Immunology: PRRs, PAMPs, and DAMPs

Broad conserved molecular patterns from microbes or damaged host tissue.

A microbial/pathogen-associated molecular pattern found across classes of microbes.

An endogenous danger signal released from stressed or damaged host tissue.

LPS, flagellin (bacteria), dsRNA & ssRNA (viruses), unmethylated CpG DNA,

ATP, heat-shock proteins, and extracellular DNA released during tissue damage.

PAMPs come from microbes; DAMPs come from damaged or stressed host cells.

LPS; gram negative

Flagellin.

Microbial lipopeptides; TLR2:1 recognizes triacyl lipopeptides and TLR2:6 recognizes diacyl lipopeptides.

Viral dsRNA.

Viral ssRNA.

Unmethylated CpG DNA.

Endosomes.

They detect microbial nucleic acids in a compartment where host RNA/DNA normally should not be present.

1. Mannose and fucose on microbes
2. Liver
3. Activates complement (important immune system)

In the cytosol; they detect bacterial peptidoglycan fragments.

Viral dsRNA in the cytosol.

Cytosolic dsDNA.

Activation of NF-κB.

Transcription of pro-inflammatory genes including cytokines, chemokines, and other inflammatory mediators.

In the cytoplasm.

- humans but not in mice
- found in mice but not humans

type 1 interferons

Large cytoplasmic multicomponent systems that sense PAMPs/DAMPs and activate a caspase cascade.

Processing pro-inflammatory cytokines into active forms.

Small signaling peptides used by the immune system to coordinate immune responses.

Cytokines specialized for directing leukocyte migration.

Autocrine = self; paracrine = nearby cells; endocrine = distant cells.

IL-1β, TNFα, IL-6, CXCL8/IL-8, and IL-12.

Recruitment and chemotaxis of neutrophils.

Activation of NK and T cells, promoting cytotoxicity and IFNγ-associated responses.

IL-10, TGF-β, and IL-1 receptor antagonist (IL-1Ra).

Inhibits production of pro-inflammatory cytokines including TNFα, IL-1β, and IL-6.

Antagonizes pro-inflammatory pathways, helps resolve inflammation, and promotes tissue repair.

A rapidly activated antimicrobial system of circulating plasma proteins produced mainly by the liver.

1. Osponization
2. Inflammation
3. Lysis
4. Immune complex clearance

Lectin, classical, and alternative.

Lectin PRRs such as mannose-binding lectin recognizing microbial carbohydrates.

C1q (PRR) binding directly to pathogens or to antibodies bound to pathogens.

Spontaneous hydrolysis of C3.

C3b and C4b.

C3a and C5a.

C5b–C9.

Promotes inflammation, stimulates phagocytosis, and acts as a neutrophil chemoattractant.

TNFα, IL-1β, and IL-6.

IL-6.

1. Serum amyloid protein
2. C-reactive protein (CRP)
3. mannose-binding lectin (MBL).

Local TNFα promotes beneficial inflammation, but systemic TNFα during sepsis can cause edema, hypotension, multi-organ collapse, and septic shock.

IFNα and IFNβ, cytokines that create an antiviral state.

Plasmacytoid dendritic cells (pDCs).

PKR, Mx proteins, and 2’-5’ oligoadenylate synthetase.

Phosphorylates eIF-2 to block protein translation.

Interfere with viral replication by trapping viral nucleoproteins.

Activates RNase L, which degrades viral and cellular RNA.

1. Apoptosis; Kill low-MHC-I infected cells, perform antibody-dependent cellular cytotoxicity
3. Produce IFNγ.

They release perforin (pores) and granzymes (proteases), which trigger apoptosis.

MHC I engages inhibitory NK-cell receptors and provides a “do not kill” signal.

Loss of the inhibitory MHC I signal allows activating signals to dominate and trigger killing.