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 turnoverImmune surveillance: dendritic cells, macrophagesSaltNormal skin biotaSALT

First-line defenses: MUCOUS MEMBRANES

High turnoverImmune surveillance: dendritic cells, macrophagesSecretionsNormal biotaMALT

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