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1 Innate Immune Responses 3

• The initial responses to: – 1. Microbes: essential early mechanisms to Innate immunity prevent, control, or eliminate infection; – 2. Injured tissues, dead cells: critical for repair and wound healing Abul K. Abbas University of California San Francisco • Limited types of defensive reactions: – Inflammation – Antiviral state

• Stimulate adaptive immunity FOCiS – Innate immunity provides “danger signals”

Take home messages

2 4 General features of innate immunity Lecture outline • Phylogenetically ancient (evolved before • Components of innate immunity adaptive immunity)

• Recognition of microbes and dead cells • Pre-existing (no prior immunization needed) • Toll Like Receptors • NOD Like Receptors/Inflammasome • Rapidly activated and/or recruited

• Inflammation • Resets to baseline (no memory)

• Antiviral defense • Bidirectional interactions with adaptive immunity Take home messages

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5 7 Innate : The components of the -1 What is recognized? • Structures that are shared by various • Epithelial barriers classes of microbes but are not present on – Defensins and cathelicidins (()antibiotics) host cells - Pathogen associated molecular patterns (PAMPs). • Phagocytes and other cells – Innate immunity often targets microbial – Macrophages molecules that are essential for survival or – Neutrophils infectivity of microbes (prevents escape – Dendritic cells mutants)

• Specialized lymphocytes with limited diversity (“innate lymphoid cells”) • Structures found in/on stressed, dying or – NK cells dead host cells - Damage associated – iNKT cells – B1 and Marginal Zone B cells molecular patterns (DAMPs). Take home messages

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The components of the Innate Immune System-2 Pathogen-Associated Molecular Patterns Microbe Type

Nucleic acids ssRNA Virus • Plasma dsRNA Virus – CmplmntComplement UthltdUnmethylated CGCpG Virus, – Pentraxins (C Reactive , serum amyloid repeats protein): coat microbes for phagocytosis Cyclic dinucleotides Bacteria – Collectins (e.g. Mannose Binding Lectin) Proteins Pilin Bacteria Flagellin Bacteria • Cytokines Cell wall lipids LPS Gram-negative bacteria – Inflammatory (IL-1, TNF) Lipoteichoic acid Gram-positive bacteria – Chemokines (IL-8, MCP-1) Carbohydrates Mannan Fungi, bacteria – Anti-viral (type I interferons) Glucans Fungi

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9 11 Specificity of Receptors of Innate and Adaptive Immunity

Damage-Associated Molecular Patterns Stress-induced Heat shock proteins ~ 1,000 > 107 proteins ATP

Monosodium urate; Crystals 2 TYPES ( Ig, TCR); cholesterol < 100 TYPES; MILLIONS OF EACH TYPE VARIATIONS INVARIANT Nuclear proteins HMGB1 OF EACH TYPE

Cellular Pattern Recognition Receptors 10 Toll-like Receptors (TLRs): specificity 12

Bacterial cell Receptors are wall located such that they can sample all cellular compartments containing different types of pathogens

4 classes of -TLRs:receptors: bacteria and Bacterial peptidoglycan viruses -CLRs (C-type lectin receptors): fungi -NLRs: bacteria Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7 th edition, 2011 c Elsevier and cell damage -RLRs: viruses Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7 th edition, 2011 c Elsevier

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13 15 Cellular Pattern Recognition Receptors Genetic evidence for the importance What do they do? of TLRs • Mutations in signaling adaptor protein MyD88 (for all TLRs except TLR3): invasive bacterial infections PAMP – Mouse knockouts are susceptible to diverse PRR infections: different extent of redundancy or differences due to experimental challenge

• Mutations affecting TLR3 and signaling Recognition Signal Effector functions: molecules: herpes virus encephalitis transduction expression Inflammation Anti-viral state • Mutations in IRAK, NF-B pathway: more complex, diverse infections

Toll-like Receptors (TLRs): signaling 14 16 Toll-like Receptors (TLRs): Clinical Relevance

• Excessive/systemic TLR signaling underlies pathophysiology of sepsis (LPS/TLR4)

• TLR signaling in B cells promotes auto- antibody production

• TLR ligands, such as CpG nucleotides, are potentially useful adjuvants to enhance effectiveness of vaccines

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17 19 * NOD -like receptors (NLRs) Physiologic functions of the • A family of more than 20 different cytosolic proteins, inflammasome best studied are two types… • To sense and eliminate necrotic cells • NOD1 and NOD2 ((ycaused by microbes, other insults) and • Bind peptidoglycan components of bacterial cell walls foreign bodies • Form signaling complexes that activate NF-Band – Reactions: Inflammation and repair induce expression of inflammatory • Mutations in components of inflammasomes are the cause of rare • NLRPs inherited “auto-inflammatoryyy” syndromes • Pyrin-domain containing NLRs characterized by periodic fever, skin rashes, • NLRP3Respond to diverse cytoplasmic PAMPs and DAMPs and amyloidosis • Form signaling complexes called inflammasomes, which – These are gain-of-function mutations that lead to generate active forms of the inflammatory cytokines constitutive activation and uncontrolled IL-1 production IL-1 and IL-18 – IL-1 antagonists are very effective treatments for these disorders. *NOD=nucleotide oligomerization domain Take home messages

Activation of inflammasome by microbial products 18 Inflammasome activation in common 20 and/or host-derived molecules inflammatory diseases

• Gout, pseudogout: Recognize crystals (e.g. urate) and induce IL-1-mediated acute inflammation • Metabolic syndrome: Recognize lipids and free fatty acids  IL-1 production in obesity  insulin resistance  type 2 diabetes? • Recognize cholesterol crystals  role of inflammation in atherosclerosis? • Reaction to abnormal protein deposits: Alzheimer disease? Other disorders?

Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7 th edition, 2011 c Elsevier

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21 23 The acute inflammatory response The major reactions and functions of innate immunity

• In duc tion of iflinflamma tion: remova l of microbes, dead cells, foreign bodies

• Induction of the anti-viral state: inhibition of viral replication

• Stimulation of the adaptive immune response Major sources of cytokines: dendritic cells, macrophages Take home messages Systemic reaction: acute-phase response (increased CRP, etc)

22 24 What is Inflammation ? Leukocyte migration • A response to infection and/or injury of vascularized tissues whereby… • Blood-derived fluid, proteins, and leukocytes accumulate, which… • Kill and remove offending agent (e.g. microbes), remove dead cells, and repair damage Leukocyte Plasma protein Blood vessel

Microbes

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25 27 Phagocytosis and killing of microbes Actions of Cytokines in Inflammation

CRP, Fibrinogen, SAA, Complement

26 28 Actions of Cytokines in Inflammation Actions of Cytokines in Inflammation

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Induction of the anti-viral state 29

30 The innate immune system provides second signals required for lymphocyte activation

Second signals for T cells: “costimulators” inddduced on A PCs bPy b microbial products, during early innate response

Second signals for B cells: products of complement activation recognized by B cell complement receptors

Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7 th edition, 2011 c Elsevier Take home messages

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