1 tema 10. reacciones inmunitarias mediadas por células.

TEMA 10. REACCIONES INMUNITARIAS
MEDIADAS POR CÉLULAS.
The nomenclature of cytokines partly reflects their first-described
function and also the order of their discovery. There is no single unified
nomenclature, and individual cytokines may belong to two groups, e.g.
the chemokine interleukin-8 (IL-8).
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Most cytokines have many effects and act
on several different cell types. A single
example of each is selected in this table.
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Four families of cytokine receptors
are identified. Examples are given
of each type. Type I is the
cytokine-receptor family, typically
consisting of separate binding and
signalling subunits. The binding
subunits have domains containing
conserved motifs (WSXWS). The
type III family consists of
molecules which have cysteinerich domains of the NGF-receptor
type. Type IV receptors have
immunoglobulin superfamily
domains.
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The high-affinity IL-2 receptor is formed
by three polypeptide chains, of which the
α and β chains bind to the cytokine, while
the γ chain is involved in signalling to the
cell. The IL-4 receptor shares the γ
signalling chain, but has a unique α chain
which specifically recognizes IL-4.
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A simple model for cytokine
activation of a cell is shown.
Cytokine binds to its receptor
on the cells and induces
dimerization or polymerization
of receptor polypeptides at the
cell surface. This causes
activation of intracellular
signalling pathways (e.g.
kinase cascades), resulting in
the production of active
transcription factors which
migrate to the nucleus and
bind to the promotor or
enhancer regions of genes
induced by that cytokine.
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The intracellular signalling pathways
activated by IFNα are illustrated
diagramatically. IFNα binding
aggregates the two subunits of the
receptor. This leads to activation and
phosphorylation of two Jak kinases,
Jak1 and Tyk2, which then
phosphorylate Stat1 and Stat2. These
two transcription factors form a
complex with a DNA-binding protein
called p48. The complex moves to the
nucleus and induces transcription of
genes bearing an interferon response
element (ISRE).
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TNF induces the trimerization of the
TNF receptor on the cell surface,
which causes adaptor molecules to
be recruited to the receptor
complex. One pathway leads to the
activation of caspase-8 and
apoptosis. Other pathways lead to
the activation of the transcription
factors AP-1 and NFκB, which
cause gene activation and may
offset the effects of the caspase
pathway.
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Los receptores Toll-like reconocen estructuras y patrones
conservados en los microorganismos.
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The diagram illustrates the
differentiation of murine Th cells
into subsets with distinctive
patterns of cytokine release. IL-12,
IFNγ and TGFβ favour
differentiation of Th1 cells and IL-4
favours Th2 cells. The cytokine
patterns influence the effector
functions that are activated.
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Not only does their cytokine output drive different effector
pathways, but Th1 cells tend to switch off Th2 cells, and vice
versa.
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Cytotoxic T cells recognize processed antigen presented on the target cell by MHC
molecules using their T-cell receptor (TCR). Most Tc cells are CD8+ and recognize
antigen presented by MHc class I, but a minority are CD4+ and recognize antigen
presented by MHC class II. By contrast, NK cells have receptors that recognize MHC
class I on the target and signal inhibition of cytotoxicity. They use a number of
different receptors (NK receptors) to identify their targets positively for killing,
including CD2, CD69, or antibody bound to their Fc receptor (CD16).
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Some of the ligands involved in the interaction between cytotoxic T cells
and their targets.
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The inhibitory receptors consist of the lectin-like CD94 disulphide bonded (red) to
peptides from the NKG2 locus, such as NKG2A which have intracellular domains
carrying ITIM motifs (immunoreceptor tyrosine inhibitory motif). The non-inhibitory
receptors, such as CD94/NKG2C, lack ITIMs, but have a charged lysine (K) in the
transmembrane segment which allows them to interact with signal transducing
molecules.
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These receptors consist of
either two or three extracellular
Ig superfamily domains. The
inhibitory forms are longer and
have intracellular ITIMs, while
the non-inhibitory forms have
the charged residue in the
membrane comparable to the
non-inhibitory forms of
CD94/NKG2.
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The molecule Fas (CD95), the two TNF receptors and the lymphotoxin receptor are illustrated
diagramatically. The extracellular domains are similar to those found in the NGF receptor. Both
Fas and TNFR-1 have death domains which are involved in the recruitment of caspases. The
ligands for these receptors are indicated at the top. Lymphotoxin-α can form homotrimers or
heterotrimers with lymphotoxin-β. Up to 25 other members of these families have been
identified by data-base searching.
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Ligation of CD95 or TNFR-1 causes
trimerization of the receptors. Death
domains in the cytoplasmic portion
of CD95 bind to the adaptor protein
FADD (=MORT-1), which recruits
caspase 8 or 10. TNFR-1 can activate
either caspase 8 or 10, via TRADD
and FADD, or caspase 2 via RIP and
RAIDD. Caspase 8 can further
activate other caspases, and these in
concert lead to apoptosis of the
target cell.
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The cytotoxic lymphoid cell degranulates, releasing perforin and various enzymes (granzymes) into the
immediate vicinity of the target cell membrane. In the presence of Ca2+ there is enzymic
polymerization of the perforin to form polyperforin channels on the target cell (1). Enzymes which
activate the apoptosis pathways, degradative enzymes or other toxic substances released from the
cytotoxic cell may pass through the channels on the target and cause cell damage or killing (2).
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