First line defences of the immune system

Transkript

1 First line defences of the immune system pathogen What does protect us Before the pathogen (or commensals) can enter the tissue?

2 First line defences of the immune system Acid enviroment skin/stomach (ph 5,5): antifungal pathogen Mucus (produced by globlet cells) Cilia movement competition (commensal versus pathogen) Bacteriocidal Substances (enzymes, defensins) in secreted fluids (saliva, sudor,lachrymal) siga physical/ chemical barrier of skin and mucosa

3 First line defences of the immune system Acid enviroment skin/stomach (ph 5,5): antifungal pathogen mucosa; cilia competition (commensal versus pathogen) Antibody isotypes Bacteriocidal Substances (enzymes, defensins) in secreted fluids (saliva, sudor,lachrymal) siga sigadimer

4 Effector functions of IgA

5 Transcytosis of IgA into Mucosa

6 Immunological outcome depends on Antigen-dosage and accompanying danger signals

7 Clinical case A 16 year old boy has an small accident with a scratch at the right hand. Few Hours later: around the wound 3 cm Erythema with swelling/edema. Wound and surrounding appears to be warmer and painful.

8 Clinical case A 16 year old boy has an small accident with a scratch at the right hand. Few Hours later: around the wound 3 cm Erythema with swelling/edema. Wound and surrounding appears to be warmer and painful. Rubor redness Tumor swelling Calor warming Dolor pain Functio laesa loss of function Celsus ca 30 AC Galen ca 150 AC

9 What can trigger an inflammation? pathogen Injury, mechanical stress, Trauma infection Cell death DANGER! Activation of the immune system Elimination of pathogen Removal of dead cells

10 Inflammation beneficial harmful Local inflammation Systemic inflammation Local activation of endothelial vessel cells for recruitment of immune effector mechanisms Elimination of inflammatory stimulus Resolution of inflammation Tissue remodelling Systemic activation of endothelial cells Septic shock Chronic inflammation No elimination of inflammatory stimulus e.g. artherosclerosis, rheumatoid arthritis

11 What can trigger an inflammation? Typical Biochemical structures= patterns pathogen PAMPs= Pathogen Associated molecular patterns Injury, mechanical stress, Trauma DAMPs=Alarmine Damage associated molecular patterns Pattern recognition receptors = PRRs (soluble and cell-associated) Activation of the immune system Elimination of pathogen Removal of dead cells

12 What can trigger an inflammation? Typical Biochemical structures= patterns pathogen PAMPs= Pathogen Associated molecular patterns Injury, mechanical stress, Trauma DAMPs=Alarmine Damage associated molecular patterns Pattern recognition receptors = PRRs (soluble and cell-associated) Activation of the immune system Elimination of pathogen Removal of dead cells

13

14 äußere Membran Peptidoglykyan (B) Zellmembran (A) Lipopolysaccharid (D) Aufbau des Lipopolysaccharids Porine Lipoprotein Peptidogykan äußere Membran Periplasmatischer Raum Zellmembran (C) Membranproteine O-spezifische Seitenkette (O-Antigen) Kern-Oligosaccharid Lipid A

15 Fungal PAMPs

16 How are viruses recognized? ssrna viruses use dsrna stage for replication

17 What can trigger an inflammation? Typical Biochemical structures= patterns pathogen PAMPs= Pathogen Associated molecular patterns Injury, mechanical stress, Trauma DAMPs=Alarmine Damage associated molecular patterns Pattern recognition receptors = PRRs (soluble and cell-associated) Activation of the immune system Elimination of pathogen Removal of dead cells

18 Mustererkennungrezeptoren (PRRs) membrangebundene PRRs scavenger Rezeptoren Toll-like Rezeptoren C-Typ-Lektin-Rezeptoren Erkennung nach Opsonisierung: mit Antikörpern: Fc-Rezeptoren mit C3b: Komplement-Rezeptoren CR3 cytosolische PRRs NOD-like Rezeptoren (NOD1, NOD2) RIG-I-likeRNA-Helikase sezernierte Proteine Collektine: (gehören auch zu C-Typ-Lektinen) Mannose-bindendes Lectin (MBL) und surfactant protein A, D (SP-A, SP-D) Ficoline Pentraxine: Serum Amyloid, C-reaktives Protein, endozytierende Rezeptoren signalgebende Rezeptoren: adaptive Immunantwort (Expression von Cytokinen, kostimulatorischen Proteinen Komplement-Aktivierung

19 1.Phase: reaction of local inflammation Activation of Plasma enzymes Complement Bradykinin

20 1) wound closure (clotting, thrombocyte activation) 2) Activation of Plasma enzymes pathogen Physical/ chemical barrier of the skin and mucosa complement Bradykinin dolor=pain Kill/Lyse pathogen Mediators Mark target (opsonization) Anaphylatoxine Chemotaxis

21 Activation of Coagulation DAMPs PAMPs

22 Kallikrein-Kinin-System Coagulation Faktor XII (Hagemann) Pre-kallikrein Kallikrein Plasmin Trypsin Bacterielle Enzymes Snake poisson Kininogen Kinine (Bradykinin, Kallidin)

23 Activation and Function of the Complementsystem

24 Komplementsystem Bordet, 1890, Komplement-vermittelte Bakteriolyse (Vibrio cholerae): hitzelabile Komponente im Serum (> 30 Proteine) verstärkt (komplementiert) die Wirkung von Antikörpern. Der MBL- und der alternative Weg sind phylogenetisch älter als der zuerst entdeckte klassische Weg.

25 Drei Wege der Complementaktivierung Figure 14-5 The early steps of complement activation by the alternative and classical pathways. The alternative pathway is activated by C3b binding to various activating surfaces, such as microbial cell walls, the classical pathway is initiated by C1 binding to antigen-antibody complexes, and the lectin pathway is activated by binding of a plasma lectin to microbes. The C3b that is generated by the action of the C3 convertase binds to the microbial cell surface or the antibody and becomes a component of the enzyme that cleaves C5 (C5 convertase) and initiates the late steps of complement activation. The late steps of all three pathways are the same (not shown here), and complement activated by all three pathways serves the same functions. Downloaded from: StudentConsult (on 28 November :30 AM) 2005 Elsevier

26 Analaphylatoxine Pathogene surface C3a C3 C5a C3 C3b Alternative pathway C3 convertase C3b,Bb Membrane attacking complex MAC complement Plasmaproteases C5b C3 C5 (C9)n MBLectin pathway MBL C3 convertase C4b2b C4 C2 C5 Convertase: C3b,Bb plus C3b C4b2b plus C3b Classical pathway Antibody Incorporation into Pathogenic membrane (pores, lysis)

27 C3b-Inaktivierung in wässriger Umgebung versus kovalente Fixierung an pathogener Oberflähce Führt zur verbesserten Phagozytose über Komplementrezeptoren Opsonierung Figure 14-7 Internal thioester bonds of C3 molecules. A schematic view of the internal thioester groups in C3 and their role in forming covalent bonds with other molecules is shown. Proteolytic cleavage of the α chain of C3 converts it into a metastable form in which the internal thioester bonds are exposed and susceptible to nucleophilic attack by oxygen (as shown) or nitrogen atoms. The result is the formation of covalent bonds with proteins or carbohydrates on the cell surfaces. C4 is structurally homologous to C3 and has an identical thioester group. Downloaded from: StudentConsult (on 28 November :30 AM) 2005 Elsevier

28 Klassischer Pathway der Komplementaktivierung Figure 14-8 The classical pathway of complement activation. Antigen-antibody complexes that activate the classical pathway may be soluble, fixed on the surface of cells (as shown), or deposited on extracellular matrices. The classical pathway is initiated by the binding of C1 to antigen-complexed antibody molecules, which leads to the production of C3 and C5 convertases attached to the surfaces where the antibody was deposited. The C5 convertase cleaves C5 to begin the late steps of complement activation. Downloaded from: StudentConsult (on 28 November :30 AM) 2005 Elsevier

29 Der C1q-Komplex C1r2s2 ist eine Protease: sie aktiviert C4 durch proteolytische Spaltung Figure 14-9 Structure of C1. C1q consists of six identical subunits arranged to form a central core and symmetrically projecting radial arms. The globular heads at the end of each arm, designated H, are the contact regions for immunoglobulin. C1r and C1s form a tetramer composed of two C1r and two C1s molecules. The ends of C1r and C1s contain the catalytic domains of these proteins. One C1r2s2 tetramer wraps around the radial arms of the C1q complex in a manner that juxtaposes the catalytic domains of C1r and C1s. Downloaded from: StudentConsult (on 28 November :30 AM) 2005 Elsevier

30 Antigen-gebundenes IgM und IgG1+3 aktivieren Komplement Figure C1 binding to the Fc portions of IgM and IgG. C1 must bind to two or more Fc portions to initiate the complement cascade. The Fc portions of soluble pentameric IgM are not accessible to C1 (A). After IgM binds to surface-bound antigens, it undergoes a shape change that permits C1 binding and activation (B). Soluble IgG molecules will also not activate C1 because each IgG has only one Fc region (C), but after binding to cell surface antigens, adjacent IgG Fc portions can bind and activate C1 (D). Downloaded from: StudentConsult (on 28 November :30 AM) 2005 Elsevier

31 Aktivierung der C5-Convertase führt zur C9-Polymerisierung und damit zur Formierung des Membran-attacking Complex (MAC) Figure Late steps of complement activation and formation of the MAC. A schematic view of the cell surface events leading to formation of the MAC is shown. Cellassociated C5 convertase cleaves C5 and generates C5b, which becomes bound to the convertase. C6 and C7 bind sequentially, and the C5b,6,7 complex becomes directly inserted into the lipid bilayer of the plasma membrane, followed by stable insertion of C8. Up to 15 C9 molecules may then polymerize around the complex to form the MAC, which creates pores in the membrane and induces cell lysis. C5a released on proteolysis of C5 stimulates inflammation. Downloaded from: StudentConsult (on 28 November :30 AM) 2005 Elsevier

32 Bildung des Membranangriffs-Komplexes (MAC) Bedeutung des MAC nicht so groß; Fehlen von C5-9 erhöht nur Empfindlichkeit für Neisseria-Erkrankungen bei Erythrocyten genügen 3-10 C5b-Moleküle, um eine Pore zu erzeugen

33 Der Membrane-attacking Complex (MAC) Figure Structure of the MAC in cell membranes. A. Complement lesions in erythrocyte membranes are shown in this electron micrograph. The lesions consist of holes approximately 100Å in diameter that are formed by poly-c9 tubular complexes. B. For comparison, membrane lesions induced on a target cell by a cloned CTL line are shown in this electron micrograph. The lesions appear morphologically similar to complement-mediated lesions, except for a larger internal diameter (160Å). CTL- and NK cell-induced membrane lesions are formed by tubular complexes of a polymerized protein (perforin), which is homologous to C9 (see Chapter 13). C. A model of the subunit arrangement of the MAC is shown. The transmembrane region consists of 12 to 15 C9 molecules arranged as a tubule, in addition to single molecules of C6, C7, and C8 α and γ chains. The C5bα, C5bß, and C8ß chains form an appendage that projects above the transmembrane pore. (From Podack ER. Molecular mechanisms of cytolysis by complement and cytolytic lymphocytes. Journal of Cellular Biochemistry 30: , Copyright 1986 Wiley-Liss. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.) Downloaded from: StudentConsult (on 28 November :30 AM) 2005 Elsevier

34 Wie schützen sich unsere eigenen Zellen vor der Lyse durch Komplement?

35 Der lösliche Inhibitor C1 INH hemmt die Aktivierung des klassischen Pathways Figure Regulation of C1 activity by C1 INH. C1 INH displaces C1r2s2 from C1q and terminates classical pathway activation. Downloaded from: StudentConsult (on 28 November :30 AM) 2005 Elsevier

36 Die zellmembran-gebundenen Inhibitoren DAF, CR1 + MCP inaktivieren die C3-Konvertase DAF = (CD55) decay accelerating factor MCP = (CD46) Membrane cofactor CR1 = (CD35) Complement receptor 1 Figure Inhibition of the formation of C3 convertases. Several membrane proteins present on normal cells displace either C2a from the classical pathway C3 convertase (A) or Bb from the alternative pathway C3 convertase (B) and stop complement activation. Downloaded from: StudentConsult (on 28 November :30 AM) 2005 Elsevier

37 Der zellmembran-gebundene Inhibitor CD59 (Protektin) verhindert die Polymerisierung von C9 und damit die MAC-Formierung Figure Regulation of formation of the MAC. The MAC is formed on cell surfaces as an end result of complement activation. The membrane protein CD59 and S protein in the plasma inhibit formation of the MAC. Downloaded from: StudentConsult (on 28 November :30 AM) 2005 Elsevier

38 Zellmembran-gebundene Inhibitoren (CD59 (Protektin), DAF) agieren species-spezifisch Problem in der Xenotransplantation Pigs transgenic for human complement inhibitors

39 Complement activation regulation

40 Analaphylatoxine Pathogene surface C3a C3 C5a C3 C3b Alternative pathway C3 convertase C3b,Bb Membrane attacking complex MAC complement Plasmaproteases C5b C3 C5 (C9)n MBLectin pathway MBL C3 convertase C4b2b C4 C2 C5 Convertase: C3b,Bb plus C3b C4b2b plus C3b Classical pathway Antibody Incorporation into Pathogenic membrane (pores, lysis)

41 Funktionen von Komplement Figure Functions of complement. The major functions of the complement system in host defense are shown. Cell-bound C3b is an opsonin that promotes phagocytosis of coated cells (A); the proteolytic products C5a, C3a, and (to a lesser extent) C4a stimulate leukocyte recruitment and inflammation (B); and the MAC lyses cells (C). Downloaded from: StudentConsult (on 28 November :30 AM) 2005 Elsevier

42 1.Phase: reaction of local inflammation Activation of Plasma enzymes Mast cells

43 Mast cell activation Dolor pain activated Complement C3a C5a Anaphylatoxines Mast cells (Basophile Eosinophile) Degranulation (few minutes) Pre-formed Bradykinin Histamin Nerve cells itching Endothelial cells Vasodilatation Rubor redness Tumor swelling

44 anaphylactic shock Komplement activation C3a C5a Mast cells (Basophiles Eosinophiles) Degranulation Histamin Bradykinin Vasodilatation Endothelial gap junctions FcεR Blood pressure IgE crosslinking Shock

45 1.Phase: reaction of local inflammation Activation of Plasma enzymes Mast cells macrophages

46 What kind of PRRs do we know? Typical Biochemical structures= patterns pathogen PAMPs= Pathogen Associated molecular patterns Injury, mechanical stress, Trauma DAMPs=Alarmine Damage associated molecular patterns Pattern recognition receptors = PRRs (soluble and cell-associated)

47

48 How are viruses recognized? ssrna viruses use dsrna stage for replication

49 Receptores for PAMPs = Pattern recognition receptors (PRRs)? LPS LBP CD14?? NF-κB Pro-inflammatorische Zytokine (z.b. TNF-α)

50 Immune response of the fruit fly (Drosophila) Nüsslein-Volhardt Jules Hoffmann

51 Drosophila Human/Mice etc

52 PAMPS-TLR-Specificities West AP, et al in Annu. Rev. CellDev. + Biology

53 TLRs can trigger immune response via 2 different signalling pathways only Myd88 dependent TLR1/2 TLR2/6 TLR5 TLR7 TLR8 TLR9 TRIF only Myd88 Independent (= TRIF dependent) TLR3

54 TLRs can trigger immune response via 2 different signalling pathways

55 How can immune system distinguish between self and viral DNA?

56 TLRs: Receptors as relays of differences in dangers Output: Patterned responses!

57 Innate recognition of molecular patterns drives inflammation and T cell fate infection Innate Immune cells Inflammatory Mediators (e.g. cytokines) adaptive Immune cells PAMPs (e.g. LPS Peptidoglycans) DAMPs (e.g. HSPs HMGB1) Cell death (DANGER!) TLRs Monocytes Macrophages DCs TNFα IL-12 IL-1 IL-6 IL-23 TGF-β TH-1 TH17 IFNγ Intracellular pathogens IL-17 PAMPs = pathogen associated molecular patterns DAMPS = danger associated molecular patterns TLRs = Toll like receptors LPS = Lipopolysaccharide extracellular pathogens

58 TLRs are located in different cell types and compartiments mainly in macrophages and mdcs mainly in pdcs NF-κB TNFα etc. Nucleus IRF7 IFNβ Also other (non-immune) cells (e.g. epithelial cells) can express TLRs

59 Other PRRs NOD1 and NOD2 as intracellular PRRs

60 How can a virally infected non-immune cell, which does not express TLR3, 7 or 9 sense the viral infection and induce IFNα expression?

61 Alternative (TLR independent) intracellular RNA recognition

62

63 Intracellular DNA and RNA sensors

64 Inhibition of virus replication by IFNα/β IFNα/β 2-5OA RNAseL Degradation of dsrna PKR eif2-p translation PKR = RNA-dependent protein kinase 2-5OA = 2-5 oligoadenylate synthetase

65 Typ-I-Interferone Bildung Induktion von IFN-β durch dsrna (TLR3 oder PKR) in allen Zellen Verstärkung autokrin oder parakrin über IFN-R, Bildung von IFN-α (wirkt dann unabhängig von NFkB) Interferon-producing cells (IPC) (1 % der Leukozyten, sehen wie Plasmazellen aus), können 1000x mehr IFN produzieren als andere Zellen) und besitzen verschiedene TLR und differenzieren zu plasmacytoid dendritic cells (pdcs) Folgen Bildung von Oligoadenylat-Synthetase (Synthese von 2-5 -oligoa, aktiviert Endonuklease, baut virale RNA ab) verstärkt Proliferation und Cytotoxizität von NK-Zellen und bewirkt Expression von Liganden für NK-Zellen (MIC-A, MIC-B) Induktion von PKR als PRR

66 Other PRRs C-type lectins

67 C-Typ-Lektin-Rezeptoren typisch ist eine Ca 2+ -abhängige CRD-Domäne (carbohydrate recognition domain) Mφ mannose receptor DC-SIGN Dectin-1 Mφ mannose receptor is a constantly recycling endocytic receptor, recognition of terminal mannose/fucose > NAc-Glc (CRD) and sulphated-nac- Gal DC-SIGN (DC-specific ICAM3 grabbing non-integrin) is largely restricted to DC, recognises highmannose oligosaccharides Mφ Mannose Receptor DC-SIGN Dectin-1 Dectin-1 exhibits specificity for β-(1,3/1,6)-glucans in fungal cell walls expressed on monocytes, MØ, neutrophils and subsets of DC

68 Scavenger receptors: PPRs for both infectious nonself and modified self erkennen modified LDL (mldl) und anionische Substanzen (z.b. LPS, Lipoteichonsäuren, einige Polynukleotide) Aufnahme von acetyliertem und oxidiertem LDL und haben eine Bedeutung bei der Entstehung der Arteriosklerose (CD 36 und SR-A) Aufnahme von Listerien, Staphylokokken, Neisserien und apoptotischen Zellen (SR-A) Aufnahme von Streptokokken (MARCO, MAcrophage Receptor with COllagenous structure) splice-varianten one receptor many ligands LDL receptor ist spezifischer 2 TM N-term. extrazellulär

69 Alarmins = DAMPs (damage/danger associated molecular patterns) Necrotic dying cells release danger signals ECM MSU Inflammasome activation infection Cell death ATP Trauma Injury burn DC inflammation HMGB1 HSPs TLR Stimulation Plasma enzymes ECM Degradation (e.g. Hyalunoric acid) (also other receptors) HMGB = high mobility group B HSPs = heat shock proteins MSU = monosodium urate; uric acid crystals ECM = extra cellular matrix cytokines

70 Inflammasome

71 Partikel, die zum lysosomalen Schaden (und damit mitochondrialen Stress) führen, aktivieren das Inflammasom und damit Entzündung Beispiele: Harnsäurekristalle (Gicht), Asbest, Nanopartikel (Kosmetika), Aluminiumsalze (Adjuvanz) fmet mtdna

72 DAMPs get released by necrotic but not apoptotic cells

73 DAMPs can get inactivated during Apoptosis

74

75 Mustererkennungrezeptoren (PRRs) membrangebundene PRRs scavenger Rezeptoren Toll-like Rezeptoren C-Typ-Lektin-Rezeptoren Erkennung nach Opsonisierung: mit Antikörpern: Fc-Rezeptoren mit C3b: Komplement-Rezeptoren CR3 cytosolische PRRs NOD-like Rezeptoren (NOD1, NOD2) RIG-I-likeRNA-Helikase sezernierte Proteine Collektine: (gehören auch zu C-Typ-Lektinen) Mannose-bindendes Lectin (MBL) und surfactant protein A, D (SP-A, SP-D) Ficoline Pentraxine: Serum Amyloid, C-reaktives Protein, endozytierende Rezeptoren signalgebende Rezeptoren: adaptive Immunantwort (Expression von Cytokinen, kostimulatorischen Proteinen Komplement-Aktivierung

76 Summary PRRs

77 Summary PRR signaling

78 Other cytokines (IL-1, TNF-α) stimulate similar pathways IL-1R IL-17 Such cytokines activate (amplify) inflammation they act as danger signals!

79 Zytokine machen Entzündung Chemokine locken Leukozyten ins entzündete Gewebe Gewebe (Haut) Chemokine Zytokine Haut (Epithel) Blutgefäß transmigration Slow rolling rolling Gefäßwand (Endothel) Blutfluss Leukozyt Entzündungsbotenstoffe weisen den Weg zur Infektionsstelle

80 Activation of inflammation by Danger is required to initiate an immune response apoptotic cell death necrotic cell death Pathogen (PAMPS) NO danger Damage (DAMPS) DC DC Ag presen tation T soluble Mediators (e.g. cytokines) Ag presen tation T costimulation

81 Adjuvantien wirken über PRRs verstärken auf unspezifische Weise die spezifische Immunität gegenüber einem Antigen (Ramon, 1925) werden häufig bei Totimpfstoffen zugesetzt lange vermutete Wirkungsweisen: Depoteffekte (verzögerte Freisetzung von Ag), unspezifische Migration von Zellen zum Injektionsort (Granulombildung), mitogener Effekt,... entfalten ihre Wirkung zumindest teilweise auch über PRRs Freunds Adjuvans (nicht beim Menschen, zu toxisch!) komplettes FA (cfa): Mineralöl, Emulgator, hitzeinaktivierte Mycobakterien inkomplettes FA (ifa): Mineralöl, Emulgator Bordetella pertussis Aluminiumsalze Aluminiumsulfat oder Aluminiumhydroxid definierte Adjuvantien... aber für die Zulassung gibt es große Hürden MF59 (mit Squalen) im Grippeimpfstoff FLUAD MPL (Monophosphoryl-Lipid A) bei einem speziellen HBV-Impfstoff (Fendrix) CpG-basiertes Adjuvans (VaxImmune) (immer noch in Erprobung)

82 Haut (Epithel) Gewebe (Haut) Mast zelle Komplement aktivierung MΦ DCs Histamin PGs Zytokine (z.b. TNFα, IL-1) Chemokine (z.b. IL-8 = CXCL8) Blutgefäß Vaso dilatation Öffnung Tight junctions Influx C +AK Induktion Adhäsions moleküle Influx Granulozyten PAMPs = pathogen associated molecular patterns DAMPS = danger/damage associated molecular patterns PRRs = pattern recognition receptors

83 Anlocken und Extravasation von Neutrophilen Glykoprotein-Selektin Chemokin-Chemokin-Rezeptor Integrin-Integrin-Ligand PECAM CXCL8 (IL-8) wirkt chemotaktisch auf Neutrophile bacterial products (fmlp), C5a, LT- B4 Ca 2+ Cytoskelett Neutrophile wandern schneller zum Entzündungort (1 d) als Monozyten (2-3 d) P-selectin glycoprotein ligand-1 P(platelet)-Selektin aus intrazellulären Vesikeln (Weibel-Palade-bodies) Sekunden nach Signal, z. B. Histamin an die Zelloberfläche E(endothelial)-Selektin: Neusynthese induziert durch TNF-α oder IL-1 über NFκB IL-12 Aktivierung von NK-Zellen TNF-α, IL-1 induzieren Bildung von Zell-adhäsionsmolekülen, erhöhte Gefäßpermeabilität (TNF-α) IL-6 Leber: Bildung von Akut- Phase-Proteinen Fieber (IL-1, TNF-α, IL-6)

84 Neutrophil ways of KILLING

85 Haut (Epithel) Gewebe (Haut) Mast zelle Komplement aktivierung MΦ DCs Histamin PGs Zytokine (z.b. TNFα, IL-1) Chemokine (z.b. IL-8 = CXCL8) Blutgefäß Vaso dilatation Öffnung Tight junctions Influx C +AK Induktion Adhäsions moleküle Influx Granulozyten PAMPs = pathogen associated molecular patterns DAMPS = danger/damage associated molecular patterns PRRs = pattern recognition receptors