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GENERAL CHARACTERIZATION OF THE IMMUNE SYSTEM MAJOR TASK MAINTAIN THE BALANCE OF THE HOST’S IMMUNE SYSTEM WITH THE ENVIRONMENT Commensal and pathogenic microorganisms Other environmental effects GENERAL FEATURES OF THE IMMUNE SYSTEM 1. STRUCTURE – various cell types, diffuse Cell communication Th Partners Mode macrophage – direct pathogen – soluble factors B extracellular matrix macrophage Cell – to – cell communication 2. ACTION – dynamic Homeostasis – environmental factors Adhesion Homing Migration Replacement vs death Activation vs differentiation 3. FUNCTION 4. SPECIAL FEATURES Recognition – self - antigen - danger Defense against pathogens Recognize, prevent spread, clear from the body Signal processing and transduction Signal storage – learning, memory Protection of self SIMILARITIES TO THE NERVOUS SYSTEM CELLULAR INTERACTIONS AND COMMUNICATION IN THE IMMUNE SYSTEM ENVIRONMENT IMMUNE CELL Indirect cellular interactions Soluble molecules Cytokines, chemokines IMMUNE CELL OTHER CELL TYPES Direct cellular interactions Receptor – ligand Adhesion Signal transduction ENVIRONMENT NEUTROPHIL MIGRATION FROM THE BLOOD TO THE INFLAMMED TISSUE neutrophil Endothelial cell Neutrophil granulocyte Bacteria Inflammed tissue How immune cells communicate? Cell surface molecules mediate cell-cell contact Resting cells Activated cells INDUCED UPREGULATED Expression and level of expression controls cell-cell adhesion Activation can induce expression. Cell adhesion, migration, antigen specificity, antigen presentation, costimulation, helper function, effector function. Cell surface molecules influenced by activation include cytokine receptors. How immune cells communicate? Cell-cell contact Peripheral lymphoid tissues trap antigen-containing phagocytic cells and concentrate cells together to promote cell-cell contact. Cell-cell contact occurs at many stages of immune responses. Killing CTL Target cell T Y Antigen presentation B T Ab production Accessory cell activation How immune cells communicate? Soluble mediators Infection CYTOKINES & CHEMOKINES Phagocyte activation INFLAMMATION Diverse collection of soluble proteins made by cells that affect the behaviour of other cells. The balance & level of cytokines and chemokines secreted affects the outcome of the response Early events involve endothelial cells and result in the accumulation of fluid, plasma proteins & leucocytes. Later events involve the activation and maturation of lymphocytes and granulocytes. INTEGRATION OF METABOLISM AND IMMUNITY Evolutionary need for survival Parallel development of organ systems & signalling pathways Phagocytosis – nutrition & protection agains harmful material Fat body of Drosophila Liver, adipose tissue & lymph nodes of mammals • • • • • Nutrient sensing Energy efficiency Energy storage Energy surplus Metabolic syndrome • • • • • • Pathogen sensing Food deprivation Defense against pathogens High energy expenditure Impaired immune responses Chronic inflammation METABOLIC HOMEOSTASIS – PROPER IMMUNE SYSTEM Hotamisligil & Erbay NRI 2008 HIGHEST ENERGY CONSUMING SYSTEMS Reproduction Thermoregulation Lactation IMMUNE RESPONSE Loss of apetite – induction of leptin synthesis Usage of local energy and nutrient stores Chronic nutrient deficiency or overnutrition lead to pathological relationships Pre-adipocytes – Macrophages – Adipocytes – Dendritic cells SHARED GENES IN PHYSIOLOGICAL CONDITIONS & METABOLIC DISEASE STATES LIPID SENSING PATHWAYS AND INFLAMMATION Increased amounts of fatty acids UPR ER stress UPR Nuclear hormone receptors Modulation Hotamisligil & Erbay NRI 2008 DEFENSE SYSTEMS ADAPTIVE IMMUNITY INNATE IMMUNITY SENSING Cells SENSING RECOGNITION Receptors RECOGNITION SIGNALING Signaling pathways SIGNALING Cell-Cell collaboration RESPONSE Effector functions RESPONSE HOW INNATE AND ACQUIRED IMMUNITY RECOGNIZE PATHOGENS? RECEPTORS Common patterns of pathogen groups Pathogen Associated Molecular Pattern PAMP Recognition by receptors Pattern Recognition Receptor PRR Toll-receptor family (9 - 13) Lectin family, scavenger receptors Innate immunity Ancient Unique structural elements Antigenic determinant Recognition by highly specific antigen receptors B cell receptor BCR (sIg) T cell receptor TCR Several millions antigen receptors Acquired immunity 450 million years TWO LINES OF IMMUNE DEFENSE INNATE/NATURAL IMMUNITY Phagocytes Neutrophil, monocyte/macrophage, dendritic cell Killer cells (NK cell, δ T cell) B1 lymphocytes (CD5+) CELLS Enzymes (lysozyme,transferrin, lactoferrin, spermin, trypsin) Antibacterial peptides HUMORAL Complement system FACTORS Cytokines, chemokines B1 cells: Fast response within 48 hrs T cell independent Surface IgM Long life span Peritoneal cavity γδ T-cells: skin, guts limited diversity Binds pathogen derived organic phosphates express NKG2D NKT-cells: fast response lipid antigens prompt cytokine release TWO TYPES IMMUNE RESPONSES INNATE/NATURAL IMMUNITY Phagocytes Neutrophil, monocyte/macrophage, dendritic cell Killer cells (NK cell, δ T cell) B1 lymphocytes (CD5+) ACQUIRED/ADAPTIVE IMMUNITY CELLS B-lymphocytes (B2) T-lymphocytes helper T-cells cytotoxic T-cells regulatory T-cells Enzymes (lysozyme,transferrin, lactoferrin, spermin, trypsin) Antibacterial peptides HUMORAL Complement system FACTORS Antibodies Cytokines, chemokines MUTUAL COLLABORATION TWO LINES OF IMMUNE DEFENSE INNATE/NATURAL IMMUNITY Innate immunity constitutes components that protect against infection without any requirement for prior activation or clonal expansion First line of defense Inherited Always present ACQUIRED/ADAPTIVE IMMUNITY Requires the activation and clonal expansion of cells to protect against pathogens Induced by antigen Response is under genetic control Depends on environmental stimuli FUNCTIONAL ATTRIBUTES OF INNATE AND ADAPTIVE IMMUNITY Chapter 1 Elements of the Immune System and their Roles in Defense • The innate immune response causes inflammation at sites of infection • The adaptive immune response adds to an ongoing innate immune response • Potent immune responses require the collaboration of innate and adaptive immune responses © Garland Science 2009 CONTACT SURFACES GASTROINTESTINAL SYSTEM Physical, chemical, biological borders EYE AIRWAY SYSTEM Sinuses Trachea Lungs Oral cavity Esophagus Stomach Alimentary tract UROGENITAL SYSTEM SKIN Kidney Bladder Vagina WALDEYER RING Tonsils, adenoids Palatinal, pharyngeal lingual and tubar tonsils Demage Mucus Infection glycoproteins, proteoglycanes, enzymes FIRST LINE OF DEFENSE BY INNATE IMMUNITY EPITHELIAL CELLS •Pattern recognition receptors (PRR) •Cytokine, chemokine secretion NEUTROPHIL GRANULOCYTES •Phagocytósis •Intracellular cytotoxicity MONOCITE – MACROPHAGE – DENDRITIC CELL NETWORK •Pattern recognition receptors (PRR) •Internalizing receptors •Phagocytosis NATURAL KILLER CELLS •Cytoxicity •Cytokine production CELLS & MECHANISMS OF INNATE IMMUNITY Soluble proteins – Defensins Enzymes - Complement system - Chemotaxis Recognition by Pattern Recognition Receptors Macrophage & dendritic cell subsets Neutrophils Pro-inflammatory cytokine secretion Local effects Systemic effects Chemokine receptors & ligands – cell recruitment, other functions Cytotoxicity – NK cells