Innate Immune Response (Ch14). Although the complement system has traditionally been considered part of the innate immune system, research in recent decades.

Innate Immune Response (Ch14) Although the complement system has traditionally been considered part of the innate immune system, research in recent decades has revealed that complement is able to activate cells involved in both the adaptive and innate immune response. Complement triggers and modulates a variety of immune activities and acts as a linker between the two branches of the immune response. In addition, the complement system maintains cell homeostasis by eliminatiing cellular debris and immune complexes. Katie Ris-Vicari To microbes, human body is nutrient-rich But most of our internal systems are sterile (gut doesnt count) Innate immunity is routine protection Skin, mucous membranes prevent entry Sensor systems detect invaders, general microbe pattern recognition Adaptive immunity develops throughout life: antigens cause response, system produces antibodies to bind Can also destroy host cells Immune System: Innate and Adaptive Immunity Overview of Innate Defense System First lines of Defense Physical Barriers Skin Mucous membranes Antimicrobial substances Lysozyme Peroxidase enzyme Lactoferrin Defensins Normal Flora Physical Barriers: bodys borders Skin Difficult to penetrate Dermis: tightly woven fibrous connective tissue Epidermis: many layers of epithelial cells Outermost are dead, filled with keratin Repels water, Continually slough off along with any attached microbes Nucleus Basement membrane Connective tissue Stratified epithelium Skin (the outer cell layers are embedded with keratin) Lining of the mouth, vagina, urethra, and anus Columnar epithelium Passages of respiratory system Various tubes of the reproductive systems Mucus- producing cell Cilia Columnar cell Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Skin as the first line of defense Intact skin protects Epidermis Dermis First-Line Defenses Physical Barriers (continued) Mucous Membranes line the inside of the body Digestive, respiratory, genitourinary tracts Constantly bathed in secretions (e.g., mucous) Peristalsis of intestines, mucociliary escalator of respiratory tract remove microbes Eye Respiratory tract Digestive tract Urogenital tract Skin Mucous membranes Skin Anus Mouth Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Ciliated cells are importantwhere? Antimicrobial Substances Protect skin, mucous membranes Salt on skin Lysozyme degrades peptidoglycan Peroxidase enzymes break down hydrogen peroxide Lactoferrin binds iron Defensins form pores in microbial membranes Acid in stomach (low p H) Normal microbiota Flushing of urinary tract pH and normal microbiota of vagina Rapid pH change from stomach to upper intestine Removal of inhaled particles Lysozyme in tears and other secretions and in phagocytes Antimicrobial factors in saliva (lysozyme, peroxidase, lactoferrin) Normal microbiota Mucus, cilia Physical barrier of skin, salty residue, fatty acids, normal microbiota Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Microbial Barriers Normal flora (biota) play a role in keeping the body protected Competitive exclusion take up spaces, and nutrients Toxic compounds Propionibacterium degrade lipids, produce fatty acids E. coli may synthesize colicins in intestinal tract Kill Salmonella and Shigella Lactobacillus in vagina produce low pHprevents infections Cells of the Immune System Formation=hematopoiesis Blood cells originate from hematopoietic stem cells In bone marrow Stem cells develop into particular types of cells because induced by different colony-stimulating factors (CSFs) Move around body, travel through circulatory systems Some reside in tissues Three general categories Red blood cells (erythrocytes) carry O 2 Platelets (from megakaryocytes) involved in clotting White blood cells (leukocytes)--defense Hematopoietic stem cell (in bone marrow) Common lymphoid progenitor Lymphoblasts B cellT cell Erythroblast Megakaryoblast Common myeloid progenitor Monoblast MyeloblastPutative mast cell precursor LymphocytesRed blood cell (erythrocyte) Platelets (thrombocytes) Megakaryocyte Mast cell White blood cells (leukocytes) Dendritic cell Macrophage Natural killer (NK) cell Monocyte Granulocytes EosinophilNeutrophil Basophil Self- renewal The Cells of the Immune System Four types of leukocytes (white blood cells) Granulocytes contain cytoplasmic granules Neutrophils engulf and destroy bacteria, other material Basophils involved in allergic reactions, inflammation Mast cells similar; found in tissues Eosinophils fight parasitic worms Also involved in allergic reactions Common lymphoid progenitor Lymphoblasts B cellT cell Erythroblast Megakaryoblast Common myeloid progenitor MonoblastMyeloblastPutative mast cell precursor Lymphocytes Red blood cell (erythrocyte) Platelets (thrombocytes) Megakaryocyte Mast cell White blood cells (leukocytes) Dendritic cell Macrophage Natural killer (NK) cell Monocyte Granulocytes EosinophilNeutrophilBasophil Self- renewal The Cells of the Immune System Four types of leukocytes (cont) Mononuclear Phagocytes monocytes (circulate in blood) and these develop into Macrophages and Dendritic cells as they leave blood stream Often named after location where found in body Dendritic Cells Sentinel cells, function as scouts Engulf material in tissues, bring it to cells of adaptive immune system for inspection Common myeloid progenitor Monoblast Dendritic cellMacrophage Monocyte Self- renewal Dendritic cells Branched cells, important in adaptive immunity Develop from monocytes, engulf material and bring it to other cells for analysis Four types of leukocytes (cont) Lymphocytes Responsible for adaptive immunity B cells, T cells highly specific in recognition of antigen Generally reside in lymph nodes, lymphatic tissues Natural killer (NK) cells lack specificity Common lymphoid progenitor Lymphoblasts B cellT cell Lymphocytes Natural killer (NK) cell How do cell coordinatecommunicate? Communication allows coordinated response Surface receptors --eyes and ears of cell Binding to specific ligand induces response Often span the membrane Adhesion molecules allow cells to stick to other cells E.g., endothelial cells can adhere to phagocytic cells, allow them to exit bloodstream Cytokinescommunication between cells Produced by cell, diffuse to others, bind to receptors --induce changes -- growth, differentiation, movement, cell death Act at low concentration; effects local, regional, systemic Cell Communication Cytokines Chemokines: chemotaxis of immune cells Colony-stimulating factors (CSFs): multiplication and differentiation of leukocytes Interferons (IFNs): control of viral infections, regulation of inflammatory response Interleukins (ILs): produced by leukocytes; important in innate and adaptive immunity Tumor necrosis factor (TNF): inflammation, apoptosis Cytokines and their function Sensor systems in the blood, tissues and cells Can detect signs of tissue damage or microbial invasion Respond by Detecting parts of bacteria/viruses using pattern recognition receptors (PRRs) Directly destroy bacteria using complement Recruit other components of host defense Pattern Recognition Receptors (PRRs) Pattern recognition receptors (PRRs) detect pathogen-associated molecular patterns (PAMPs), see signs of microbial invasion Cell wall (lipopolysaccharide, peptidoglycan, lipoteichoic acid, lipoproteins), flagellin subunits, viral RNA molecules Also called MAMPs (for microbe-associated) Some are DAMPs (for danger-associated), which indicate host cell damage Pattern Recognition Receptors Toll-Like receptors (TLRs) Membrane bound receptors which detect bacterial parts NOD-like receptors (NLRs) Cytoplasmic proteins detect bacterial parts RIG-like receptors (RLRs) Cytoplasmic proteins detect viral RNA Pattern Recognition Receptors (PRRs) Toll-like receptors (TLRs) in membranes of sentinel cells Detects flagellin Detects lipopolysaccharide (LPS) Detects peptidoglycan Phagosome or endosome TLRs in cytoplasmic membrane TLRs in phagosomal or endosomal membrane Cytoplasm Detects ssRNA Detects bacterial DNA Detects dsRNA Lumen of endosome Outside of cell Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. (e.g., macrophages, dendritic cells, cells lining sterile body sites) Cells see PAMPs in extracellular environment --signal transmitted to nucleus --Induces gene expression, e.g. inflammatory response, antiviral response Pattern Recognition Receptors (PRRs) NOD-like receptors (NLRs found in cytoplasm Detect bacterial components --cell invasion; some detect damage Unleash series of events to protect host Some at expense of cell Some NLRs join cytoplasmic proteins to form an inflammasome Activates inflammatory response NLR - Detects flagellin RLR - Detects dsRNA NLR - Detects peptidoglycan RLR - Detects uncapped ssRNA NLR - Detects compounds that indicate cell damage Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Fig.14.9 Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Virus infects neighboring cells. Cell 1: Productive infection; cell is destroyed as a result of infection. AVP iAVP Induction of programmed cell death (apoptosis) Cell 2: Infection of cell (detected by the presence of long dsRNA) results in activation of the antiviral proteins, leading to apoptosis. Although the cell dies, the virus does not have the opportunity to replicate, thus preventing viral spread. Cell 2: Interferon induces synthesis of a group of inactive antiviral proteins (iAVP). These have no effect on the cell unless they are activated. iAVP IFN activates genes for iAVP synthesis. IFN Cell 1: Cell is infected by a virus; viral replication produces long dsRNA, which induces the synthesis and secretion of interferon (IFN). dsRNAVirusssRNA Long dsRNA activates genes for IFN synthesis. IFN IFN diffuses to neighboring cells. Complement Proteins are part of the Complement system Consists of a collection of 9 interacting proteins found in blood and tissues Activation of these proteins promote Opsonization Inflammatory response Lysis of foreign cell Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Classical pathwayLectin pathwayAlternative pathway Antibody C3b binding to microbial invaders Mannose-binding lectin (MBL) binding to microbial invaders Antibodies binding to microbial invaders Opsonization C3b binds to microbial cells, functioning as an opsonin. Inflammatory response C3a and C5a induce changes that contribute to local vascular permeability and attract phagocytes. C3 Splits C3 C3bC3a C5 C5a C5b C3b C9 C5b C6 Lysis of foreign cells C5b combines with complement proteins C6, C7, C8, and C9 to form membrane attack complexes that insert into cell membranes. Combines with C3 convertase to form an enzyme that splits C5 C3bMBL C9 C8 C7 Triggered by Formation of C3 convertase Summary of the system and roles of the complement components C1 C9 Regulation of the complement system What have we covered so far? The innate immune system is composed of Cells Chemicals released by cells to communicate with each other Receptors to recognize invaders Responses to kill invaders, and to interact with the adaptive immune elements. What happens during phagocytosis? Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Chemotaxis C5a Recognition and attachment Pseudopod C3b receptors on phagocyte C3b Microbes C3b Phagocyte Lysosomes Exocytosis Destruction and digestion Phagosome maturation and phagolysosome formation Engulfment Digestive enzymes Phagolysosome Phagosome (top): Meckes/Ottawa/SPL/Photo Researchers, Inc How do phagocytes work? Inflammation response Purpose? Contain a site of damage, localize the response, eliminate the invador and restore tissue function. What are the key cells involved Macrophages (residents initially detect trouble), Neutrophils (rapid response team) What activates the inflammation response? What are the symptoms? Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Bacteria Blood vessel Normal blood flow in the tissues as the injury occurs. (a) (b) Inflammatory mediators cause small blood vessels to dilate. The phagocytic cells tumble to a halt and then squeeze between the endothelial cells and enter the tissues. Diapedesis Tighter adherence Loose adherence; cells tumble to a halt. As the infection is brought under control, macrophages ingest dead cells and debris. Neutrophils are the first phagocytes recruited to the site. Monocyte Recruited macrophage Neutrophil Phagocytic cells destroy and remove invaders. Pro- inflammatory chemicals Resident macrophage Inflammatory mediators are released in response to microbial components and tissue damage. Neutrophil 1.Macrophages detect and cause an alarmproduce cytokines to attract other cells (T-cells, and Neurtophils). All granulomas 2.Become activated Macrophages and can interact with antibodies, and fuse to become GIANT cellshelp to wall off area. 3.Neutrophils early recruits to the sitemove faster into the site and are more effective at killing than macrophages. But live only 1-2 days. 4.Neutrophils release NETneutrophil extracellular traps. DNA and granule contentcatches and kills bacteria outside the cells. Inflammation response steps Inflammation steps Macrophages--Involves TLRs (detect PAMPs) and NLRs(detect DAMPs)release inflamatory mediators (cytokines, histamines) TNF-tumor necrosis factorshelp make proteins to increase phagocytosis and activate the complement system. Increase coagulation of blood and blood vessel leakiness, allows macrophages and neutrophils through In the fluid there is transferrin (binds Fe), complement system proteins, and antibodies. When things seem under control, neutrophils slow entrance and macrophage clean up cell debris, etc. Fever is a nonspecific response Il-1 increases T lymphocytes Decreases available iron Increases cellular reactions pyroptosis