Immunology Part II. Innate Immunity. 18. April 2018, Ruhr-Universität Bochum Marcus Peters,

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1 Immunology Part II Innate Immunity 18. April 2018, Ruhr-Universität Bochum Marcus Peters,

2 Conserved structures of pathogens PAMPs are detected by Pattern Recognition Receptors PRRs

3 innate adaptive Innate immunity evolved early in evolution MASP=MBL associated serine protease

4 Stages of the immune response to infectious microbes

5 Innate Immunity Humoral immune response 1) lysozyme: enzyme that is able to cleave peptidoglycan of bacterial cell walls 2) Antimicrobial peptides: e.g. Defensin (direct bactericidal activity by pore formation in the cell wall) 3) Complement system (chemotaxis of leucocytes, opsonization of pathogens, destruction of pathogens)

6 Different ways of how the complement system protects against an infection 1. Production of activated complement proteins, which bind covalently to pathogens and opsonise them, so that an incorporation by phagocytes, which carry CR, will facilitate (opsonization). 2. Smaller fragments that can be released after complement activation act as chemoattractants (attract phagocytes and activate these) (anaphylatoxin). 3. Destruction of pathogens by pore formation (bacteriolysis).

7 Three different mechanisms of complement activation Classical pathway MB-lectin pathway Alternative pathway Antigen-antibodycomplex Lectin binds on the surface of the pathogen Pathogen surfaces Complement activation Attraction of inflammatory cells Opsonisation of pathogens Destruction of pathogens

8 Effect Regulation Recognition Essential components and effector impacts of the complement system Classical way MB-lektin way Alternative way Antigen: antibody-complexes (pathogen surfaces) Mannan binding lectin binds mannose on the pathogen surface Pathogen surfaces C1q, C1r, C1s, C4, C2 MBL, MASP-1, MASP-2, C4, C2 C3, B, D C3-convertase C4a*, C3a, C5a C3b Terminal complement components C5b, C6, C7, C8, C9 Inflammatory mediated peptides, attraction of phagocytes binds on complement receptors on the phagocytes Opsonisation of pathogens Removal of immunocomplexes Membrane offending complex, lyse of specific pathogens and cells

9 Innate Immunity NK cells

10 Innate Immunity - NK cells Natural killer cells Found in tissue and blood Characteristic marker CD56, Fcg III Receptor

11 From innate to adaptive immunity Time line of development Figure 2-49

12 Inhibition of NK cell activation by normal cells Figure 2-50 part 1 of 2

13 Activation of NK cell by altered cell surface Mechanism I Figure 2-50 part 2 of 2

14 Innate Immunity Third defense Mast cells

15 Innate Immunity - Mast cells mast cells cells found in tissue characteristic markers: c-kit, Fce Receptor, cytoplasmatic granula stains blue with Methylen-Blue

16 Activation of mast cells in allergic disease allergen IgE FceR Mast cell

17 But mast cells have also some very useful functions Mast cell deficient mice Yellow scorpion (Leiurus quinquestriatus) (LD50 value of toxin approx. 0,50 mg/kg) J Clin Invest. 2011;121(10):

18 Innate Immunity Eosinophilic granulocytes

19 Innate Immunity - Eosinophilic granulocytes Eosinophilic granulocytes cells found in tissue and blood orange-staining granula with EosinY granula contains toxic molecules

20 Atopic asthma is a disease where inflammation is triggered by eosinophils Large airway

21 However, similar to the mast cell eosinophilic granulocytes can have some useful functions too Schistosome larva Eosinophilic granuloctes attacking IgE coated parasite

22 Innate Immunity Phagocytes

23 Innate Immunity - Phagocytes Phagocytic cells: macrophages of tissues monocytes of blood neutrophilic granulocytes

24 Phagocytosis of yeast particles by neutrophils (left) and macrophages (right) TRENDS in Immunology Vol.26 (2005)

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26 Formation of neutrophil extracellular traps (NET)

27 Innate Immunity Third defense Dendritic Cells

28 Dendritic cells Innate Immunity Dendritic Cells Found in tissue and blood Characteristic marker CD1a, CD11c, MHC II uptake of antigen via endocytosis

29 Dendritic cells bridge innate and adaptive immune response via presentation of antigens to T-lymhocytes

30 PRR Receptors of Innate Immune Cells Pattern recognition receptors (PRR) detect pathogen associated molecular patterns PAMPs Three types of PRR are known: 1. Toll like receptors =TLR 2. nucleotide-binding oligomerization domain-like receptors (NOD) NLR 3. c type Lectin-receptors =CLR

31 The receptor Toll was identified in Drosophila Toll Toll-like Receptor Toll was identified 1996 as a key receptor for immune response against fungi Human Toll-like recepors (TLR) are homologous to Drosophila tollprotein and have a key function in mediation of the immune response

32 Known ligands for the Toll-like receptors TLR1/2:triacyl- Lipoprotein TLR2/6:diacyl- Lipoprotein TLR3: dsrna TLR4: LPS TLR5: Flagellin TLR7: ssrna TLR8: ssrna TLR9: unmethylated CpG oligonucleotides TLR10:?? TLR11: uropathogenic bacteria TLR12: Profilin of T. gondii TLR13: rrna By Jeff Dahl - GFDL, commons.wikimedia.org/

33 O Neill et al. IRAK=Interleukin-1 receptor-associated kinase MKK= Mitogen-activated protein kinase kinase IKK=IκB kinase TIR domain=toll-interleukin receptor MyD88=Myeloid differentiation response

34 The importance of the TLR signal transduction is apparent in MyD88 knock out mice when they become infected with bacteria

35 Phagocytes induce inflammation After activation of TLRs by PAMPs phagocytes release a specific pattern of cytokines triggering inflammation that results in Inflammation:calor (heat), dolor (pain), rubor (redness) and tumor (swelling) Tissue vessel

36 endocrine paracrine Proinflammatory cytokines have a broad spectrum of functions

37 An example for the endocrine activity of IL6

38 LPS of gramnegative bacteria TLR-4 Lipopeptide of grampositive bacteria TLR-2 IL-1 TNF-a IL-6 Additionally controlled by Inflammasome activation! Inflammation

39 Maturation of Interleukin-1b by the Inflammasome

40 Activation of the inflammasom leads to recruitment of Caspase-1 Known activators for inflammasom -Uric acid -ATP binds to Pyrin Domain after oligomerization! pro IL-1b IL-1b

41 Dysregulated Inflammasome activation is involved in Inflammatory disease

42 Another group of pattern recognition receptors are the c-typ Lectins (CLR) - Carbohydrate Recognition Domain (CRD) -Type 1 (more than one CRDs) - Type 2 (only one CRD) - Binding of sugar is Ca 2+ dependent -Can facilitate endocytosis of antigens -Some have also signaling properties Quelle: Figdor et al. 2002

43 Examples for the activation of DCs via CLRs