Chapter 16: Innate Immunity - Los Angeles Mission … Chapter 16.pdfChapter 16: Innate Immunity 1....
Transcript of Chapter 16: Innate Immunity - Los Angeles Mission … Chapter 16.pdfChapter 16: Innate Immunity 1....
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Chapter 16:Innate Immunity
1. Overview of Innate Immunity
2. Inflammation & Phagocytosis
3. Antimicrobial Substances
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1. Overview of Innate Immunity
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The Body’s Defenses
The body has 2 types of defense against infectionInnate Immunity
• physical barriers (the skin & mucous membranes)
Adaptive Immunity (covered in ch. 17)• delayed, highly specific responses to foreign material
• immediate, non-specific responses to pathogens, injuries
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Innate ImmunityThe innate immune response is the body’s 1st
line of defense and includes:
1) physical barriers between inside & outside• the skin and the mucous membranes of the digestive,respiratory and genito-urinary tracts
• all substances secreted at these barriers and allof the normal microbiota that live on these surfaces
2) non-specific cellular & physiological responses• i.e., inborn (innate) general responses to the presence of pathogens that breach the body’s physical barriers
• independent of prior exposure, response is immediate• eliminates the vast majority of pathogens that gain entry
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Physical DefensesKey features of the Skin:
• dry, acidic surface (resists microbial growth)
• multiple layers of tough yet dead keratinized cells
• sebum from hair follicles (lowers pH) & lysozyme from sweat resist microbial growth
• continual loss of outer deadskin layers removespotential pathogens
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Key features of the Eyes:• tears continually released bylacrimal ducts
• contain antimicrobial substances (e.g. lysozyme), wash away any microbes, debris on the eye surface
Key features of the Mucous Membranes:
• vulnerable due to very thin epithelial layer, moist surface
• continually produce mucus, a viscous glycoprotein that traps microbes and debris
• includes the linings of the respiratory, digestive & genito-urinary tracts
• acidic environment of stomach kills most microbes
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Summary of Physical Defenses
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Roles of the Normal MicrobiotaThe “normal microbiota” are the microorganismsthat live on the body surfaces of a healthy individual and inhibit the growth of pathogensin the following ways:
• acidifying body surfaces• e.g., in the female reproductive tract, inhibits yeast inf.
• the production of bacteriocins and other toxins• i.e., toxins that are specific for other microorganisms• e.g., in the large intestine (E. coli)
• out-competing pathogens for nutrients• on the skin and basically all mucous membranes
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Organs of the Immune System
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The Lymphoid OrgansBone Marrow
• blood cell formation
Thymus• where T cells are “educated”
• “where all blood cells (red & white) are born”
• weeds out T cells that would react to “self” molecules
Spleen• immune response to pathogens, foreign
material in blood
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…the Lymphatic System
Lymph Nodes
Lymph (& Blood)• fluids through which immune cells patrol the body
• immune response to pathogens, foreign material in lymph
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Cells of the Immune System…These include all of the white blood cells (akaleukocytes), some of which appear “granular”…
GranulocytesNeutrophils• phagocytes w/strangely shaped nuclei, poorly stained granular vesicles
Basophils• release histamine, other mediators ofinflammation, vesicles bind basic dyes
Eosinophils• phagocytic, attack parasites w/toxicproteins, vesicle bind acidic eosin dye
Dendritic Cells• phagocytes with very important rolesin initiating adaptive immune response
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…more Cells of the Immune System
Agranulocytes
…& others which have an “agranular” appearance
Monocytes/Macrophages• monocytes become activelyphagocytic macrophages whenstimulated via infection, injury
Natural Killer (NK) cells• recognize and destroy cells withfeatures of tumor cells, cellswith intracellular pathogens
T & B cells• have central roles in adaptiveimmunity (covered in ch. 17)
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2. Inflammation & Phagocytosis
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What is Inflammation?Inflammation is a localized response initiated bydamaged or infected tissues to aid tissue repairand the elimination of pathogens.
Vasodilation & increased capillary permeability• increases blood flow to area, blood fluid in tissue
The basic stages of inflammation are as follows:
Migration of phagocytes, phagocytosis• phagocytes exit the blood, enter affected tissue via chemotaxis & consume pathogens
Tissue repair• removal of dead cells, regeneration of the tissue
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Inflammation TriggersAny type of physical damage to and/or microbial penetration of a tissue will trigger a local inflammatory response:
• can be short-lived (acute) or extended (chronic)
• initiated by therelease of inflammatorymediators fromcells in the tissuethat is damaged
e.g.histamineprostaglandinsleukotrienes
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Vasodilation & Increased PermeabilityIncreased blood flow due to vasodilation and theincreased permeability of capillaries results in fluid from blood seeping into affected tissue:
• causes swelling of the region (edema)
• facilitatesclotting
• facilitatesentry of antimicrobialproteins,leukocytes
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Phagocyte Migration (Chemotaxis)
• endothelium of capillaries inthe area expresses proteinsthat “stick to” phagocytes
• phagocytes then “squeeze” their way out into the tissue and follow a “trail” of chemical signals towardthe source (chemotaxis) and gobble up microbes
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Tissue RepairOnce the area has been secured (all pathogensare destroyed, all breaches are sealed), dead & damaged cells can be broken down and thetissue can regenerate.
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What is Phagocytosis?It’s the process by which a cell ingests a solidextracellular particle (such as a bacterium) byengulfing it within a membrane enclosedvesicle (sometimes called a vacuole).
• cells that normally carry out this function arereferred to as phagocytic, or simply as phagocytes
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Types of PhagocytesAll of the phagocytes in the human body aretypes of white blood cells (leukocytes):
Neutrophils• highly phagocytic cells that rapidly exit the blood intodamaged or infected tissue, “gobble up” bacteria, etc…
Eosinophils (occasionally)
Macrophages• monocytes migrate to damaged, infected tissue fromblood & differentiate into highly phagocytic macrophages
Dendritic Cells• found in skin, mucous membranes, thymus, lymph nodes
• some are fixed (non-mobile) in various tissues & organs
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The Phagocytic Process
• all phagocytic white blood cells ingest & destroy pathogens & other debris by this basic process
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OpsonizationAs we learned in the previous chapter, bacteria have a variety of ways to resist phagocytosis.
• antibodies
2 kinds of molecules involved in the immune response bindto pathogens and greatly enhance phagocytosis:
• complement protein C3b
This process is called opsonization and such proteins are called opsonins.
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3. Antimicrobial Substances
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Some Antimicrobial SubstancesThere are many different kinds of antimicrobialsubstances, however we will focus our attention on 2 of the more interesting ones*:
*Complement system• a set of proteins present in the blood important forthe destruction of pathogenic cells
*Interferons• a class of cytokines that are especially important incontrolling viral infections
Transferrins (bind & keep iron away from pathogens)
Antimicrobial peptides (cause lysis of microbes)
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The Complement SystemThe complement system (aka “complement”) isa set of >30 proteins produced by the liver thatcirculate in the blood in an inactive state.
The presence of microbial pathogens activatesthe “complement cascade” in 1 of 3 ways to eliminate the pathogens by:
• cytolysis (cell lysis)
• triggering inflammation
• enhancing phagocytosis (opsonization)
• eukaryotic pathogens, Gram- bacteria (not Gram+)
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The Complement Cascade• the activation of complement proteins C3 & C5-C9 as shownis central to complement carryingout its roles
• the key event setting off the processis the splitting of C3 protein intoC3a & C3b fragments
• C3b triggers the cascade resulting in a cytolytic structure…
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Cytolysis by Complement• C3b binds to outer membraneof Gram- bacteria and splits C5 into C5a & C5b
• C5b on the outer membranethen recruits C6, C7, & C8
• the C5b-C8 complex triggersmultiple C9 proteins to completethe circular membrane attackcomplex (MAC)
• MAC formation produces ahole in membrane & cytolysis
**C3b also functions as an opsonin to aid phagocytosis**
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The Classical Complement PathwayThe “classical” pathway was characterized first andactivates C3 as follows:
• specific antibody binds to thesurface of a target cell
• this activates C1 which thensplits C2 into C2a & C2b, andC4 into C4a and C4b
• C2a & C4b form a complex which then cleaves C3 settingoff the formation of the MAC
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Alternative Complement PathwayThe “alternative” pathway activates C3 in a different way:
• spontaneouslyformed yet unstablecomplexes of C3 &Factors B, D & Pbecome stabilized on the surface of a pathogen
• stabilized C3-BDPacts to cleave otherC3 molecules andtrigger cascade
**This is antibody-independent!**
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Lectin Complement PathwayLectins are protein produced by the liver that bindspecific carbohydrate structures
• mannose-bindinglectin (MBL) isproduced during infections and binds carbohydrates with the sugar mannose on pathogens
• MBL on the cellsurface triggers thecomplement cascadeas does C1 in theclassical pathway
**Antibody-independent!**
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Inflammation via Complement
C3a and C5a are powerful inducers of inflammation• bind to receptors on mast cells triggering the release ofhistamine, etc, causing vasodilation, incr. in permeability
C5a is also a powerful chemoattractant for phagocytes • phagocytes follow gradient of C5a to site of infection
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InterferonsThe interferons (IFN-α, IFN-β & IFN-γ) are a classof cytokines (soluble protein signals) released by virally infected cells and certain white blood cells to stimulate other cells to protect themselves from viral infection:
• the presence of viral proteins, RNA in a celltriggers IFN production & release
• neighboring cells bind IFNs via specific receptors
• this triggers the expression of various anti-viralgenes in the cell receiving the IFN signal
• the resulting anti-viral proteins (AVPs) degradeviral RNA, thus protecting cell from infection
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Effects of Interferons on Cells
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Key Terms for Chapter 16
• granulocytes: neutrophils, basophils, eosinophils dendritic cells
• opsonization, opsonin
• agranulocytes: monocytes, macrophages, NK cells, T & B cells
• complement: classical, alternative, MBL paths
• innate vs adaptive immunity
• lectins, interferons, cytokines, transferrins
Relevant Chapter Questions rvw: 1-5, 7-9, 12, 13, 15, 16 MC: 1-6, 10