Module 3 (Pt 1) - Innate Immunity, Induced Response

What is the difference between immediate and induced immune response?

Immediate: mediated by preformed effector proteins and resident effector cells, includes alt complement pathway, other protein systems, and resident macrophages

Induced: mediated by inflammation and nonspecific leukocytes, includes resident and circulating macrophages, granulocytes, monocytes, dendritic cells, NK cells, lectin+classical pathway, and interferons

What bridges the gap between immediate and induced innate responses?

Resident macrophages; pathogens coated in complement are recognized by CR on macrophages triggering phagocytosis and release of cytokines to recruit more leukocytes which helps this transition

What are PRRs?

Pattern recognition receptors; these recognize pathogen’s surface proteins and abnormal self cells

What are PAMPs?

Pathogen-associated molecular patterns, distinct pathogenic structures that PRRs bind to

What are DAMPs?

Damage-associated molecular patterns, abnormal cell antigens that PRRs bind to

What are CLRs?

C-type lectin receptors, transmembrane glycoproteins with variable number of C-type lectin domains (CTLDs) that binds to carbs

What are TLRs?

Toll-like receptors, made up of a horseshoe-shaped pattern recognition domain that can dimerize upon PAMP binding, recognize a variety of different molecules, can be found in plasma membrane or endosomes

What are NLRs?

(Nucleotide oligomerization domain)-like receptors, recognize debris from phagocytized bacteria that escapes the phagolysosome and enters the cytoplasm

What are ALRs?

(absent-in-melanoma)-like receptors, form an inflammasome (activated by pro-caspase 1 to caspase 1) in the cytoplasm that recognizes double stranded DNA from phagocytized pathogens or damaged host cells in PAMPs

What are RLRs?

(retinoic acid-inducible gene-1)-like receptors, target double stranded RNA (viruses) and located in cytoplasm, viral RNA binding → dimerization of RIG-1-like helicases with mitochondrial antiviral signaling protein (MAVS) on the outside of the mitochondrial membrane, this leads to activate interferons

What are scavenger receptors?

Broad classes of PRRs with a larger range of molecule recognition (only includes CLRs and TLRs; expressed by macrophages, dendritic cells, neutrophils, B cells, and other cells to trigger phagocytosis, cell adhesion, and changes in intracellular signaling; if no infection, imp for clearing cell debris from stress and death

What are dectins?

A type of CLR that can identify carbs in fungal and bacterial cell walls.

Describe the process of CD206.

aka Mannose receptors

1) The mannose receptor has 10 extracellular domains of 4 types, this recognizes mannose residues of a PAMP

2) Surface sugars of a bacterium are bound by 2 CTLD domains

3) Macrophage ingests bacterium by receptor-mediated endocytosis

4) Bacterial degradation begins in the endosome

5) Endosome fuses with lysosome to gorm a phagolysosome in which bacterium is further degraded

6) Mannose receptor is returned to cell surface and repeat

If a CLR doesn’t have lectin domain, what is the other type?

Collagen-like, good for recognizing bacterial cell wall components and has 2 types:

SR-A1: recognizes LPS, LTA, hepatitis C virus, B-amyloid, and heat shock proteins

MACRO: recognizes LPS, intact Gram (+) bacteria, and proteins

Describe the activation of the NF-kB transcription factor.

When TLRs bind to PAMPs, these triggers an intracellular signaling cascade leading to the activation, this leads to production of pro-inflammatory cytokines to mediate inflammation and recruit leukocytes

What is the significance of genentic polymorphism in TLR genes?

Different alleles of the same TLR gene can produce different TLF variants (allotypes), this mostly impacts membrane TLRs and their structures, which can give greater disease susceptibility, ie TLR4 change = inc risk of septic shock

Ligand binding involving NLRs will lead to what?

NOD dimerization which signals to NF-kB activation

What are the two proteins that can undergo NOD dimerization?

NOD1: recognizes γ-glutamyl diaminopimelic acid from peptidoglycan of Gram(-) cell walls, expressed on many cells

NOD2: recognizes muramyl dipeptide found in most peptidoglycan, expressed only on myeloid and lymphoid leukocytes

What are IFN?

Interferons, small proteins produced by viral-infected cells, functions to interfere with viral replication, alert neighboring cells of virus, and make viral-infected cells more susceptible to NK cells

List the IFN classes

I: a, b, d, k, e, w

II: y

III: l

Describe the anti-viral response of interferons

1) Virus infects an epithelial cell that responds by secreting the cytokine IFN-B

2) IFN-B is bound by the cell’s type I interferon receptors, stimulating an autocrine IFN-a response

3) IFN-B binds to type I IFN receptors on adjacent uninfected cell, giving paracrine IFN-B response

What are pDCs?

Plasmacytoid dendritic cells, secrete up to 1000x more IFN, located in blood and lymphoid tissues, detect viruses through endosomal TLRs: 7 - ssRNAs, 9 - unmethylated CpG motifs in dsDNA