Pattern recognition receptors (
PRR) are a class of
innate immune response-expressed proteins that respond to
pathogen-associated molecular patterns (
PAMP) and endogenous stress signals termed
danger-associated molecular patterns (
DAMP).
▼
adaptive :
adaptor proteins :
alarmins :
CARD domain :
CATERPILLER :
collectin :
complement receptors :
damage-associated molecular patterns :
DAMP :
helicases :
innate :
LGP2 :
lipid transferases :
Mal :
Mda5 :
multicellular animals :
MyD88 :
NALP :
NLR :
NOD :
PAMP :
pathogen-associated molecular patterns :
pattern recognition receptors :
pentraxin :
PGR :
plant R :
PRR :
RIG-I :
RNA helicases :
SARM :
SARM action :
TIR :
TLR :
TLR-1 :
TLR-3 :
Toll-like receptors :
TRAM :
TRIF ▼
Adaptive immunity employs clonally distributed
B and
T lymphocytes that are coated by millions of
lymphoid cell-
surface receptors, which are generated by complex
VDJ recombination rearrangements so as to specifically recognize an enormous variety of
antigens (specificity and memory). Evolutionarily more ancient, the
innate immune system relies on a much smaller number of receptors, called
pattern recognition receptors (
PRRs).
Multicellular animals employ
pattern recognition receptors to recognize pathogen-associated molecular patterns (
PAMPs) in order to detect
pathogens. However,
cellular stressors are another causative agent of
cell and
tissue damage. Cells recognize both stressors and their associated tissue damage via receptor-mediated detection of intracellular proteins ("
alarmins") released by the
lysed cells.
Pattern recognition receptors (PRR) are a class of
innate immune response-expressed proteins that respond to
pathogen-associated molecular patterns (
PAMP) and endogenous stress signals termed
danger-associated molecular patterns (
DAMP). The
evolutionarily more recent
adaptive immune response employs diverse
surface receptors that display decremental
binding affinities for
epitope stimuli.
Pattern recognition receptors (PRRs) include:
●
Membrane-associated PRR_____ ●
Toll-like receptors (
TLR) sense pathogen-associated or danger-associated molecular patterns extracellularly or in endosomes and receptors may link
innate and
adaptive immune responses (
Drosophila signaling Fig).
●
Cytoplasmic PRR of the
CATERPILLER family (also known as NACHT–leucine-rich repeat (
NLR) proteins):
_____ ● Nucleotide-binding oligomerization domain proteins (
NODs) recognize intracellular MDP (muramyl dipeptide) and transduce signals via
NF-κB and
MAP kinase pathways through the
serine/threonine kinase RIP2. The nucleotide-binding oligomerization domain binds nucleotide triphosphate. NODs signal via N-terminal
caspase recruitment (
CARD)
domains to activate downstream gene induction events.
_____ ● Pyrin domain–containing proteins (
NALPs) contain contain a nucleotide binding site (NBS) for nucleotide triphosphates plus C-terminal leucine-rich repeats (LRRs), which appear to act as a regulatory domain and may be involved in the recognition of microbial pathogens. NALPs appear to recognize endogenous or microbial molecules or stress responses and to form oligomers with
caspase-1, which cleave
IL-1 into its active form.
_____ ●
RNA helicases –
LGP2 acts as a dominant-negative inhibitor, and
RIG-I and
Mda5 activate antiviral signaling. These RNA Helicases recruit factors via twin N-terminal
CARD domains, activate antiviral gene programs.
_____ ● plant
R proteins that share structural and functional similarity with PRRs found in higher animals.
●
Secreted PRR_____ ●
Complement receptors
_____ ●
Collectins_____ ●
Pentraxin proteins, such as
serum amyloid P component (
SAP),
acute-phase C-reactive protein (
CRP),
cytokine-modulated
PTX3 . Pentraxins utilize calcium dependant ligand binding and display a distinctive flattened β-jellyroll structure comprising five monomers with radial symmetry that form a ring approximately 95Å across and 35Å deep.
_____ ●
Lipid transferases_____ ●
Peptidoglycan recognition proteins (
PGRs) are most critical for insect immunity, and are less well characterized in mammals.
PAMPs are small molecular sequences consistently found on
pathogens that are recognized by
Toll-like receptors (TLRs) and other pattern recognition receptors (PRRs). PAMPs include bacterial lipopolysaccharide "endotoxin" (LPS→TLR4), bacterial flagellin, lipoteichoic acid, lipoproteins and peptidoglycan (→TLR1,-2,-6), mannose residues, N-formylmethionine, fungal glucans, endogenous
heat shock proteins,
extracellular matrix molecules, and nucleic acid variants associated with viruses (vRNA→TLR3, unmethylated cytosin-guanosin dinucleotide (
CpG islands)→TLR9, dsRNA) and bacteria (bacterial DNA, unmethylated cytosin-guanosin dinucleotide (CpG)→TLR9).
DAMPs – Effector cells of innate and adaptive immunity employ nonclassical pathways to secrete
alarmins when they are activated by
PAMPs or other alarmins. Endogenous alarmins and exogenous PAMPs therefore elicit similar responses, and can be considered subgroups of a larger set, the
damage-associated molecular patterns (DAMPs).
Toll-like receptors (
TLRs) appear to be one of the most
ancient,
conserved components of the immune system, and are the
basic signaling receptors of the
innate immune system.
TLRs (TLR1-TLR11) show homology with the
Drosophila Toll protein and the human
interleukin-1 receptor family, and are transmembrane proteins that recognize extracellular or endosomal pathogen-associated molecular patterns. The TLR
family is characterized by the presence of
leucine-rich repeats, which mediate ligand binding, and the Toll/interleukin-1 receptor-like domain (
TIR), which mediate interaction with intracellular
signaling proteins. TLRs function as homo- and heterodimers with different ligand-binding specificity, and rely upon TIR co-receptors for effective ligand sensitivity. Thus, the
specificity of Toll-like receptor signaling is due to
adaptor proteins containing
Toll–interleukin 1 receptor (
TIR)
domains. Five TIR adaptors display activating functions:
MyD88,
Mal,
TRIF,
TRAM, and
SARM. The adaptor proteins activate intracellular molecules, including
protein kinases (IRAK1, IRAK4, TBK1, and IKKi) that amplify the signal, ultimately inducting or suppressing genes that orchestrate the
inflammatory response. Thousands of genes are thus activated by TLR signaling, making TLRs one of the most important gateways for
gene modulation.
TLRs are
activated by
molecules associated with
pathogens (
PAMPs) or with injured host cells/tissue (
DAMPs). Most identified TLR
ligands are either conserved
microbial products that signal the presence of an infection, or
endogenous ligands resulting from other
danger conditions. TLRs trigger signals evoking synthesis and secretion of
cytokines and activation of host defenses through
NF-κB,
MAP kinases, and
costimulatory molecules.
To avoid excessive
inflammatory responses, TLR signalling must be tightly
regulated. MAPK phosphatase 1 (MKP1) is a key negative regulator of Toll-like receptor (TLR)-induced inflammation in vivo. Phosphorylation of MAPK p38 — which is associated with the modulation of cytokine production — is considerably increased and prolonged in the absence of MKP1. [
MKP1]
Table
Toll-like ReceptorsToll-like receptor-1 (TLR-1) displays homology to the receptor for interleukin-1 (
IL-1) by virtue of similar cytoplasmic portions.
Toll-like receptor–3 (TLR-3) responds to double-stranded (ds)
RNA, which is a
viral replication intermediary for many
viruses. TLR-3 activation transduces its signal into an intracellular
transduction pathway, leading to activation of JNK, p38
MAPK, and
NF-κB.
NF-κBs, Nuclear Factor kappa Bs, are ubiquitous
transcription factors involved in responses to
cellular stressors such as
cytokines,
bacterial antigens, and
viral antigens. Free NF-κB translocates to the
nucleus where it binds to specific κB sequences in DNA, initiating
transcription of related genes, including those for
immunoreceptors,
cytokines, and its own
inhibitor,
IκB. Inhibitor of kappa B (IκB, IkappaBalpha) inactivates NF-κB by sequestering NF-κB dimers within the cytoplasm.
Physiological activities mediated by
NF-κB include
cellular proliferation, and
inflammatory,
immune, and
cellular survival responses.
[]
signaling pathways []
The specificity of Toll-like receptor signaling is due to
adaptor proteins containing
Toll–interleukin 1 receptor (
TIR) domains. Five TIR adaptors display activating functions:
MyD88,
Mal,
TRIF,
TRAM, and
SARM.
SARM is a negative regulator of TRIF-dependent Toll-like receptor signaling, which blocks gene induction 'downstream' of TRIF but not of MyD88. The association fo SARM with TRIF, and the 'knockdown' of endogenous SARM expression by interfering RNA leads to enhanced TRIF-dependent
cytokine and
chemokine induction.[
r]
▲
adaptive ф
adaptive :
adaptor proteins §
adaptor protein :
alarmins :
allograft rejection :
CARD domain §
CARD domains :
CATERPILLER ~
cellular stress response ~
chemokine :
collectin :
complement receptors ф
complement system ф
costimulatory molecules ~
cytokines :
damage-associated molecular patterns :
DAMP :
graft rejection ~
heat shock proteins :
helicases ~
helicases :
innate ф
innate ф
immune response ф
inflammatory response :
LGP2 :
lipid transferases :
Mal ♦
MAPKs ♦
MAP kinases :
Mda5 :
multicellular animals :
MyD88 :
NALP : §
NF-κB :
NLR :
NOD :
PAMP ф
pathogens :
pathogen-associated molecular patterns :
pattern recognition receptors :
pentraxin :
PGR :
plant R :
PRR :
RIG-I :
RNA helicases :
SARM :
SARM action ♦
serine/threonine kinases ф
signaling ф
surface receptors :
TIR :
TLR :
TLR-1 :
TLR-3 :
Toll-like receptors :
TRAM :
TRIF ф
VDJ recombination ▲ф
Tables
Complement Receptors
Cytokines
Fc receptors
Immune Cytokines
Immunoglobulins
Interferons
Scavenger Receptors
Toll-like Receptors
▲
Top ▲
[
pdf review]
See
TOLLing away in Brazil.
Mitchell JA,
Fitzgerald KA,
Coyle A,
Silverman N,
Cartwright N. [
Free Full Text]
Nat Immunol. 2006 Jul;7(7):675-9.
Toll, A New Piece in the Puzzle of Innate Immunity.
Wright SD. [
Free Full Text Article]
J Exp Med. 1999 Feb 15;189(4):605-9.
tags
[Immunology] [pattern recognition] [cytokine] [Toll-like receptor] [receptor] [PAMP] [DAMP]Labels: DAMP, danger-associated molecular patterns, innate, PAMP, pathogen-associated molecular patterns, pattern recognition receptors, PRR, Toll-like receptors
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