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Innate immunity

Rapid host defense that uses germline-encoded receptors to recognize conserved microbial or damage-associated patterns

Adaptive immunity

Antigen-specific immunity mediated by B and T cells that undergoes clonal expansion and generates memory

Innate vs adaptive response time

Innate responses begin within seconds to hours whereas primary adaptive effector responses usually require days

Innate immune recognition

Uses germline-encoded pattern-recognition receptors to recognize PAMPs and DAMPs

Adaptive immune recognition

Uses highly diverse antigen-specific BCRs and TCRs generated by somatic gene rearrangement

Innate immune specificity

Recognizes conserved molecular patterns shared by groups of pathogens

Adaptive immune specificity

Recognizes specific antigenic epitopes

Adaptive immune memory

Memory B and T cells produce faster and stronger responses after subsequent antigen exposure

Major role of innate immunity

Provides rapid early control of infection and helps initiate and shape adaptive immunity

Major role of adaptive immunity

Provides highly specific pathogen elimination and long-term immunologic memory

Innate-adaptive cooperation

Innate mechanisms contain threats and activate adaptive immunity while adaptive responses enhance innate effector mechanisms

Physical barriers

Skin epithelia mucus cilia and mechanical clearance prevent microbial attachment penetration and invasion

Chemical barriers

Antimicrobial substances in body secretions inhibit or kill microorganisms at portals of entry

Microbial barriers

Normal microbiota compete with pathogens for nutrients and attachment sites and reduce colonization

Lysozyme

Antimicrobial enzyme that damages bacterial peptidoglycan

Lactoferrin

Antimicrobial protein that limits microbial growth by sequestering iron

Defensins

Antimicrobial peptides that disrupt microbial membranes

Psoriasin

Antimicrobial epithelial protein that helps prevent bacterial colonization

Surfactant proteins SP-A and SP-D

Soluble proteins at respiratory surfaces that recognize microbes and promote their clearance

PAMP

Conserved microbial molecular pattern recognized by innate immune receptors

DAMP

Host-derived danger signal released or exposed during tissue damage

PRR

Germline-encoded pattern-recognition receptor that recognizes PAMPs or DAMPs

LPS

Gram-negative bacterial PAMP recognized primarily through TLR4

Lipoteichoic acid

Gram-positive bacterial PAMP recognized by innate immune receptors

Viral dsRNA

Viral PAMP recognized by receptors including TLR3

Viral ssRNA

Viral PAMP recognized by receptors including TLR7 and cytosolic RNA sensors

Unmethylated CpG DNA

Microbial DNA pattern recognized by TLR9

TLR2

Cell-surface Toll-like receptor important for recognition of Gram-positive bacterial components

TLR4

Cell-surface Toll-like receptor important for recognition of Gram-negative bacterial LPS

TLR3

Endosomal Toll-like receptor that recognizes double-stranded RNA

TLR7

Endosomal Toll-like receptor that recognizes viral single-stranded RNA

TLR9

Endosomal Toll-like receptor that recognizes microbial CpG DNA

Endosomal TLRs

PRRs that recognize microbial nucleic acids exposed within endosomes

RIG-like receptors

Cytosolic PRRs that recognize viral RNA

NOD-like receptors

Cytosolic PRRs that recognize intracellular microbial products and can participate in inflammasome activation

C-type lectin receptors

Cell-surface PRRs that recognize microbial carbohydrate structures

cGAS

Cytosolic PRR that detects DNA and activates the STING pathway

STING

Signaling protein activated by cytosolic DNA sensing that promotes type I interferon production

Generic PRR signaling

PAMP or DAMP binding activates intracellular signaling that turns on transcription factors and immune-response genes

NF-kB

Transcription factor activated by PRR signaling that promotes proinflammatory gene expression

IRFs

Transcription factors activated by PRR signaling that promote antiviral type I interferon responses

Inflammasome

Innate signaling complex activated by PAMPs or DAMPs that activates caspase-1

Caspase-1

Inflammasome-associated protease that generates mature IL-1beta and IL-18

Pyroptosis

Inflammatory programmed cell death that releases cellular contents and amplifies inflammation

Major innate phagocytes

Neutrophils and monocytes or macrophages

Neutrophil

Short-lived phagocyte rapidly recruited during acute inflammation and important against extracellular bacteria and fungi

Macrophage

Long-lived phagocyte involved in recognition phagocytosis microbial killing cytokine production and tissue repair

Monocyte

Circulating leukocyte that can migrate into tissues and differentiate into macrophages

Phagocytosis

Receptor-mediated engulfment of microbes or other particulate material by a phagocyte

Phagocytosis sequence

Recognition and attachment followed by engulfment phagosome formation phagolysosome formation and microbial killing

Phagosome

Intracellular vesicle containing an engulfed microorganism or particle

Phagolysosome

Microbicidal compartment formed when a phagosome fuses with lysosomal granules

Opsonization

Coating of a microbe with molecules that enhance attachment to and phagocytosis by leukocytes

Major opsonins

C3b and IgG are major molecules that enhance phagocytosis

Respiratory burst

Rapid production of reactive oxygen intermediates by activated phagocytes

NADPH oxidase

Enzyme complex that initiates the respiratory burst by generating superoxide

Superoxide

Initial reactive oxygen intermediate generated by NADPH oxidase

Hydrogen peroxide

Reactive oxygen intermediate produced downstream of superoxide

Myeloperoxidase

Neutrophil enzyme that uses hydrogen peroxide to generate potent antimicrobial hypochlorite

Hypochlorite

Bleach-like antimicrobial molecule generated through the myeloperoxidase pathway

iNOS

Enzyme that generates antimicrobial nitric oxide from arginine

Peroxynitrite

Antimicrobial reactive product generated from nitric oxide and superoxide

Oxidative microbial killing

Killing involving NADPH oxidase and reactive oxygen or nitrogen intermediates

Non-oxidative microbial killing

Killing by antimicrobial peptides enzymes and granule proteins independent of the respiratory burst

Examples of non-oxidative killing

Defensins lysozyme BPI elastase cathepsin and other proteolytic enzymes

NK cells

Innate lymphoid cells that rapidly kill infected or abnormal host cells without prior sensitization

NK cell recognition

Depends on the balance between activating and inhibitory receptor signals

NK inhibitory receptors

Recognize normal class I MHC and prevent killing of healthy host cells

Missing-self recognition

Loss of normal MHC I inhibitory signaling favors NK-cell activation and target-cell killing

ITAM

Activation motif associated with signaling that promotes NK-cell activation

ITIM

Inhibitory motif associated with signaling that suppresses NK-cell activation

NK-cell cytotoxicity

Perforin and granzymes are released to induce apoptosis of target cells

Type I interferons

IFN-alpha and IFN-beta produced during antiviral innate responses

Type I interferon trigger

Recognition of viral nucleic acids by intracellular PRRs stimulates IFN-alpha and IFN-beta production

Type I interferon antiviral state

Type I IFNs induce proteins in infected and neighboring cells that inhibit viral replication

Three major functions of type I IFNs

Induce antiviral proteins enhance NK cytotoxicity and increase MHC class I expression

PKR

Interferon-induced protein that phosphorylates eIF2alpha and inhibits translation

2-prime-5-prime oligoadenylate synthetase

Interferon-induced enzyme that activates RNase L to promote viral RNA degradation

IFIT proteins

Interferon-induced proteins that inhibit viral RNA translation

Mx proteins

Interferon-induced proteins that inhibit viral gene expression and virion assembly

IFN-gamma

Type II interferon that enhances macrophage antimicrobial activity

IL-12 and NK cells

IL-12 stimulates NK cells to produce IFN-gamma

ILC1

Innate lymphoid subset associated with type 1 immunity

ILC2

Innate lymphoid subset associated with type 2 immunity

ILC3

Innate lymphoid subset associated with type 3 immunity and extracellular microbial defense

Innate defense against extracellular bacteria

Barriers complement inflammation neutrophils macrophages and phagocytic killing are especially important

Innate defense against intracellular viruses

Viral PRRs type I interferons and NK cells are especially important

Complement system

Plasma-protein cascade that promotes inflammation opsonization phagocytosis and microbial lysis

Three complement pathways

Classical, lectin and alternative pathways

Complement pathway convergence

All three complement pathways converge on C3 activation and then the common terminal pathway

Classical complement initiation

Antigen-bound IgM or IgG activates the C1 complex

C1 complex

C1q C1r and C1s form the initiating complex of the classical complement pathway

C1q

Binds Fc regions of appropriately positioned antigen-bound IgM or IgG

Classical C3 convertase

C4b2a

Classical C5 convertase

C4b2a3b

Classical pathway antibody dependence

Usually requires antigen-bound antibody and therefore connects adaptive immunity to complement

Lectin pathway initiation

Mannose-binding lectin recognizes microbial carbohydrate patterns and activates associated proteases

Mannose-binding lectin

Soluble pattern-recognition molecule that binds microbial carbohydrates and promotes complement activation

MASPs

MBL-associated proteases that cleave C4 and C2

Lectin C3 convertase

C4b2a