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

SENSINGRECOGNITION SIGNALING RESPONSE INNATE IMMUNITY CellsReceptors Signaling pathways Cell-Cell collaboration Effector functions DEFENSE SYSTEMS ADAPTIVE IMMUNITY SENSINGRECOGNITION SIGNALING RESPONSE

3. FUNCTION Defense against pathogens Recognize, prevent spread, clear from the body Protection of self 2. ACTION – dynamic Homeostasis – environmental factors Replacement vs death Activation vs differentiation Th GENERAL FEATURES OF THE IMMUNE SYSTEM 1.STRUCTURE – various cell types, diffuse Cell communication Partners Mode– direct – soluble factors macrophage extracellular matrix Adhesion Homing Migration macrophage pathogen B Cell – to – cell communication 4. SPECIAL FEATURES Recognition – self - antigen - danger Signal processing and transduction Signal storage – learning, memory SIMILARITIES TO THE NERVOUS SYSTEM

IMMUNE CELL OTHER CELL TYPES IMMUNE CELL Direct cellular interactions Receptor – ligand Adhesion Signal transduction Indirect cellular interactions Soluble molecules Cytokines, chemokines CELLULAR INTERACTIONS AND COMMUNICATION IN THE IMMUNE SYSTEM ENVIRONMENTENVIRONMENT

Neutrophil granulocyte Bacteria neutrophil Endothelial cell Inflammed tissue NEUTROPHIL MIGRATION FROM THE BLOOD TO THE INFLAMMED TISSUE

How immune cells communicate? Cell surface molecules mediate cell-cell contact 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. Resting cells Activated cells INDUCEDUPREGULATED

Infection Phagocyte activation How immune cells communicate? Soluble mediators CYTOKINES & CHEMOKINES 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 INFLAMMATION 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.

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. T CTL T B Y Ab production Accessory cell activation Antigen presentation Target cell Killing

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 sensingNutrient sensing Energy efficiency Energy storage Energy surplus Metabolic syndromeMetabolic syndrome Metabolic syndrome A cluster of conditions, such as hypertension, hyperinsulinaemia, hypercholesteraemia and abdominal obesity, that occur together, increasing the risk of heart disease, stroke and diabetes. Pathogen sensingPathogen sensing Food deprivation Defense against pathogens High energy expenditure Impaired immune responses Chronic inflammationChronic inflammation METABOLIC HOMEOSTASIS – PROPER IMMUNE SYSTEM Hotamisligil & Erbay NRI 2008

IMMUNE RESPONSE ReproductionThermoregulationLactation HIGHEST ENERGY CONSUMING SYSTEMS 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

Gene expression largely overlaps between macrophages and adipocytes.

LIPID SENSING PATHWAYS AND INFLAMMATION Hotamisligil & Erbay NRI 2008 Increased amounts of fatty acids ER stress UPR Modulation Nuclear hormone receptors UPR

SENSINGRECOGNITION SIGNALING RESPONSE INNATE IMMUNITY CellsReceptors Signaling pathways Cell-Cell collaboration Effector functions DEFENSE SYSTEMS ADAPTIVE IMMUNITY SENSINGRECOGNITION SIGNALING RESPONSE

HOW INNATE AND ACQUIRED IMMUNITY RECOGNIZE PATHOGENS? 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 RECEPTORS Innate immunity Ancient Unique structural elements Antigenic determinant Recognition by highly specific antigen receptors B cell receptor BCR (sIg) T cell receptor TCR 450 million years Acquired immunity Several millions antigen receptors

CELLS HUMORAL FACTORS Phagocytes monocyte/macrophage, Neutrophil, monocyte/macrophage, dendritic cell Killer cells (NK cell,  δ T cell) B1 lymphocytes (CD5+) Enzymes (lysozyme,transferrin, lactoferrin, spermin, trypsin) Antibacterial peptides Complement system Cytokines, chemokines TWO LINES OF IMMUNE DEFENSE INNATE/NATURAL IMMUNITY 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

ACQUIRED/ADAPTIVE IMMUNITY CELLS HUMORAL FACTORS Phagocytes monocyte/macrophage, Neutrophil, monocyte/macrophage, dendritic cell Killer cells (NK cell,  δ T cell) B1 lymphocytes (CD5+) Enzymes (lysozyme,transferrin, lactoferrin, spermin, trypsin) Antibacterial peptides Complement system Cytokines, chemokines INNATE/NATURAL IMMUNITY TWO TYPES IMMUNE RESPONSES B-lymphocytes (B2) T-lymphocytes helper T-cells cytotoxic T-cells regulatory T-cells Antibodies 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 ACQUIRED/ADAPTIVE IMMUNITY Requires the activation and clonal expansion of cells to protect against pathogens First line of defense Inherited Always present Induced by antigen Response is under genetic control Depends on environmental stimuli

FUNCTIONAL ATTRIBUTES OF INNATE AND ADAPTIVE IMMUNITY

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 Chapter 1 © Garland Science 2009 Elements of the Immune System and their Roles in Defense

FIRST LINE OF DEFENSE BY INNATE IMMUNITY EPITHELIAL CELLS Pattern recognition receptors (PRR) Cytokine, chemokine secretion NEUTROPHIL GRANULOCYTES Phagocytosis Intracellular cytotoxicity MONOCYTE – 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 (PRR) Macrophage & dendritic cell subsets Neutrophils Pro-inflammatory and inflammatory cytokine secretion Local effects Systemic effects Chemokine receptors & ligands – cell recruitment, other functions Cytotoxicity – NK cells

α2 macroglobulin is an inhibitor of potentially damaging proteases A molecular mousetrap About 10% of serum proteins are protease inhibitors

Anti-microbial peptides- DEFENSINS a aa amphipathic peptides b.Disrupt structure of microbial membranes c.High variability within the human and show rapid evolution d.Ongoing race between pathogens and the immune system of the host