RECOGNITION BY SOLUBLE MOLECULES MANNOSE BINDING LECTIN

PHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENS PHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENS CR3 Toll receptor OTHER PATTERN RECOGNITION MOLECULES MANNOSE RECEPTOR MANNOSE BINDING LECTIN

Eukariotic cells Glucoseamin Mannose Galactose Neuraminidase GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES Mannose Prokariotic cells

Macrophage/dendritic cells Mannose Receptor Bacterium Mannose MANNOSE RECEPTORS ON PHAGOCYTES

PATTERN RECOGNITION BY MANNAN BINDING LECTIN Strong binding No binding Bacterium lysis Complement activation Macrophage Phagocytosis CR3 LECTIN PATHWAY

WHAT IS RECOGNIZED BY INNATE AND ACQUIRED IMMUNITY? HOW DO THEY RECOGNIZE PATHOGENS? Common pattern of groups of pathogens Pathogen Associated Molecular Pattern PAMP Recognition by receptors Pattern Recognition Receptor PRR 9-13 various Toll-receptors TLR family RECEPTORS Innate immunity Ancient

RECOGNITION INNATE IMMUNITY CYTOPLASMIC SENSORS

TLR CYTOPLASM CARD-CARD-helicase RLH CONSERVED RECEPTORS SENSING DANGER SIGNALS NLR Leucin rich repeats Nucleotide binding domain NLRP1 – ASC NLRP3 – ASC – CARDINAL NBD NC PYR CARD NOD1/2, IPAF/NLRC4 MEMBRANTLR3 BIR IPAF Fibroblast Epithelial cell DC NBD NBD

SIGNALING INNATE IMMUNITY

paracrine autocrine Infected cell subtypes IFN-  IFN-  IFN response IRF-3 IRF-7 Virus IFN-  IFN-  NF  B AP-1 Type I IFN receptor IFN response VÍRUS INDUCED TYPE I INTERFERON PRODUCTION

Plasma membrane Cytoplasm Type I. IFN receptor Type II. IFN receptor Type III. IFN receptor (IFNλ) TYK2JAK1TYK2JAK1 JAK2 JAK1 JAK2 STAT1 STAT2 Nucleus STAT1STAT2 P P STAT1STAT2 P P STAT1 P P P P IRF9 ISRE GAS – promoter elements Antiviral immunityAntimycobacterial immunity ISG15, Mx, OAS and PKR IL-10R2IFNLR1IFNAR1/2IFNAG1/2 Interferon-stimulated genes

INTERFERON EFFECTOR PATHWAYS 1. Mx GTPase pathway –block viral transcription 2. 2',5'-oligoadenylate-synthetase (OAS)-directed ribonuclease L pathway –degrade viral RNA 3. Protein kinase R (PKR) pathway –inhibit translation 4. ISG15 ubiquitin-like pathway –modify protein function CONTROL ALL STEPS OF VIRAL REPLICATION

Oligomer accumulation in cytoplasmic membranes (e.g. ER) (Nucleus) (Cytoplasm) ISRE MxA MxA monomer MxA oligomer Trapped viral components (Nucleus) (Cytoplasm) ISRE OAS1 Inactive OAS1 monomer Induction by viral dsRNA Active OAS1 tetramer synthetized pppA(2’p5’A)n inactive RNaseL monomer active RNaseL dimer cleaved RNA (Nucleus) (Cytoplasm) ISRE PKR Inactive PKR monomer Active PKR dimer Induction by viral RNAs EIF2  P Inhibition of translation Mechanism of action of MxA, OAS1 and PKR

EFFECTS OF TYPE I INTERFERONS Plasmacytoid dendritic cells produce 1000x more type I interferon than other cells NATURAL INTERFERON PRODUCING CELLS – IPC After viral infection they are accumulated at the T cell zone of the lymph nodes vírus

NF-κBIRF3 ACTIVATION OF TRANSCRIPTION FACTORS UPON INNATE IMMUNE RESPONSE Primary response

INNATE/NATURAL IMMUNITY MECHANISMS

TRIF TANK IKKεTBK1 IRF-3 TRIF TRAM TLR3 TLR4 MyD88 IRF-5 TLR7 TLR8 TLR9 IFN-β, IFN-α1 RIG-1 Stimulation of Ig-production in B-cells Type I interferon receptor IRF-7 Increased citotoxicity of NK-cells Activation of  - and γδ T-cells Increased cross-presentation in myeloid dendritic cells IRAK-1 TRAF-6 IRF-7 MULTIPLE EFFECTS OF TYPE I INTERFERONS

Bacterium Complement proteinsLysis of bacteria Inflammation Complement-dependent phagocytosis COMPLEMENT Phagocytosis Intracellular killing PHAGOCYTOSIS Phagocyte Bacterium CELLULAR AND HUMORAL MECHANISMS OF INNATE IMMUNITY INFLAMMATION Bacterium LPS Cytokines Neutrophil NK-cell Macrophage TNF IL-12 IFN  NK-CELLS Virus-infected cell NK-cell Lysis of infected cell

Degradation ACTIVATION Uptake PHAGOCYTOSIS MECHANISMS OF INNATE IMMUNITY Phagocyte PRR hours The amount of internalized particles is limited Antigen + Antibody ACQUIRED IMMUNITY Bacterium Intracellular killing Antigen presentation T cell ACQUIRED IMMUNITY

Cytokines/chemokines produced by activated macrophages - local and systemic effects Szisztémás hatás

Failure of phagocytes to produce reactive oxigen species in chronic granulomatous dideasePROTECTION against bacteria and fungi is down regulated

Lysis of bacteria COMPLEMENT ACTIVATION Inflammation Chemotaxis Complement-dependent phagocytosis Bacterium COMPLEMENT Lectin pathway Alternative pathway Antigen + Antibody ACQUIRED IMMUNITY Complement-proteins Few minutes – 1 hour Enzymes get fragmented, complement activity can be exhausted MECHANISMS OF INNATE IMMUNITY

NK-cell IL-12 macrophage IFN  cytokines neutrophil TNF-  INFLAMMATION – ACUTE PHASE RESPONSE hrs Plasma level LPS (endotoxin) (Gram(-) bacteria) TNF-  IL-1  IL-6 Kinetics of the release of pro- inflammatory citokines in bacterial infection TNF-  IL-1  IL-6 Few hours ACUTE PHASE RESPONSE Bacterium LPS DANGER SIGNAL ACTIVATION PRR MECHANISMS OF INNATE IMMUNITY

Lysis of infected cell ACTIVATION OF NATURAL KILLER CELLS Kinetics of the activity of the complement system and NK cells in virus infection IFN  IL-12 Complement system NK-cells days Relatív szint/aktivitás NK-CELLS Virus-infected cell PRR RECOGNITION ACTIVATION RECOGNITION OF ALTERED HOST CELLS MECHANISMS OF INNATE IMMUNITY

CELLS HUMORAL FACTORS Phagocytes (monocyte/macrophage, neutrophil, dendritic cell) Killer cells (NK cell,  δ T cell) B1 lymphocytes (CD5+) Enzymes (lysozyme,transferrin, lactoferrin, spermin, trypsin) Antibacterial peptides Complement system Cytokines, chemokines TWO LINES OF IMMUNE DEFENSE TWO TYPES OF IMMUNE RESPONSES INNATE/NATURAL IMMUNITY B1 cells: Fast response within 48 hrs T cell independent Surface IgM Long life span Peritoneal cavity γδ T-cells: skin, guts limited diversity Binds pathogen derived organic phosphates express NKG2D NKT-cells: fast response lipid antigens swift cytokine release

NATURAL/INNATE Rapid, prompt response (hours) No variable receptors Limited number of specificities No improvement during the response No memory Not transferable Can be exhausted, saturated CHARACTERISTICS OF INNATE IMMUNITY COMMON EFFECTOR MECHANISMS FOR THE ELIMINATION OF PATHOGENS

TOW LEVELS OF DEFENSE TWO TYPES OF THE IMMUNE RESPONSE INNTE/NATURAL IMMUNITY Protects without prior activation or multiplication against pathogens AQUIRED/ADAPTIVE IMMUNITY Protects after activation and clonal expansion against pathogens First line of defense Inrerited Persistant presence Rapid response Short term protection