Lecture 9: The Innate Immune System

(The innate immune system) Lecture 9 The Immune System · The bodies defense against: ↳ pathogens ↳ cancers ↳ organ transplants · Functions of the immune system: - keeps microorganisms out - removes microorganisms that get in - combats microorganisms that remain inside - fight cancer (mutated transformed cells) A well-balanced immune system should be able to distinguish between SELF and NON-SELF (ie. pathogen) 1st Line of Defense ① Skin · a physical barrier that functions to stop microorganisms before they get in ↳ no adherence = no invasion · Keratin: water repelling protein · sebum: secreted from pores in skin, antibacterial antifungal · dendritic cells: in skin, process antigens & initiates adaptive immunity · sloughing cells: cells that fall off top layer of skin, taking bacteria with it ② Mucous Membranes and Secretions Mucous membranes · forms thin and permeable barriers · mucous membranes line the gastrointestinal (GI) tract, respiratory tract, and genitourinary tract · mechanical removal: ↳ goblet cells produce mucous ↳ mucous other secretions flush away microorganisms ↳ ciliated cells in the respiratory tract (ciliary escalator) · Mucociliary Escalator: a major defense mechanism that protects the lungs ↳ involves ciliated cells in respiratory tract ↳ mucous sits on top and prevents binding to host cells Secretions · Tears and Saliva: lysozyme that breaks down peptidoglycan · Crevicular fluid: fluid that flows into gums (gingival crevice) between teeth ↳ similar composition to blood serum (immune cells/molecules) · Gastric Juice: stomach acid PH 1-2 · Urine/Vaginal secretions: flushing action, PH, etc. ③ Normal Flora · competition for space and nutrients · attaches to intestinal walls and attaches to receptors there ↳ bad bacteria may not find a receptor to attach onto · E. coli produce vitamin K ↳ Vitamin K helps the blood clot, preventing excessive bleeding ↳ Vitamin K helps the binding of calcium to bones 2nd Line of Defense ① Innate immune cells Innate Immune Cells : WBC (leukocytes) Neutrophils Granulocytes Eosinophils (or PMNL, polymorphonuclear Basophils leukocytes) Mast Cells Direct destruction (killing) of pathogens Monocytes Macrophages Antigen Presentation Dendritic Cells Natural Killer cells Destroys infected host cells (Intra-cellular bacteria, virus, or cancer cells) · Neutrophils ↳ target bacteria, make up 60-70% of WBC ↳ first to arrive and initiate phagocytosis at infected site - ↳ fast moving, short life span (less than 1 day by no mitochondria) ↳ form NETS when they die (sticky DNA that traps bacteria) ↳ have vacuoles containing granules with anti-microbial proteins and inflammatory mediators - eg. myeloperoxidase (turns pus greenish yellow), superoxide radicals · Eosinophils ↳ major role in defense against parasitic infection - ↳ secretes cytolytic enzymes upon contact with pathogens ↳ cells circulate in blood until recruited to inflamed tissue · Basophils ↳ found in blood ↳ similar function to mast cells ↳ releases histamine from granules Histamine increases peripheral blood vessel permeability · Mast cells ↳ most abundant in submucosal tissue (not bloodstream) ↳ cell surface receptor for immunoglobulin E (IgE) ↳ important role in allergic reactions ↳ releases histamine once IgE receptor is activated · Macrophages ↳ 3-8% of total WBC ↳ professional phagocyte (also eats damaged host cells like dead neutrophils) ↳ in blood circulation → called monocyte ↳ in tissue → called macrophage ↳ antigen presenting cell ↳ break down infections pathogen and present "pieces" (antigen) on receptors located on cell surface · Dendritic Cell ↳ professional antigen presenting cell, phagocytic ↳ role in activation of adaptive immunity ↳ carries antigen from tissues to the lymph glands where the T and B lymphocytes reside ↳ presents antigen to T helper lymphocytes to initiate adaptive immune response · Natural Killer (NK) cells ↳ lymphocytes without immunological memory ↳ first line of defense against intracellular pathogens Non specific - virally infected cells - intracellular bacteria/protozoa - cancer cells ↳ release cytolytic granules = targeted cell destruction which cells are destroyed? · infected cells: microbial antigen presented on MHC I · virally infected cells: which have lost surface expression of MHC I · cancer cells: that have lost MHC I Granuloma · reaction instigated by macrophages · layers of macrophages surround bacteria Granules · leukocyte granules contain chemicals & enzymes that break down pathogens & stimulate other immune cells · Two types of Granules: ① Lytic granules ↳ contain digestive enzymes (eg. lysozyme) to break down endocytosed pathogens ② Secretory granules ↳ function to kill pathogens that are too big to eat ↳ contain chemical messenger substances that attract other immune cells to the site (chemokines) ↳ some have inflammatory mediators (like histamine) MHC = Major Histocompatibility Complex MHC Class I · receptor found on surface of all normal nucleated cells ↳ healthy cells: "self" protein is bound in the MHC I ↳ sick cells (virus/cancer): may have foreign peptide "non-self" bound in the MHC I · provides a way for cytotoxic T cells to scan & detect intracellular infection · NK cells detect cells that are NOT showing self-peptides and kill them · In humans MHC = Human Leukocyte Antigen (HLA) MHC Class II · found only on antigen presenting cells (macrophages, dendritic cells & B lymphocytes) · Bind and present peptides to T-helper cells MHC II in order to initiate the adaptive immune response MHC Class I MHC Class II · presents endogenous peptides · presents exogenous peptides · found on ALL cells with nuclei (self marker) · Found only on APCs · activates CD8+ cytotoxic cells · activates CD4+ helper cells Diapedesis: the migration of cells from inside blood vessels across endothelium through cell junctions (blood vessel wall) Chemotaxis: the directed movement of cells in a concentration gradient Cytokines · cytokines: small proteins made by host cells ↳ function to change behaviour or communicate with other cells · types of cytokines: ① Chemokines: used for attracting other cells to site of infection ② Interleukins: alter the function of other cells Pattern Recognition Receptors (PRR) · Toll-like Receptors (TLRs) recognize different molecules from pathogens: ↳ RNA, DNA, LPS, Peptidoglycan, Flagellin · Triggering TLRs leads to: ① Chemokine release: calls in help from the circulation ② Proinflammatory cytokine release: activates neighbouring cells ③ Increased microbiocidal activity: destroys ingested pathogens faster and more efficiently ② Inflammation · inflammation: the localized tissue response to infection or injury · cuts lead to an inflammatory response "SHARP" ↳ Swelling ↳ Heat ↳ Altered function ↳ Redness ↳ Pain · If cut is infected, WBC counts increase · swollen lymph nodes (LN): where immune cells (T & B lymphocytes) multiply, preparing for an effective immune response Pus: mixture of dead cells, neutrophils, and body fluids Abscess: accumulation of pus (pustules and boils) Pyogenic (Pus producing) Bacteria: ↳ streptococcus pyogenes ↳ staphylococcus aureus Important Definitions: · Antigen: a foreign substance capable of provoking an immune response ↳ eg. bacteria, virus, protozoa, pollen, transplanted tissue · Epitope: the specific spot or site on an antigen recognized by immune cells or antibodies · Antibody: protein produced by B lymphocytes that can bind to a specific epitope on an antigen (leads to removal of that antigen) ↳ aka immunoglobulin or Ig ③ The Complement System · complement system: a group of serum proteins in the circulation (made in liver) which function to enhance the immune functioning and defend against pathogens ↳ reaction occurs on the surface of a cell · pathogens can sometimes get into the blood circulation ↳ eg. meningococcal sepsis caused by N. meningitidis · 3 activation pathways (complement pathways): 1. Classical Pathway Note: the Alternative and Lectin Pathways are antibody independent ↳ activated by antibody-antigen (Ab-Ag) complexes 2. Alternative Pathway ↳ activated by cell surface molecules on pathogens (cell wall materials: polysaccharides) 3. Lectin Pathway ↳ activated by MBL on pathogens (mannose binding lectin) Activated complement · complement is activated by one of three pathways ↳ once activated, a cascade of molecules function to amplify many aspects of inflammation · all pathways converge at formation of the C5 convertase, followed by the complement proteins C5 → C9 ↳ Forms the membrane attack complex (MAC) ↳ MAC inserts into the bacterial cell membrane causing lysis Membrane Atack Complex (MAC) · C5 initiates the generation of the MAC ↳ membrane attack complex is the result of the deposition of C5b, C6, C7, C8, and C9 in target cell membranes · This pore structure disrupts osmotic integrity, resulting in cell death (Forms pores in the membrane and causes lysis) Important C products & their Function C3b: Opsonization - coats bacteria to enhance phagocytosis C5a: Chemoattractant - recruits phagocytes C3a & C5a: Anaphylatoxins - causes histamine release, Direct Destructive Effect on Pathogens mediates inflammation C5-C9: MAC -kills pathogens Functions of Complement "OlL" · Opsonization · Inflammation · Lysis ④ Antimicrobial Substances · Interferons (IFN) (Inhibits virus replication) ↳ produced by virally infected cells ↳ defense molecule against virus · Antimicrobial Peptides (AMPs) ↳ production is triggered by activation of TLRs (Toll-like receptors) ↳ broad spectrum ↳ examples: -Demcidin: produced by sweat glands -Defensins: produced by neutrophils and macrophages -Thrombocidin: produced by platelets · C-reactive protein (CRP) ↳ acute phase reactant (a substance rapidly produced after infection or tissue damage) ↳ marks bacteria for enhanced phagocytosis (opsonization) ↳ produced in liver during infections -increased levels indicate bacterial infection