INNATE IMMUNİTYINNATE IMMUNİTY

If any invader penetrate the body’s If any invader penetrate the body’s first line defense mechanisms:first line defense mechanisms:

The second line or the first line The second line or the first line immunologic defense immunologic defense Innate immunity Innate immunity

Always active or nearly activeAlways active or nearly activeAdaptive responses devolope usually later Adaptive responses devolope usually later

(after 96 hours)(after 96 hours)

Innate immunity is prorammed to:Innate immunity is prorammed to:- To recognize broad range of molecules To recognize broad range of molecules

asscociated with pathogensasscociated with pathogens- To destroy the invaders rapidly: Activation To destroy the invaders rapidly: Activation

of the phagocytic system and devoloping of the phagocytic system and devoloping an inflmmatory responsean inflmmatory response

Recognition of the microbes by Recognition of the microbes by innate immunityinnate immunity

To recognize those structures, common to To recognize those structures, common to the various agent, but bor present in the various agent, but bor present in humanhuman

Phagocytes have LPS specific receptorsPhagocytes have LPS specific receptorsPhagocytes recognize mannose residues Phagocytes recognize mannose residues

which are present only in glycoproteins of which are present only in glycoproteins of mammalian originemammalian origine

Phagocytes recognise and response also Phagocytes recognise and response also to:to:

Ds RNA, unmethylated CpG Ds RNA, unmethylated CpG oligonucleotidesoligonucleotides

The molecules of the microbes targeted by The molecules of the microbes targeted by th immune system are -th immune system are -pathogen pathogen asscociated molecular patterns (PAMPs)asscociated molecular patterns (PAMPs)

The receptors of the innate immunity for The receptors of the innate immunity for these molecules are “pattern recognition these molecules are “pattern recognition receptors” (PRRs)receptors” (PRRs)

The targets of the innate immunity are The targets of the innate immunity are critical regarding the survival and critical regarding the survival and infectivity of the microbesinfectivity of the microbes

Innate immunity can also recognise those Innate immunity can also recognise those molecules released from demaged or molecules released from demaged or stressed cells of the body stressed cells of the body damage damage asscociated molecular patterns (DAMPs)asscociated molecular patterns (DAMPs)

These receptors are encoded in the These receptors are encoded in the germline germline Receptors expressed on all Receptors expressed on all cells of a certain type (not clonal)cells of a certain type (not clonal)

Innate immunity does not reat against the Innate immunity does not reat against the hosthost

İnnate immunity respond in the same way İnnate immunity respond in the same way to repeated invasionsto repeated invasions

The main goals of the innate immunityThe main goals of the innate immunity

- To induce inflammationTo induce inflammation- To achieve antiviral defenseTo achieve antiviral defense

Receptors expressed onReceptors expressed on

Phagocytes, DC, lynphocytes, epithelial Phagocytes, DC, lynphocytes, epithelial and endothelial cellsand endothelial cells

Receptors are expressed on different Receptors are expressed on different compartments of these cellscompartments of these cells

Toll like receptors (TLR)Toll like receptors (TLR)

TLR activates transcrition TLR activates transcrition factors, which stimulate the factors, which stimulate the expression of genes encoding expression of genes encoding cytokines, enzymes and other cytokines, enzymes and other proteinsproteins

Most important transcription Most important transcription factors are:factors are:

Nuclear factor-kappaB (NF-Nuclear factor-kappaB (NF-kappaB) and interferon kappaB) and interferon response factor -3 (IRF-3)response factor -3 (IRF-3)

NF-kappaB promotes expression of NF-kappaB promotes expression of cytokines and endothelialadhesion factorcytokines and endothelialadhesion factor

IRF-3 stimulates type I interferons and IRF-3 stimulates type I interferons and cytokines with antiviral activitycytokines with antiviral activity

Soluble defense mechanismsSoluble defense mechanisms

TYpe I interferons: DC (IFN-TYpe I interferons: DC (IFN-alfa), fibroblasts (IFN-beta)alfa), fibroblasts (IFN-beta)

Microbicidal molecules: Microbicidal molecules: Epithelial cells, PMN and Epithelial cells, PMN and macrophages secrete cystein macrophages secrete cystein rich peptides (defensines). rich peptides (defensines). Others are cathelicdine, Others are cathelicdine, lysozyme, DNAase, RNAaselysozyme, DNAase, RNAase

ComplementComplement

Steps in PhagocytosisSteps in Phagocytosis

AttachmentAttachmentbacterial carbohydrates (lectins)bacterial carbohydrates (lectins)receptor for opsoninsreceptor for opsoninsfibronectin receptorsfibronectin receptorsFc receptorsFc receptors

Internalization Internalization (phagocytic vacuole)(phagocytic vacuole)Digestion Digestion (phagosome)(phagosome)

Antibacterial compounds of the Antibacterial compounds of the phagolysosome Iphagolysosome I

Oxygen-dependent compoundsOxygen-dependent compoundsHydrogen peroxide: NADPH oxidase Hydrogen peroxide: NADPH oxidase

and NADHand NADHSuperoxideSuperoxideHydroxil radicals (OH)Hydroxil radicals (OH)Activated halides (ClActivated halides (Cl

__, I, I

__, Br, Br

__): ):

myeloperoxidasemyeloperoxidaseNitrous oxideNitrous oxide

Antibacterial compounds of the Antibacterial compounds of the phagolysosome IIphagolysosome II

Oxygen-independent compoundsOxygen-independent compoundsAcidsAcidsLysosome (degrades bacterial Lysosome (degrades bacterial

peptidoglycan)peptidoglycan)Lactoferrin (chelates iron)Lactoferrin (chelates iron)Defensin and other cationic proteins Defensin and other cationic proteins

(damage membranes)(damage membranes)Proteases, elastase, cathepsin GProteases, elastase, cathepsin G

Phagocytosis & killing of bacteriaPhagocytosis & killing of bacteria

Macrophages in antibacterial Macrophages in antibacterial responseresponse

Important antibacterial phagocytic cellsImportant antibacterial phagocytic cellsKilling by oxygen-dependent and oxygen-Killing by oxygen-dependent and oxygen-

independent mechanismsindependent mechanismsProduction of IL-1, IL-6, and IL-12; TNF-Production of IL-1, IL-6, and IL-12; TNF- and and

TNF-TNF-, and interferon-, and interferon-Activation of acute-phase and inflammatory Activation of acute-phase and inflammatory

responsesresponsesPresentation of antigen to CD4 T cellPresentation of antigen to CD4 T cell

1.1. Expansion of capilaries to increase blood Expansion of capilaries to increase blood flow (seen as blushing or a rash)flow (seen as blushing or a rash)

2.2. Increase in the permeability of the Increase in the permeability of the microvasculature structure to allow microvasculature structure to allow escape of fluid, plasma proteins, and escape of fluid, plasma proteins, and leukocytes from the circulationleukocytes from the circulationedemaedema

3.3. Exit of leukocytes from the capillaries Exit of leukocytes from the capillaries and their accumulation at the site of and their accumulation at the site of injuryinjury

Acute-Phase ReactantsAcute-Phase Reactants 11-antitrypsin-antitrypsin

11-glycoprotein-glycoprotein Amyloid A & PAmyloid A & P Antithrombin Antithrombin C-reactive proteinC-reactive protein C1 esterase inhibitorC1 esterase inhibitor C3 complementC3 complement

CeruloplasminCeruloplasmin FibrinogenFibrinogen HaptoglobulinHaptoglobulin OrosomucoidOrosomucoid PlasminogenPlasminogen TransferrinTransferrin Lypopolysaccharide-Lypopolysaccharide-

binding proteinsbinding proteins