In cells of the immune system,
signaling leads to
activation of cell-type specific
immune activities.
Ligand interaction with
receptors on the surface of cells of the
immune system triggers intracellular
signal transduction directly
or through association with assistant signal transduction molecules (CD3, IgαIgβ, etc.).
Cytokines are secreted by immune cells in response to cellular signaling, and bind to specific membrane
receptors, which then signal the cell via
second messengers, often
tyrosine kinases, to alter cellular activity (
gene expression).
Interleukins comprise the largest class of cytokines, and are manufactured by one
leukocyte to act on
other leukocytes as
signaling ligands. Cytokines are often produced in
cascades.
Cytokine receptors:
●
Hematopoietin family receptors___ ●
Colony-stimulating factors (
CSFs)
●
Interferon family receptors●
Tumor Necrosis Factor family receptors●
Chemokine family receptorsPhagocytic cells of the
innate immune response employ:
●
Fc receptors (FcR, Ig-Fc)
●
Complement receptors●
Scavenger receptors●
Toll-like receptors__ ●
adaptor proteins with
TIR domains
Activation of
lymphocytes signaling of the
adaptive immune response requires:
●
lymphocyte receptors, associated with
●
ITAM-bearing
signal transduction molecules, and
●
CD45●
adaptor proteins●
second messengersImmune signaling serves a variety of
functions:
●
Pre-peripheral-antigen binding
_ ●
apoptotic deletion of cells bearing receptors against self-peptides
●
Post-peripheral-antigen binding
_ ●
activation of
immune and
inflammatory response activities
__ ●
secretion of immune mediator molecules –
acute phase components,
antibodies,
ingestion,
disgestion, externalization, and
presentation of fragmented
antigen (
epitope peptide),
complement components,
cytokines,
eicosanoids (
prostaglandins and
leukotrienes),
kinins__ ● production of
inhibitory molecules, such as
IκB that regulate immune activity
__ ● surface expression of cell-type specific
markers and receptors
__ ●
expression of
surface receptors fine-tuned by
somatic hypermutation__ ●
activation of
clonal expansion by
entry into cell cycle and
proliferation__ ●
activation of cellular
differentiation from
precursor to committed cell lines
__ ●
activation of cellular
maturation from cell line to specialized cells
__ ●
cellular survival responses
__ ●
chemotaxis,
migration, and
leukocyte adhesion cascadeSignaling in the innate immune response :
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 include:
●
Membrane-associated PRR_____ ●
Toll-like receptors (
TLR) that sense
pathogen-associated or
damage-associated molecular patterns. In
Drosphila, Toll and immunodeficiency (Imd) receptors may link
innate and
adaptive immune responses (
Fig), responding to bacterial and fungal pathogens and activating
NF-κB homologs (Dif, dorsal and Relish), thus driving antimicrobial peptide gene expression.[
ffta]
●
Cytoplasmic PRR●
Secreted PRR, including
complement receptors
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 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.
The TLR
family is characterized by the presence of
leucine-rich repeats, which mediate ligand binding, and co-receptors with the Toll/interleukin-1 receptor-like domain (
TIR), which mediate interaction with intracellular
signaling proteins. 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 ReceptorsNF-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 []
Signaling in the adaptive immune response :
Antigens act as ligands for
BCR, while
epitope peptide•
MHC complexes act as ligands for
TCR.
Hematopoietic growth factors stimulate
cell division in immune and blood cell lines.
Signal transduction molecules:
Because both
BCR and
TCR have very short cytoplasmic
domains, they must associate with
invariant signal transduction molecules in order to generate an
intracellular signal (
IgαIgβ for BCR,
CD3 for TCR). The
antigen-specific receptors and signal transduction molecules
cluster together in the
plasma membrane, and signaling is effected by long
ITAM-containing cytoplasmic domains on the signal transduction molecules. ITAMs are
immunoreceptor tyrosine-based activation motifs that are
phosphorylated by
src-family
protein tyrosine kinase enzymes (
PTK).
Protein kinases add phosphate groups to
tyrosine (or
serine or
threonine) residues of other proteins, often those of enzymes.
Phosphatases remove the phosphate groups, reversing the effects of protein kinases.
Phospholipases such as PLC cleave specific ester bonds in phosphoglycerides or glycerophosphatidates, converting the phospholipids into fatty acids and other lipophilic substances.
Phospholipase C-γ cleaves the membrane phospholipid,
phosphatidylinositol bisphosphate (PIP2) into the signaling molecules,
inositol trisphosphate (
IP3) and
diacylglycerol (
DAG).
Phosphorylation can activate or inactivate enzymes, or can create binding sites that lead to increased concentration of cytoplasmic proteins (and hence
their accessibilty for phosphorylation).
Activation of
lymphocytes also requires
CD45 (
common leukocyte antigen), which is necessory for
receptor-mediated
activation of
lymphocytes.
Phosphorylated ITAMs can bind to
other PTKs (
Syk for
B cells,
ZAP-70 for
T cells), triggering a cascade of cytoplasmic
enzymes or
second messengers, such as
calcium ions,
diacylglycerol,
G-proteins,
IP3,
MAP kinases,
PKCs, and
transcription factors, such as
NF-κB. Ultimately, gene expression via
transcription of
mRNA leads to immune activities.
Tables
Apoptosis vs Necrosis
Apoptosis
Cell Adhesion Molecules
Cell signaling
Complement Receptors
Cytokines
Eicosanoid Actions
Fc receptors
Immunoglobulins
Interferons
Receptor Tyrosine Kinases (RTKs)
Receptor Signal Transduction
Second Messengers
Scavenger Receptors
Toll-like ReceptorsLabels: activation, cytokines, IL, ligand, receptors, signaling
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