Basic immunology
Lecture 7-8. Innate immunity, Inflammatory reaction, pattern recognition Timea Berki The levels of host defense • Anatomical „barriers” • Innate immunity, inflammation • Adaptive immunity
J Allergy Clin Immunol. 2010 ;125:S24–S32. I. First line of defense: anatomic „barriers”
1. Mechanical defense 2. Slightly acidic environment 3. Normal (commensal) microorganisms 4. Antimicrobial factors in the body fluids, on the skin / in the gut. 5. Cilia
Janeway CA Jr, Travers P, Walport M, Shlomchik MJ. Immunobiology, 2005. The role of epithelial barriers
Defensins, cathelicidins
Mast cells, IEL: γδ T cells
Abbas, Lichtman, Pillai: Cellular and Molecular Immunology 7th Edition , 2012. Antimicrobial peptides I
Defensin
Cathelicidin
Nat Rev Immunol. 2003 ;3:710-720. Cell Tissue Res. 2011 ;343:175-88. Antimicrobial peptides II The kinetics of innate and adaptive immune response
Abbas, Lichtman, Pillai: Cellular and Molecular Immunology 7th Edition, 2012. Routes of Antigen Entry
Fig. 6-3
th Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 edition. Copyright © 2012 by Saunders, an imprint of Elsevier Inc.Copyright © 2011 by Saunders, an imprint of Elsevier Inc. Activation of the specific immunity
Fig. 2-6
Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. CopyrightCopyright © © 2012 2011 by by Saunders, Saunders, an imprint an of imprint Elsevier Inc. of Elsevier Inc. Effector phase: cells and antibodies return to the place of infection
Fig. 2-6
Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. CopyrightCopyright © © 2012 2011 by by Saunders, Saunders, an imprint an of imprint Elsevier Inc. of Elsevier Inc. Leukocyte Migration
All lymphocyte circulates approx. 1-2 times per day. Fig. 3-1
Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. CopyrightCopyright © ©2012 2011 by by Saunders, Saunders, an imprint an ofimprint Elsevier Inc. of Elsevier Inc. Specificity of innate and adaptive immunity
Abbas, Lichtman, Pillai: Cellular and Molecular Immunology 7th Edition, 2012. Pattern recognition receptors: Toll-like receptors (TLR)
Abbas, Lichtman, Pillai: Cellular and Molecular Immunology 7th Edition, 2012. Trends in Biochemical Sciences 2009; 34: 553-561. Main groups of pattern recognition receptors
Abbas, Lichtman, Pillai: Cellular and Molecular Immunology 7th Edition, 2012. Pattern recognition receptors
Toll-like receptors (TLR) NOD-like receptors (NLR) RIG-like receptors (RLR)
Abbas, Lichtman, Pillai: Cellular and Molecular Immunology 7th Edition, 2012. Pattern recognition receptors: NOD-like receptors (NOD, NLRP, IPAF)
NOD: Nucleotide oligomerization domain
NOD1 and NOD2 recognize peptidoglycan motifs from bacterial cell
Abbas, Lichtman, Pillai: Cellular and Molecular Immunology 7th Edition, 2012. Pattern recognition receptors: RIG-like receptors (RLR)
Abbas, Lichtman, Pillai: Cellular and Molecular Immunology 7th Edition, 2012 . • Local acute inflammation Acute, local inflammation: - Infection or tissue-injury initiate the cascade of non-specific reactions - Immediate reaction - Its role is to inhibit the spreading of infection and tissue injury
Celsus: 4 signs of inflammation: - rubor (red), calor (hot), dolor (painfull), tumor (swelling) + functio laesa (loss of function)
3 main events: - Vasodilation – minutes - Increased capillary permeability, fluid efflux, oedema - Phagocytes migration: - hours Goldsby RA, Kindt TJ, Osborne BA: Kuby Immunology 4th Edition, 2000. Molecular mediators of inflammation
Plasma enzyme mediators:
- kinin kallikrein system - Fibrinolytic system - Complement cascade - Clotting cascade
Lipid mediators: leukotrienes, prostaglandins (PGE)
Chemoattractants: -Chemokines: IL-8 -Complement components - PAF (platelet activating factor) Inflammatory cytokines: IL-1, IL-6, TNFalpha
Goldsby RA, Kindt TJ, Osborne BA: Kuby Immunology 4th Edition, 2000. Mediators of inflammation Initation of acute inflammation
Goldsby RA, Kindt TJ, Osborne BA: Kuby Immunology 4th Edition, 2000. Leukocyte Recruitment Into Tissues
Fig. 3-3
Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. CopyrightCopyright © ©2012 2011 by by Saunders, Saunders, an imprint an ofimprint Elsevier Inc. of Elsevier Inc. Chemokine action Recognition of pathogens, phagocytosis
PRR= „Pattern Recognition Receptors”
àBinding to the PAMPS of microbes
PAMP=„Pathogen Associated Molecular Patterns
Janeway CA Jr, Travers P, Walport M, Shlomchik MJ. Immunobiology, 2005. Phagocyte receptors
Abbas, Lichtman: Cellular and Molecular Immunology 5th Edition, 2005. Process of phagocytosis
Abbas, Lichtman, Pillai: Cellular and Molecular Immunology 7th Edition, 2012 . Reactive oxygen/nitrogen intermediers
Owen, Punt, Stranford : Kuby Immunology 7th Edition, 2013. Neutrophil extracellular traps (NETs)
Networks of extracellular fibers, primarily composed of DNA from neutrophils, which bind pathogens and granule content. Maturation of Macrophages and DCs
Fig. 2-2
Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. CopyrightCopyright © © 2012 2011 by by Saunders, Saunders, an imprint an of imprint Elsevier Inc. of Elsevier Inc. Role of macrophages in acute inflammation: classical activation Resting macrophage: à Phagocytosis
LPS
Activated macrophage: à antigenpresentation, MHCII ↑ cytokine-production
IFNγ
Hyperactivated macrophage: à citotoxicity MHCII ↓ (TNFα)
Abbas, Lichtman, Pillai: Cellular and Molecular Immunology 7th Edition, 2012. Janeway CA Jr, Travers P, Walport M, Shlomchik MJ. Immunobiology, 2005. Activated macrophages produce infalmmatory cytokines LPS originated from Gram – bacterium LPS activates the macrophages, those produce various cytokines
Local effects Activation of Chemotaxis of Lymfocyte- Activates NK-cells, endothel and leukocytes, Activates vascular activation, Th cells induce effector endothelium and Increased Th1 differentiation lymphocytes Activation of increase vascular antibody effector cells permeability production
Systemic effects fever, GM-CSF fever, fever, IL-6 production Complement septic shock Production of acute- IFNα phase-proteins
Janeway CA Jr, Travers P, Walport M, Shlomchik MJ. Immunobiology, 2005. Polarization of macrophages
Abbas, Lichtman, Pillai: Cellular and Molecular Immunology 7th Edition, 2012. Janeway CA Jr, Travers P, Walport M, Shlomchik MJ. Immunobiology, 2005. Mast cells and their activation
TLR4 – LPS àIL-1β, TNF-α, IL-6 and IL-13, without mast cell degranulation TLR2 – peptidoglycan à mast cell degranulation and production of IL-4 and IL-5, IL-6, IL-13 TLR3,7,9 – Poly (I:C), CpG oligonucleotid à release of pro-infalmmatory cyítokines and chemokines
they express several hundred thousand high affinity receptors for IgE (FcεR1) and thus respond to IgE- directed antigens
express the pathogen-recognizing Toll-like receptors (TLRs) which probably account for the ability of mast cells to mount an effective innate immune response Biochemical Events of Mast Cell Activation (1)
Fig. 19-5 Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition.Copyright © Copyright2011 by Saunders, © 2012 an imprint by of Saunders, Elsevier Inc. an imprint of Elsevier Inc. Outcomes of acute inflammation
• Systemic inflammation Local and systemic effects of TNF
TNF inhibitors, Steroids
Abbas, Lichtman, Pillai: Cellular and Molecular Immunology 7th Edition, 2012. Systemic acute inflammation = acute phase reaction
Bone marrow
Goldsby RA, Kindt TJ, Osborne BA: Kuby Immunology 4th Edition, 2000.
Extracellular, soluble pattern recognition molecules I
Collectin (MBL, Ficolin: SP-A, SP-D): C- Fibrinogen type lectin domain Abbas, Lichtman, Pillai: Cellular and domain Molecular Immunology 7th Edition, 2012 . Extracellular soluble pattern recognition molecules II: pentraxins
C-reactive protein- CRP
Murphy. Janeway’s Immunobiology, 8th Edition ,2012. J Biol Chem. 2004 Nov 19;279(47):48487-90. Clinical significance of C-reactive protein level Risk of infection, sepsis
CRP test, complete blood count, blood culture Then start Antibiotics treatment CRP <10 mg/L & Discontinue CRP 48 hr blood culture antibiotic treatment negative CRP >10 mg/L, Continue antibiotics therapy CRP at 7 days CRP <10 mg/L: discontinue antibiotic treatment
CRP >10 mg/L: reevaluate (new blood count, change antibiotics)
Acute phase proteins in serum Nobel Laureates in 2011 for medicine and physiology
Jules A. Hoffmann Bruce A. Beutler Ralph M. Steinmann