146
Cytokines: Interleukins
birth. The remainder developed an inflam-
matory bowel disease, probably resulting
from an abnormal immune response to a
normal antigenic stimulus. In man, a child
with a defect in IL-2 mRNA production
(but not due to a defect in the IL-2 gene)
was found to be more susceptible to infec-
tions. In addition, a few patients suffering
from a particular form of severe combined
immunodeFciency disease (SCID), which
has been linked to the X chromosome (thus
XSCID), are characterized by a lack of ex-
pression of IL-2R
γ
. XSCID patients are
therefore unable to form high-afFnity IL-2
(or IL-4, -7, -9, -15, -21) receptors and their
immunocytes cannot respond to IL-2 or the
other interleukins that require IL-2R
γ
.In
total, these studies provide strong evidence
for IL-2 playing a key role in the regulation
of immune and inflammatory responses.
In contrast, either IL-15 or IL-15R
α
knock-
out mice are lymphopenic with selective
loss particularly of NK and CD8
+
T-cell
subsets, rendering these mice suscepti-
ble to vaccinia virus infection. Thus, this
phenotype is distinctive from that of IL-2
knockouts and indicates a role different to
IL-2 for IL-15, despite the latter sharing
two of the high-afFnity IL-2R components
(see Sect. 4.15).
Other knockout mice that are interesting
in this respect are those of the IL-4 and
IL-10 null phenotypes. In IL-4 knockout
mice, it has been found that they generally
are unable to mount a Th2 cell type of
immune response. ±or instance, IgE was
undetectable in these mice. In addition,
when these mice were parasitized with the
nematode
Nippostrongylus brasiliensis
,on
ly
a weak eosinophilia was observed. Since
eosinophil proliferation is dependent on
IL-5 (see Sect. 4.5), this Fnding indicates
that IL-4 is required for inducing Th2
cell interleukin production, that is, IL-
4, IL-5, IL-10, and so on. In the case of
IL-10 knockout mice, it might be expected
th
a
tth
e
s
ean
im
a
l
sa
r
ea
l
sol
e
s
sab
l
eto
mount a Th2 cell immune response, since
loss of IL-10, which actively suppresses
macrophage ‘‘help’’ (IL-12) for Th1 cell
generation, would relieve the inhibition
on Th1 cell development. However, the
main observable effect in IL-10 knockout
mice is chronic bowel inflammation where
mice are not kept under speciFc pathogen-
free
conditions.
This
Fnding
indicates
that IL-10 acts as a regulator of immune
responses stimulated by enteric antigens
in the intestine. In the absence of IL-10,
such immune responses are uncontrolled
leading to bowel inflammation, probably
due to a loss of IL-10-mediated suppression
of macrophage cytotoxicity and release of
inflammatory cytokines, for example, IL-
1, TN±
α
. In support of this hypothesis,
it
has
been
shown
that
normal
mice
become more sensitive to LPS-induced
endotoxic shock by treatment with anti-
IL-10 antibodies, while lethal endotoxemia
and elevated serum TN±
α
levels were
suppressed by injected IL-10.
Another
interesting
cohort
of
inter-
leukin knockouts that is currently emerg-
ing is that with knockouts of IL-12 or IL-23.
Knockouts of IL-12 p40 (which lack both
IL-12 and IL-23) are more immunocom-
promised than knockouts of IL-12 p35
(which lack only IL-12). However, knock-
outs of IL-23 p19 (which lack only IL-23)
manifest a phenotype that can be distin-
guished from the p35 knockout. The p19
null mice can still generate Th1 cells and
I±N
γ
, but are susceptible to experimental
autoimmune encephalitis (EAE), whereas
p35 null mice cannot generate Th1 cells,
but are highly susceptible to EAE. Such
studies indicate the importance of the in-
terleukin recognition components of their
cognate receptors in determining their
functional roles.
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