MICR2209. Innate Immunity. Dr Allison Imrie

Transcription

1 MICR2209 Innate Immunity Dr Allison Imrie

2 Synopsis: In this lecture we will review the different mechanisms which consbtute the innate immune response, and examine the major cells involved Outcomes: You should be able to describe the major components of innate immunity, the cells that are involved, and the anbgen recognibon pathways

3

4 Three phases of immune response Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recognibon of pathogen by germline-encoded receptors of the innate immune system Adap7ve immunity occurs late because the T cells and B cells specific for the invading pathogen must first undergo clonal expansion before they differenbate into clonal cells which migrate to site of infecbon

5 Many barriers prevent pathogens from crossing epithelia and colonizing 7ssues Surface epithelia provide mechanical, chemical, and microbiological barriers to infecbon

6 Mucosal epithelia Internal epithelia are known as mucosal epithelia because they secrete a viscous fluid called mucous (which contains glycoproteins called mucins) Mucous has many protecbve funcbons: Microorganisms coated in mucous may be prevented from adhering to epithelium, or expelled in outward flow of mucous driven by beabng of cilia

7 A=er entering 7ssues, many pathogens are recognized, ingested, and killed by phagocytes Infec7on and an7gen recogni7on triggers an inflammatory response Macrophages encountering bacteria or other types of microorganisms in Bssue are triggered to release cytokines that increase the permeability of blood vessels, allowing fluid and proteins to pass into Bssues Also secrete chemokines, which direct the migrabon of neutrophils to the site of infecbon Neutrophils and macrophages are the principal inflammatory cells

8 Tissue macrophages are derived from blood monocytes

9 Neutrophils make up the first wave of cells to cross the blood vessel wall to enter an inflamed Bssue

10 Phagocytosis Macrophages express receptors that enable them to take up microbes by phagocytosis Phagosomes fuse with lysosomes, forming an acidified phagolysosome in which the ingested material is broken down by lysosomal hydrolases OpsonizaBon by anbbody or complement enhances phagocytosis

11 Receptor binding results in synthesis of immune mediators via ac7va7on of transcrip7on factors TLRs acbvate transcripbon factors to induce expression of molecules which mediate immune responses One such transcripbon factor is nuclear factor kappa beta (NFκB) NFκB acts primarily to induce expression of pre-inflammatory cytokines and chemotacbc factors

12 Complement System Pathogens which breach host epithelial barriers and inibal animicrobial defenses then encounter Complement Three different pathways: Classical, LecBn, and AlternaBve Each generates a C3 convertase, which cleaves the plasma protein C3 to form 2 subunits, C3a and C3b C3b is an opsinizing molecule coats microbes to enhance phagocytosis SequenBal cleavage of complement proteins by proteases produces inflammatory mediators (eg. C3a) which for example recruit phagocytes Endpoint of complement cascade is formabon of membrane aeack complex which lyses bacteria

13 Complement func7ons

14 Toll-like receptors recognize array of microbes Each of the TLRs whose specificity is known recognizes one or more molecular pa]erns, generally by direct interacbon with molecules on pathogen surface (PAMPs) Flies deficient in Toll receptor are suscepbble to fungal infecbon

15 AcBvaBon of TLRs and NLRs triggers changes in gene expression in macrophages and dendribc cells that directly affect the immune response

16 TLR are expressed on internal and external cell surfaces Some TLRs are located on cell surface of dendribc cells, macrophages, and other cells, where they can detect extracellular PAMPs TLRs act as dimers heterodimers are indicated here, rest are homodimers TLRs located intracellularly in endosome walls can recognize genomic material DNA and RNA The diacyl and triacyl lipopepbdes recognized by the heterodimers TLR-2:TLR2 and TLR-1:TLR2, respecbvely, are derived from lipoteichoic acid of Gram +ve bacterial cell walls and the lipoproteins of Gram ve bacterial cell surfaces

17 TLRs ac7vate the transcrip7on factors NFκΒ, AP-1, and IRF to induce the expression of inflammatory cytokines and type 1 interferons

18 The NOD receptors act as intracellular sensors of bacterial infec7on Some intracellular receptors can detect PAMPs in the cytoplasm These proteins contain a nucelobdebinding oligomerizabon domain (NOD) NOD proteins recognize fragments of bacterial cell wall pepbdoglycans Expressed in cells roubnely exposed to bacteria eg. epithelial cells; also in macrophages and dendribc cells that ingest bacteria which have entered body NOD gene loss-of-funcbon mutabons are associated with Crohn s disease in humans

19 TLRs ac7vate innate immune response to viruses TLR-3, TLR-7 and TLR-9 located on endosomal membranes sense genomic material and hence can detect viral and bacterial RNA and DNA viral ssrna in the cytoplasm can be sensed by RIG-1 (rebnoic acid inducible gene-1), widely expressed across many Bssue and cell types viral dsrna in the cytoplasm may be sensed by MDA-5 (melanoma differenbabon-associated 5) Sensing by RIG-1, MDA-5, and TLRs induces producbon of Interferon-α and Interferon-β via the IRF (interferon regulatory factor) transcripbon factors Interferons inhibit virus replicabon and acbvate natural killer (NK) cells

20 TNF-α is an important cytokine that triggers local containment of infecbon but induces shock when released systemically TNF-α is produced by macrophages acbvated by pathogen in Bssues

21 Natural killer cells Arise from lymphoid progenitor but are not T cells do not express T cell receptor, therefore are not MHCrestricted Kill viral-infected cells using same molecules as CD8+ T cells Recognize targets (virus-infected cells) using different mechanisms : lack of MHC on target cell surface triggers killing

22 Innate vs Adap7ve immunity