Basic immunology

Lecture 7-8. Innate immunity, Inflammatory reaction, pattern recognition Timea Berki The levels of host defense • Anatomical „barriers” • Innate immunity, • 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: - – 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:

- kallikrein system - Fibrinolytic system - Complement cascade - Clotting cascade

Lipid mediators: leukotrienes, (PGE)

Chemoattractants: -Chemokines: IL-8 -Complement components - PAF (platelet activating factor) Inflammatory : 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 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 : à Phagocytosis

LPS

Activated macrophage: à antigenpresentation, MHCII ↑ -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 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 , 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, , 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