells 3. Dendritic cells travel to PALS 4. Antigen presentation to lymphocytes in PALS 5. Activated lymphocytes leave through splenic vein Secondary lymphoid organs – Lymph Nodes (LNs) Networks of stromal cells packed with lymphocytes, macrophages, and dendritic cells Cortex: Mostly B cells, macrophages, and follicular dendritic cells organized in follicles Antigen comes in through afferent lymphatics Paracortex: Mostly T cells and dendritic cells that migrated from the tissues Medulla: Most inner layer, lymphocytes exit the LNs here through efferent lymphatics Some plasma cells that actively secrete antibodies Swartz and Lund, Nat Reviews Cancer, 2013 Secondary lymphoid organs – Lymph Nodes (LNs) T cells in the LNs: Low peptide: green High peptide: blue DCs: red • T cells probe DCs for antigen in the LN • Stable contacts are formed when a stimulation threshold is reached • Stable contacts lead to T cell activation Henrickson et al., Nat. Immunology 2008 Secondary lymphoid organs – Lymph Nodes (LNs) B cell migration pathways within follicles during early activation. 1: CXCR5 2: CXCR5, CCR7 3: CXCR5, Ebi2 4: CXCR5, Ebi2 3 4 2 1 Pereira et al., Nature 2009 Islam and Luster, Nat. Med. Reviews 2012 The Multistep model of lymphocyte migration Fibroblastic reticular cells Capillary endothelial cells High endothelial cells Selectin-mediated Rolling 1 Activation 2 1 Firm adhesion 2 3 Diapedesis 4 3 Selectin Chemokine receptor Inactive/active integrin Addressin Chemokine Adhesion molecule