Innate immune recognition Flashcards
The innate immune system recognises
- Highly conserved molecular patterns expressed by large groups of pathogens.
- Common biologic consequences of infection.
PAMPs
Gram positive bacteria: lipoteichoic acid, peptidoglycan, lipoproteins, DNA, flagellin
Gram negative: all the same plus lipopolysaccharide
Virus: coat protein, nucleic acid
Parasite: GPI anchor
Yeast: zymosan
Gram+
Gram-
Thick cell wall with no outer envelope
Thin cell wall with outer envelope.
DAMPs
Endogenous molecules - signal tissue injury and initiate repair.
Molecules: DNA, RNA, Glucose
Particles: Amyloid-B, Silica, Nanoparticles
Others: UVB, Mutations
PRRs
Secreted and circulating receptors.
Receptors on the cell surface and cell membranes.
Receptors inside cells (cytoplasmic).
Secreted and circulating PRRs
Antimicrobial peptides secreted into lining fluids (from epithelia and phagocytes).
Pentraxins: proteins like CRP; react with the C-polysaccharide of pneumococci, some antimicrobial actions. Activate complement, promotes phagocytosis.
Lectins and collectins: CHO-containing proteins, bind CHO or lipids on microbe walls. Activate complement, improve phagocytosis.
MBL and Surfactant proteins A and D.
Cell associated PRRs
Receptors present on the cell membrane or on organelles within the cytosol.
TLRs main one.
Recognise a broad range of molecular patterns.
TLRs and their ligands (examples)
TLR1/2 -> triacyl lipopeptides
TLR2 -> peptidoglycan, hemagglutinin, inositol, mucin, zymosan, SARS-COV-19.
TLR5 -> flagellin
TLR and PAMP signalling
Different TLRs activate different signalling cascades (depending what pathogen they bind) and tailor the immune response accordingly.
TLR signalling and DAMPs
TLR2,4,6 -> inflammation repair
TLR7, 9 -> autoimmunity + inflammation
Other membrane bound PRRs
Mannose receptor (on macrophages) - fungi.
Dectin-1 (on phagocytes) -> beta glucans in fungal walls.
Scavenger receptors (on macrophages) -> wide range of lipid related ligands.
RIG-I-like Receptors (RLRs)
Detect viral RNA in the cytoplasm:
Retinoic acid-inducible gene I (RGI-I)
Influenza A and Respiratory Syncytial virus.
short dsRNA, 5’ppp caps
Melanoma differentiated gene 5 (MDA-5) long ds RNA
Rhinovirus
Laboratory of genetics and physiology 2 (LGP2). dsRNA
Positive regulator for other two.
NOD-like receptors
Sensing cytoplasmic bacterial pathogens and DAMPs.
Regulates inflammatory and cell death responses.
Nucleotide-binding and oligomerisation domain (NOD=NACHT)
4 subfamilies - based on N-terminal effector domain.
NOD1
Activated by meso-aminopimelic acid (Meso-DAP)-containing PGN fragments (gram-) in periplasmic space.
NOD2
Muramyl dipeptide (MDP)=breakdown of PG in the cell wall. ~ in all gram negative and positive bacteria.
Dynamically traffic to intracellular membranes upon detection of PG derivatives.
NOD signalling
Activation of MAPK and NF-KB
Induction of pro-inflammatory cytokines and chemokines
Activation of antimicrobial functions
DO NOT activate IRF transcription factors (interferon regulatory factors).
Inflammatory response to infection
NFkB-MAPK
IL1B - activates vascular endothelium and lymphocytes. Local tissue destruction= increased access to effector cells.
FEVER and production of IL-6.
TNF-A- Increased vascular permeability. IgG increased lymph drainage.
FEVER.
IL-6 - lymphocyte activate and increased AB production.
CXCL8 - recruits neutrophils, basophils and T cells.
IL-12 - activate NK cells induces diff of CD4 into Th1.
Acute phase response (actions of IL-1B/IL-6/TNF-alpha)
Liver: acute phase proteins (C-reactive; MBL) -> activation of complement opsonisation.
Bone marrow endothelium: neutrophils -> phagocytosis.
Hypothalamus: increased body T -> decreased replication; increased AG processing, increased spec. immune response.
Fat, muscle: protein and energy mobilisation: allows for increased temp. -> decreased replication; increased AG processing, increased spec. immune response.
Dendritic cells: TNF-alpha stimulation migration to lymph nodes and maturation -> initiates adaptive response.
What is the interferon stimulated response element made up of?
STAT1, STAT2, IRF9
Activates macrophages and dendritic cells.
Activate NK to kill viral cells.
Induces chemokines to recruit lymphocytes.
Induces resistance to viral replication (destruct mRNA; inhibits translation)
Increases MHC-I expression and AG presentation (CD8)
The damage chain reaction
Harmful stimuli
Pathogen
Injury
Heat
Autoantigens
Tumours
Necrotic cells
High levels of DAMPs - associated with inflammatory and autoimmune disorders as well as atherosclerosis and CA.
Cytokine storm
Profound increase in CK, CXCL, and INFs= severe inflammation and tissue damage.
Induced by: genetic makeup of host, persistent pathogen
Role in sepsis.
Immunomodulation has two main strategies…
Agonists and antagonists.
Agonists (enhance TLR signalling)
Adjuvant effect - promotes protective responses, i.e. vaccines
Immune stimulators.
Modify adaptive immune response: Th and Treg
Side effect: potentially enhance inflammation.
Antagonists (inhibit TLR signalling)
Block receptor-ligand binding -> interferes with signalling.
Sepsis syndromes, inflammation, arthritis.
Side-effects: allow pathogen outgrow, mutation.
NOD2 mutations
Non functions mutation: Crohn’s disease
Hyperfunctioning mutations: Blau syndrome (granulomatous inflammation of skin, eyes, joints).
TLR7 mutation
Novel gain of function: SLE
TLR4 mutation
Asp299Gly and Thr399Ile overexpressed in infants <12 months = hospitalised for RSV bronchiolitis.
Fail to translocate TLR4 to cell surface - reduced NFkB signalling.
