Chapter 14: Innate Immune System

Overview of Immune Defenses First-line defenses: – Intact, healthy skin and mucous membranes – Normal microbiota

Overview of Immune Defenses Sensory systems: – Pattern recognition receptors Toll-like receptors NOD-like receptors RIG-like receptors – Complement system Alternative pathway Classic pathway Lectin pathway

Overview of Immune Defenses Innate effector actions: – Inflammatory response – Interferon response – Opsonization – Membrane attack complex

First-line defenses: SKIN High turnover Immune surveillance: dendritic cells, macrophages Salt Normal skin biota SALT

First-line defenses: MUCOUS MEMBRANES High turnover Immune surveillance: dendritic cells, macrophages Secretions Normal biota MALT

Mucosal epithelium: intestinal mucosa

Mucosal surfaces: respiratory mucosa

Antimicrobial substances Produced by animals: – Lysozyme – Peroxidase enzymes – Lactoferrin – Transferrin – Defensins Produced by your microbiota: – Fatty acids – Colicins – Lactic acid

Cells of the Immune System Granulocytes: – Neutrophils – Eosinophils – Basophils – Mast cells Mononuclear phagocytes: – Monocytes – Macrophages – Dendritic cells Lymphocytes: – T cells – B cells – NK cells

Neutrophils Phagocytic Granules: – Lysozyme, Phospholipase A2, myeloperoxidase, elastase, acid hydrolases, lactoferrin... Most numerous leukocyte in circulation Migration to tissue = major component of inflammatory response Short life span NETs

Macrophages Phagocytic Lysosomes: – Lysozyme, peroxidase... Mature, tissue form of monocyte Increased migration and maturation of monocytes to tissue in inflammatory response Long life span TLRs: on cell surface & in lysosomes Cytokines: Activation → enhanced killing power

Dendritic Cells Phagocytic sentinel cells Antigen presenting cells Most = monocyte/ macrophage cell line Long life span Important bridge between innate & adaptive immunity

Natural Killer Cells Non-specific lymphocytes – Do not require antigenic stimulation

Cell Communication: SURFACE RECEPTORS

Cell Communication: CYTOKINES Chemokines Colony stimulating factors Interferons Interleukins Tumor necrosis factor (TNF)

Interferons α and β

Cell Communication: ADHESION MOLECULES Integrins: large family, widely expressed, involved in interaction with ECM Selectins: small family, differentially expressed by leukocytes & endothelial cells, involved in leukocyte extravasation Cadherins: large family, widely expressed, involved in adhesion between cells ICAMs & VCAMs: part of immunoglobulin superfamily; many roles in immune response/inflammation

Pattern Recognition Receptors Recognition of PATHOGEN-ASSOCIATED MOLECULAR PATTERNS / MICROBE-ASSOCIATED MOLECULAR PATTERNS (PAMPs / MAMPs): – Peptidoglycan – Lipopolysaccharide – Techoic acid – Flagellin subunits – Viral RNA Recognition of DANGER-ASSOCIATED MOLECULAR PATTERNS (DAMPs): – Molecules that indicate cellular damage

Pattern Recognition Receptors Toll-like receptors (TLRs): – Membrane-bound receptors – Macrophages, dendritic cells, cells lining sterile sites (i.e., mesothelial cells) – Detection of PAMPs → signal to nucleus → upregulation of gene expression → response

Pattern Recognition Receptors NOD-like receptors (NLRs): – Located in the cytoplasm – most (all?) cells – Detect PAMPs or DAMPs

Pattern Recognition Receptors RIG-like receptors (RLRs): – Located in the cytoplasm – most (all?) cells – Recognize viral RNA – Allow cells to detect a viral invader – Recognition of viral RNA by RLR → synthesis and secretion of interferons → expression of inactive viral proteins → activation of IVPs by dsRNA → apoptosis of infected cells

The Complement System Consists of interacting proteins produced in the liver and found in blood and tissues These proteins promote – Opsonization – Inflammation – Cell lysis

The Complement System Central feature = splitting of C3 → C3a & C3b Enzyme that splits C3 = C3 convertase C3 also spontaneously degenerates to form C3a & C3b at a constant rate Alternative pathway: C3b binds to foreign cell surface receptors → formation of C3 convertase Lectin pathway: pattern recognition receptors = mannose binding lectins (MBLs): bind to mannose molecules on microbial surface → formation of C3 convertase Classical pathway: antibody binds antigen = antigen-antibody complex → formation of C3 convertase (adaptive immune response)

Phagocytosis Chemotaxis Recognition and attachment Engulfment Phagosome maturation and formation of phagolysosome Destruction and digestion Exocytosis

Phagocytosis

The inflammatory response Acute inflammation – example of activation: – TLR on sentinel MØ recognizes PAMP → MØ produces TNF → induces liver to synthesize acute phase proteins → activation of phagocytes, activation of complement – Tissue damage: “Danger Model” of immune system – ex. = activation of coagulation cascade in response to blood vessel damage

The Acute Inflammatory Response Calor = heat: increased blood flow to site Rumor = redness: increased blood flow Tumor = swelling: fluid and cells accumulate Dolor = pain: pressure + chemical mediators Functio laesa: many possible causes

The acute inflammatory response

Recruitment of leukocytes from the blood to a site of acute inflammation:

Chronic inflammation Acute response is unsuccessful in resolving the problem Can last years, often associated with significant tissue damage May be due to chronic infection, repetitive injury, chronic implantation of foreign material or self- perpetuating because of damage induced by the immune system itself in the absence of ongoing infection/other external cause

Fever Protective mechanism = resetting of the thermostat – Make the body less hospitable to pathogens – Slowed microbial growth = time to raise a defense – Increases rate of enzymatic reactions → enhanced inflammation, phagocytosis, lymphocyte proliferation, hematopoiesis, production/release of cytokines and antibodies Pyrogens: – Endogenous: interferons – Exogenous: LPS

Fever

Fever ≠ acute inflammation! Fever = a systemic change in the body temperature Heat associated with acute inflammation = localized increase in temperature