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!! LYMPHOID ORGANS Primary lymphoid organs: - Bone marrow - Thymus Secondary lymphoid organs: - Spleen - Lymphatic vessels - Lymph nodes - Adenoids and tonsils - MALT (Mucosal Associated Lymphoid Tissue) GALT (Gut Associated Lymphoid Tissue) BALT (Bronchus Associated Lymphoid Tissue) SALT (Skin Associated Lymphoid Tissue) NALT (Nasal Associated Lymphoid Tissue) THE TWO ARMS OF THE IMMUNE SYSTEM Monocytes, Macrophages, Monocytes, Macrophages, Dendritic cells, Granulocytes, NK Dendritic cells, Granulocytes, NK cells and Complement components cells and Complement components B and T cells !! Professional phagocytic cells macrophages neutrophyl granulocytes dendrtitic cells !! the phagocytosed cells or molecules may modify the functions of the cell phagocytosis followed by enzymatic degradation Professional antigen presenting cells macrophages B lymphocytes dendrtitic cells they express MHCII molecules the protein degradation products (peptides) can be presented to T lymphocytes by MHC molecules !! Cells of innate immune system: !! Macrophages: Macrophages are constitutively present in tissues and recognize microbes that enter these tissues and respond rapidly to these microbes. Initiate the immune response •These cells are phagocytes (eliminate the pathogens) •Activate the innate immune response (by secreted proteins, called cytokines) •Activate the adaptive immune system. Macrophages serve as APCs that display antigens to and activate T lymphocytes •Dendritic cells are constitutively present in tissues and recognize rapidly microbes that enter these tissues. Initiate the immune response. •They have phagocytic capabilities migrate to lymph nodes, and display microbial antigens to T lymphocytes,professional antigen presentimg cells (APC) Neutrophil granulocytes are phagocytes, the main function to eliminate the pathogens Appear only in the circulation under normal condition Main actors In inflammatory processes How do immunocytes communicate: Soluble mediators Infection CYTOKINES & CHEMOKINES Phagocyte activation Soluble proteinsproduced by cells. They have strong effect on the function of other cells. Bit similar to hormones. How do immunocytes communicate: Cell-cell interaction Cell-cell communication takes place commonly in all the phases of the immune response Cell killing CTL Target cell T Y Antigen presentation B T Antibody production Activation of accessory cells Dendritic cell macrophage THE MOST IMPORTANT FEATURES OF CYTOKINES The most important mediators of indirect cell communication in the immune system („hormones” of the immune system). Act in low concentrations. Cytokines can affect in an autocrine way, in a paracrine way, or in an endocrine way pleiotropic effect. Cytokines can act by synergistic or antagonistic ways to each other. A given cell may by affected by many cytokines resulting in the same effect redundant effect. - The responsiveness of the given cell is based on the expression of cytokine-specific receptors. ! Cytokines can be devided into sub-groups by origin and functional properties. Functional groups: Inflammatory cytokines Direct the development and maturation of immune cells Direct activation and differentiation of immune cells Categories of cytokines hormons cytokines interleukins chemokine interferons General schema of receptor funtion MOLECULES OF THE IMMUNE SYSTEM Most important receptors of the imune system •receptors (BCR, TCR, MHCI, MHCII, PRR, etc.) Soluble molecules: • cytokines • antibodies • complement components Receptors responsible for the recogniton of pathogens in the immune system Caracteristics of innate PRR Pattern recognition immune system, receptors macrophage, dendritic cells Danger signal and Pathogen recognition mainly in the innate immun system B cells BCR (B cell receptor) T cells TCR (T cell receptor) All nucleated cells in human MHC (MHCI) Major Histocompatibility Complex Antigen recognition of B cell Antigen recognition of T cell Do not recognise pathogens, but present intracellular peptides required for T cell receptor professional antigen presenting cells: macrophages, DC, B cells MHCII Do not recognise pathogens, but present extracellular peptides required for T cell receptor INNATE IMMUNITY I Physical and chemical barriers Stomach pH of 3-4 Pepsin Skin Tight junctions Keratin layer Antibacterial peptides; Defensins pH of 5.5 Fatty acids Burns and susceptibility to infections! Eye Tear film (Oils, lactoferin, mucin and lyzosyme) Vagina pH of 3.8-4.5 Lactobacillus Lactic acid Respiratory tract Cilliary movement Coughing, sneezing Impaired cilia movement (CF)! Monocite / macrofage Recogni -tion Cell-cel (APC) Communi cation Soluble effector function DC Mast cell Granulocites NK cell B cell T cell Complement INNATE IMMUNITY Pathogen recognition PRRs (TLRs, C type lectins, Mannose and Glucan binding lectins, NLRs and RIG-I helicases) Phagocytosis, effector functions Communication/ Antigen presentation Intracellular – on surface MHC I complex proteins Extracellular – on surface MHC II complex proteins Innate immunity as a first line of defence Innate immune cells recognize frequently found structures of pathogens, these are not found in human cells! Examples: duple strain RNA bacterial cell wall components bacterial flagellin…. Recognition is inevitable !! Danger signal! !! The innate immune system also recognizes molecules that are released from damaged or necrotic cells. Such molecules are called damage-associated molecular patterns (DAMPs). Innate immunity as a first line of defence Innate immune cells recognize frequently found structures of pathogens, these are not found in human cells! Examples: duple strain RNA bacterial cell wall components bacterial flagellin…. Recognition is inevitable !! PAMPs- Pathogen associated molecular patters Structures on pathogens recognized by the innate cells PRR types TOLL RIG like receptors NOD Scavanger receptors C type lectin receptors Mannose recognizing receptors TLRs RECOGNIZE VARIOUS MICROBIAL STRUCTURES Bacteria Virus CpG DNA ssRNS dsRNA Peptidoglycane Gram+ TLR3 IFN TLR7 TLR8 TLR2 Interferon producing cell PC/DC Flagellin LPS Gram- TLR4 TLR6 TLR9 Macrophage/Dendritic cell TLR5 TLR receptors: • Intracellular and cell surface sensors. • Viral RNA, non-methylated DNA characteristic of bacteria, bacterial flagella, bacterial surface components (lipoproteins, peptidoglicans) and fungi structures. • Partial overlapping recognition between NOD and RIG like receptors. TLRs TLR1:TLR2 Ligands: Lypopotreins lypoteichoic acid proteoglycan zymosam Microorganis m recognized: Cells carrying receptor: Cellular location: Bacteria Parasites DCs, mono, Eos/Baso, mast cells Plasma mem. -”- Plasma mem. TLR2:TLR6 -”- G+ Bacteria Fungi TLR3 dsRNA Viruses NK cells Endosomes TLR4:TLR4 LPS G- Bacteria Mϕ, DCs Plasma mem. TLR5 Flagellin Motile Bacteria Intestinal Epi. Plasma mem. Endosomes TLR7 ssRNA Viruses pDCs B cells Eos/Baso TLR8 ssRNA Viruses NK cells Endosomes Bacteria Viruses pDCs B cells Endosomes TLR9 Unmethylated CpG-ODN (ssDNA) NOD like receptors NOD-like receptors: • Intracellular receptors. • Recognizing intracellular pathogen and danger signals. • Partial overlapping recognition with TLRs. RIG receptors: •Intracellular sensors. •Recognizing viral RNA, inducing an anti-viral response. •Partial overlapping recognition with TLRs. Additional PRRs: Prokaryotes Eukaryotes Mannóz Glucosamine Galactose Siallic acid Mannose Mannose Bacterium Mannose receptors Macrophage / Dendritic cell Specificity of innate immunity ( ) ! direct connetion between innate cells and pathogen Few receptors (20-30) are responsible for the recognition of all the pathogens OPSONIZATION !! Opsonization facilitate and accelerate the recognition of the pathogen by phaogocytes, opsonins form a bridge between pathogen and a phagocyte connecting them. Main opsonins: antibodies Complement fragments Acute-phase proteins Soluble mediators Pathogen recognition by innate immune system 1. Directly via PRR 2. Indirectly via opsonization INNATE IMMUNITY Pathogen recognition PRRs (TLRs, C type lectins, Mannose and Glucan binding lectins, NLRs and RIG-I helicases) Effector functions, elimination of pathogens Communication/ Antigen presentation Intracellular – on surface MHC I complex proteins Extracellular – on surface MHC II complex proteins INNATE IMMUNITY II Effector functions, elimination of pathogens 1. Phagocytosis 2. Killing with soluble mediators 3. Complement system 4. NK cell activation !! PHAGOCYTOSIS PRR Degradation ACTIVATION Bacterium Phagocyte Uptake Intracellular killing 0.5 - 1 hours The amount of internalized particles is limited Antigen presentation T cell ACQUIRED IMMUNITY THE PHAGOCYTIC SYSTEM MACROPHAGES DENDRITIC CELLS NEUTROPHILS Phagocytic cells Professional antigen presenting cells -Macrophages -Macrophages -Dendritic cells -Dendritic cells -Neutrophil granulocytes - B lymphocytes (No presentation on MHC II) (no killing action, only Ag presentation) PHAGOCYTOSIS Extracellular pathogen phagocytosis and killing Extracellular pathogen phagocytosis and killing 2. Soluble mediators reeased from macrophages, granulocytes are responsible for kiliing of extracellular pathogens ROS reactive oxigen species NO nitric oxide Destructive enzymes, antimicrobial substances Intracellular bacterial evasion of killing in phagocytes Macrophage effector capacity Defensins Phagosome acidification Phagosome–lysosome fusion Lysosomal enzymes Intraphagolysosomal killing ROI RNI Iron starvation Tryptophan starvation 3. COMPLEMENT ACTIVATION COMPLEMENT Complement-proteins Lysis of bacteria Inflammation Chemotaxis Bacterium Lectin pathway Alternative pathway Complement-dependent phagocytosis Antigen + Antibody Few minutes – 1 hour ACQUIRED IMMUNITY Enzymes get fragmented, complement activity can be exhausted NK cells Major differences between NK cells and B/T lymphocytes: Contain large cytoplasmic granules. Responds fast, circulate in a partly activated state. Do not express surface receptors produced by rearranged genes. Have a range of cell-surface receptors that deliver activating or inhibitory signals Have two main types of receptors: Ig-like Rs and the Lectin-like Rs (inhibitory and activating) that recognize altered cell surface proteins as a result of a virus infection. Overall balance of inhibitory or activating signals decides if the NK cell killing action will take place. Individual NK cells express different combinations of receptors- heterogeneity repertoire of responses to pathogens. ! Killing of the cells infected with intracellular pathogens 1. The activity of NK cells is enhanced by activatory receptors 2. Inhibitory receptors block NK cell activity. Self cells lysis are protected by inhibitory receptors. KAR 3. Infection or tumors may increase the amount of activation and/or decrease the efficacy of inhibition Target MHC+ Target MHC- Inhibition of lysis KIR NK KAR KIR NK KIR – Killer Inhibitory Receptor association to MHC I KAR – Killer Activatory Receptor Adaptive components are also able to activate NK cells ADCC-Antibody Dependent Cell Cytotoxicity Activating NK cells through FcR on NK cells recognizing pathogen-bound Antibodies ACTIVATION OF NATURAL KILLER CELLS NK-CELLS PRR RECOGNITION ACTIVATION RECOGNITION OF ALTERED HOST CELLS Kinetics of the activity of the complement system and NK cells in virus infection Relatív szint/aktivitás Virus-infected cell Lysis of infected cell IFN IL-12 NK-cells Complement system 1 2 3 4 5 6 7 8 9 10 11 12 13 days RECOGNITION RECEPTORS, SIGNAL TRANSDUCTION, PHAGOCYTOSIS, EFFECTOR MECHANISM Pattern recognition Receptors (PRRs) Engagement of PRRs triggers phagocytosis and cytokine production INNATE IMMUNITY Pathogen recognition PRRs (TLRs, C type lectins, Mannose and Glucan binding lectins, NLRs and RIG-I helicases) Phagocytosis, effector functions Communication/ Antigen presentation Intracellular – on surface MHC I complex proteins Extracellular – on surface MHC II complex proteins Recognition of PAMP or DAMP induce inflammation Reminder INFLAMMATION – ACUTE PHASE RESPONSE PRR TNF- neutrophil LPS IL-12 DANGER SIGNAL ACTIVATION IFN Few hours LPS (endotoxin) (Gram(-) bacteria) ACUTE PHASE RESPONSE Kinetics of the release of proinflammatory cytokines in bacterial infection macrophage cytokines TNF- IL-1 Plasma level Bacterium NK-cell TNF- IL-1 IL-6 IL-6 1 2 3 4 5 hrs INNATE IMMUNITY Pathogen recognition PRRs (TLRs, C type lectins, Mannose and Glucan binding lectins, NLRs and RIG-I helicases) Phagocytosis, effector functions Communication/ Antigen presentation Intracellular – on surface MHC I complex proteins Extracellular – on surface MHC II complex proteins INTERFERON RESPONSE Besides virus infected cells.. Plasmacytoid dendritic cells (pDCs) 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 EFFECTS OF TYPE I INTERFERONS vírus Activate cellular genes that destroy viral mRNA and inhibit translation of viral proteins NK cells have a basal cytotoxicity level that is increased up to x100 fold with the exposure to type I IFNs and produce IFN-γ when exposed to IL-12 Helping the initiation of effector T cells- adaptive immune response. VIRUS INDUCED TYPE I INTERFERON PRODUCTION Type I IFN receptor IFN response Virus IFN- IRF-3 NFB AP-1 IRF-3 IFN- paracrine IFN- IRF-7 autocrine Infected cell IFN response IFN- subtypes IRF: interferon regulatory factor MULTIPLE EFFECTS OF TYPE I INTERFERONS on immune cells Increased cytotoxicity and proliferation of NK-cells TLR4 TRAM TRIF TLR7 TLR8 TLR9 TLR3 TRIF MyD88 IRAK-1 TRAF-6 TANK Activation of - and γδ T-cells RIG-1 IKKε TBK1 IRF-7 IRF-3 IRF-5 IFN-β, IFN-α1 Increased antigen presentation in myeloid dendritic cells IRF-7 Type I interferon receptor Stimulation of Ig-production by B-cells INTERFERON EFFECTOR PATHWAYS induction of the „antiviral state” 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 (Ser/Thr kinase, dsRNAdependent) – inhibit translation, preventing viral protein synthesis 4. ISG15 ubiquitin-like pathway – modify protein function LULAR GENES THAT CONTROL ALL STEPS OF VIRAL REPLICA Type I. IFN receptor Type III. IFN receptor (IFNλ) IFNAR1/2 IFNLR1 IL-10R2 Type II. IFN receptor IFNG1/2 JAK2 TYK2 JAK1 TYK2 JAK1 STAT1 STAT2 P JAK2 JAK1 JAK1 Signal Transducers and Activators of Transcription STAT1 Plasma membrane Cytoplasm STAT1 ISGF-3 P STAT2 STAT1 IRF9 P P STAT1 Interferon-stimulated genes STAT1 P STAT1 P STAT2 ISRE ISG15, Mx, OAS and PKR Antiviral immunity Interferon-stimulated Regulatory elements P Nucleus P STAT1 GAS: Gamma Activating sequence GAS – promoter elements Antimycobacterial immunity Oligomer accumulation in cytoplasmic membranes (e.g. ER) MxA oligomer Mechanism of action of MxA, OAS1 and PKR MxA monomer (Cytoplasm) ISRE MxA (Nucleus) synthetized pppA(2’p5’A)n inactive RNaseL monomer Trapped viral components P EIF2 EIF2 Active PKR dimer Active OAS1 tetramer active RNaseL dimer Induction by viral RNAs Induction by viral dsRNA Inactive PKR monomer Inactive OAS1 monomer cleaved RNA ISRE (Cytoplasm) OAS1 (Nucleus) Inhibition of translation (Cytoplasm) ISRE PKR (Nucleus) Reminder INFLAMMATION – ACUTE PHASE RESPONSE PRR TNF- neutrophil LPS IL-12 DANGER SIGNAL ACTIVATION IFN Few hours LPS (endotoxin) (Gram(-) bacteria) ACUTE PHASE RESPONSE Kinetics of the release of proinflammatory cytokines in bacterial infection macrophage cytokines TNF- IL-1 Plasma level Bacterium NK-cell TNF- IL-1 IL-6 IL-6 1 2 3 4 5 hrs RECEPTORS ON MACROPHAGES TLR4 + CD14 Scavanger receptor Mannose receptor FcRI (CD64) Ag + IgG complex MHCI TLR – pathogen pattern FcRII (CD32) MHCII FcRIII (CD16) LFA1 (CD11a/CD18) CR1 (CD35) CR3 (CD11b/CD18) FcRs Receptors and molecules of macrophages RECEPTOR LIGAND FUNCTION FcR IgG, IgE Opsonized phagocytosis, ADCC, release of inflammatory mediators CR3 iC3B, ICAM-1 Opsonized phagocytosis Macrophage Mannose Receptor Lectin Endocytosis, phagocytosis, antigen capture and transport SR-A LPS, polianions, lipoteikolic acid Endocytosis, phagocytosis, adhesion CD14 LPS Transduces LPS activation , TNFa release CCR1 MIP1a, MCP-3 Recruitment, migration of monocytes CCR3 Eotaxin Haematopoiesis, HIV-1 coreceptor CCR5 MIP1 Haematopoiesis, HIV-1 coreceptor CXCR4 SDF-1a Haematopoiesis, HIV-1 coreceptor INNATE IMMUNITY Pathogen recognition PRRs (TLRs, C type lectins, Mannose and Glucan binding lectins, NLRs and RIG-I helicases) Cell activation Increase in MHC, co-stimulation, killing efficiency (ROI, NO, lysosomal enzymes) and cytokine secretion Phagocytosis and Antigen processing Intracellular – degradation in Proteosomes Extracellular – Endiocytosis then degradation in Phagolysosomes Antigen presentation Intracellular – on surface MHC I complex proteins Extracellular – on surface MHC II complex proteins