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Innate Immunity I What is it and what does it do?^ Lindsay Nicholson^ Advanced Immunology L1^ [email protected]

-^ Lecture 1^ ƒ^ Defining Innate Immunity^ ƒ^ Recognition and effector mechanisms (I) •^ Lecture 2^ ƒ^ Recognition and effector mechanisms (II)^ ƒ^ Integration of innate and adaptive immuneresponses

Innate Immunity 1 –

Key Concepts

-^ Hard wired specificity •^ Multiple molecular mechanisms; commoneffector pathways •^ Tightly integrated with adaptive immuneresponses

Endotoxin

-^1890

Richard Pfeiffer

described a heat stable

intrinsic poison derived from the cholera vibrio

later

called endotoxin • Endotoxin^ is identified as lipopolysaccharide, (and lateras lipid A) a component of the gram negative bacterialcell wall • Administration of small amounts leads to fever, shockand death … • 1960s^ …except in C3H/HeJ mice which can be filled upwith endotoxin

and still remain happy. They are,

however, very susceptible to bacterial infection. • 1997 Medzhitov and Janeway

identify TLR4 as

mediating an activating immune signal • 1998 Bruce Beutler

uses a positional cloning strategy to

identify the LPS receptor as TLR

Signalling Other ligands

Other^ receptors

Signalling

A simple paradigm for innate immunity

TLR Other ligands^^ Lipid A

Other receptors Disease

How do we define the InnateImmune System • An ancient set of immune responses,predating bony fish • Those parts of the immune system thatare not adaptive • A collection of specific cells and effectormechanisms

Janeway, Travers, Walport

and

Shlomchik

-^ “Defense

mechanisms that do not require a prolonged period of induction becausethey do not rely on the clonal

expansion of

antigen-specific lymphocytes are themechanisms of innate immunity"

Summary 1

-^ The Innate Immune system is anintegrated part of the immune responsecharacterised by mechanisms andmolecules that respond rapidly

to infection

and adapt on an evolutionary timescale,rather than over a single lifespan.

Foreign Pattern Recognition • Charlie Janeway

1989 Cold Spring Harb. Symp. Quant. Biol. 54:1-

“The immune system has evolved specifically to recognize andrespond to infectious microorganisms, and that this involvesrecognition not only of specific antigenic determinants, but also ofcertain characteristics or patterns common on infectious agents butabsent from the host” • Called PAMPs

(^ pathogen associated molecular patterns

) or

MAMPs^ (microbe associated molecular patterns

-^ This implies co-evolution •^ Medzhitov, Preston-Hurlburt

& Janeway

Nature 388:394 1997 TLR-4 signals adaptive immune activation

Danger

-^ Polly Matzinger^ Ann. Rev. Immunol. 12:991-1045 1994^ Cells may die in ways that are associated with normal function(apoptosis: good death) or with trauma (necrosis: bad death) •^ Shi and Rock^ Nature 425:516 2003^ Identified crystals of uric acid as an endogenous adjuvant releasedby stressed cells. •^ HSPs, fragments of extracellular matrix.Beware LPS. •^ DAMPs^ (Danger associated molecular patterns)^ May use common PRR (pattern recognition receptors)e.g. TLR-2 (Immunity

^27 :321 –^ 333 2007)

-^ Toll-like receptor 9 (TLR9)^ Intracellular sensing of unmethylated

CpGs^ in monocytes, dendritic cells and lymphocytes • NOD2 (CARD15) Muramyl^ dipeptide

binding intracellular protein, signalling via NF-

κb

Mutations increase the risk of Crohn’s

disease and other granulomatous

conditions

-^ NLRP1 (Nalp1)

NLR family,^ pyrin^

domain containing 1 Intracellular sensing of anthrax lethal toxin (LT); caspase-1activation of IL-

β^ etc.

Intracellular Pattern Recognition • RIG-I Intracellular sensing of RNA viruses e.g. Hepatitis C.Induces type I interferons

Extracellular and intracellular

pattern sensing

• NLRP NLRPinflammasome

Activator NF-κB TLR^ MyD

Intracellular sensing Extracellular sensing

Missing Self

-^ NK cells •^ Large lymphocytes that kill tumours (1973) •^ NK cells in mice (1977) •^ Require constitutive inhibition (1992) •^ Mouse and humans use different familiesof inhibitory molecules

Missing Self