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2_innate_immunity.md

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Induced Response of Innate Immunity

Innate immunity consist of (molecular) pattern recognition receptors:

  • free receptors in serum (ficolins and histatins (complement))
  • membrane bound phagocytic
  • membrane bound signaling
  • cytoplasmic signaling

Phagocytes are a diverse family of cells that kill microbes

Many phagocytic cells

Macrophages come from:

  • Progenitor cells that enter various tissues in the fetal state and produce macrophages throughout life of organism (!)
  • Monocytes circulate freely throughout blood or crawl endothelium

Found in especially large numbers in connective tissues: gastrointenstinal submucosal layer, lungs (bronchi, alveoli), spleen (where they remove senescent cells).

Examples include microglial cells in neurons and Kupffer cells in the liver, stimulated by IL-34 in both.

Monocytes come in two forms:

"Classic" monocytes, that differentiate into active monocytes and macrophages, circulating freely in blood. They make up 90% and express CD14 only.

"Patrolling" monocytes that "crawl" along endothelium. They express both CD14 and CD16. Do not differentiate.

Granulocytes include:

  • Neutrophil
  • Eosinophil
  • Basophil

Dendritic cells:

  • cDCs (classical) digest and expose microbes as antigen material for the adaptive immune system (the bridge between active and innate immunity)
  • pDCs (plasmacytoid) produce type I interferon

Phagocytosis

Phagosome fuses with lysosome to form phagolysosome.

Some chemistry terminology:

  • A radical is an atom, molecule, ion that has at least one unpaired valence electron
  • Red(uction)Ox(idation) reactions are thsoe that transfer electrons between species
  • Reactive Oxygen Species (ROS) are:
    • Superoxide ( (O_2)- )
    • Nitric Oxide is an example of a radical

Nitric oxide and superoxide are produced in the phagolysosome to neutralize microbes.

Phagocytic Receptors

  • C-type lectin-like receptors (eg. Dectin 1)
  • Mannose Receptor (now believed to clear endogenous carbs that are released during inflammation)
  • Scavenger receptors (Some bind to low density lipoproteins (see notes on "foam cells" here)
  • Complement / Fc receptors (connection to complement system and active immune system respectively)

G-Protein-Coupled Receptors

Class of ancient receptors that stimulate intercellular killing.

  • fMet-Leu-Phe (fMLF) receptor (fMet initiates peptides in bacteria)
  • C5a receptor (cleaved C5 molecule from activated complement system)

The receptor has 7 membrane spanning regions and associate with (do not "have") G-proteins - heterotrimeric units. When a ligand binds to the receptor, it swaps a GDP with a GTP, and the G-protein splits into alpha and beta-gamma blocks.

These subunits interact with Rho family GTPase proteins, Rac and Rho, that activate microbicidal behavior. These induce, among other things, the production of Reactive Oxygen Species (ROS).

NADPH oxidase, also called phagocytic oxidase, produces superoxide (O_2-) when fully assembled, but requires recruitment of cytosolic components to membrane components. The cell then can use NADPH oxidase in a process called respiratory burst, to consume lots of oxygen and produce ROS. Neutrophils using lots of respiratory burst die and create pus.

Genetic defficiency of NADPH cause release of less reactive oxygen species. Those with CGD are more prone to bacterial/fungal diseases.

Neutrophils can also release their nuclear chromatin as web like traps called NETs (nuetrophil extracellular trap) to immobolize microbes for phagocytosis (!).

Inflammation

Cytokines + chemokines facilitate inflammation.

Four kinds of modification to blood vessels:

  • Vessels dialate
  • Endothelial cells express adhesion factors to trap circulating leukocytes. (Leukocyte migration is called extravasation)
  • Endothelial activation - Endothelial cells become permissive and blood flows into tissue (edema)
  • Clotting

What causes these inflammatory responses? Few things:

  • Lipid mediators of inflammation (prostaglandins, leukotrienes, PAF) produced by degraded membranes
  • chemokines + cytokines eg. TNF-alpha
  • C5a from complement

If there is wounding, the kinin cascade and coagulation cascade are also spun up that regulate blood pressure, pain, coagulation.

Toll-like receptors

Broad class of PRR (pattern recognition receptors)

Toll was a receptor initially discovered to control dorso-ventral (front-back) patterning in fruit fly embryo. It was later discovered by Jules Hoffman that the same receptors released antimicrobial peptiedes.

Important PAMPs:

  • lipoteichoic acid (gram positive)
  • lipoprotein (gram negative)
  • flagellin
  • unmethylated DNA

TLR Structure

Each TLR has 20-25 Leucine Rich Repeats (LRR) that form a convex hook. They sometimes form dimers with eachother.

Binding a ligand causes TLR to dimerize or causes a conformation change with a preformed dimer.

All mamallian TLRs have an interleukin receptor in their tail. (Not really sure the role of this. Assume its involved in sigaling cascade)

TLR 1 / 2 / 6

Among other ligands recognized are:

  • lipoteichoic acid (gram negative)
  • Triacyl + diacyl lipoprotein (gram negative)

These guys dimerize (1 <> 2; 2 <> 6)

TLR 5

Bind to a conserved (intact) flaggelin domain that is deep within flagella

TLR 11 / 12

Bind to whole proteins (many unknown) from protozoans and microbes. Expressed in mice.

TLR 10

Ligand unknown. Expressed in humans