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Class
I
phosphoinositide
3-­-kinases
in
immunity…

models
of
arthritis,
the
collagen-­-induced
arthritis
(CIA)
dependent
on
T-­-cell

dependent
cytokines
and
B
cell
help,
and
in
the
neutrophil-­-dependent
arthritis

induced
by
anti-­-collagen
II
monoclonal
antibodies
(104).
Similarly,
in
a
neutrophil-­-
dependent
model
of
arthritis
induced
by
serum
from
arthritis
K/BxN
mice,
clinical

symptoms
were
dependent
on
p110d
and
p110?,
and
IC87114
inhibited

progression
of
the
disease
(105).
In
the
rat
model
of
adjuvant-­-induced
arthritis

(AIA),
therapeutic
oral
administration
of
the
wide
spectrum
phosphatidylinositol

3-­-kinase
inhibitor
ZSTK474
ameliorated
clinical
signs
of
the
disease
and
inhibited

the
production
of
the
effector
cytokines
IFN-­-?
and
IL-­-17
by
T
cells
in
vitro,
or
the

proliferation
and
prostaglandin
E2
(PGE2)
production
by
fibroblast-­-like

synoviocytes
cells
(FLS)
(106).
PI3K?
deficiency
in
a
model
of
arthritis
induced
by

transgenic
expression
of
human
TNF
reduced
metalloproteinase
secretion
by

fibroblasts,
cartilage
damage
and
clinical
score,
yet
did
not
affect
recruitment
of

inflammatory
leukocytes
(107).
The
p110?-­-specific
inhibitor
AS252424
also

inhibited
invasiveness
and
matrix
metalloproteinase
secretion
by
human
synovial

fibroblasts
from
patients
with
RA.
Intriguingly,
in
FLS
from
rheumatoid
arthritis

patiens
PI3K
p110d
was
specifically
induced
in
FLS
from
rheumatoid
arthritis

patients
by
pro-­-inflammatory
cytokines
like
tumor
necrosis
factor
(TNF),
TNF

signaling
as
well
as
platelet-­-derived
growth
factor
(PDGF)-­-dependent
synoviocyte

growth
were
inhibited
by
PI3K
p110d
inhibitors
CAL-­-101
or
INK007,
but
not
by

p110a
inhibitors
like
A66
(108).

12.b.
Systemic
Lupus
Erythematosus.

Systemic
Lupus
Erythematosus
(SLE)
is
an
autoimmune,
chronic,

inflammatory,
multisystemic
disease
with
a
particularly
high
incidence
in
females.

SLE
is
due
to
tissue
and
cell
damage
induced
by
autoantibodies
generated
by
early

expansion
of
long-­-lived
autoreactive
T
helper
memory
cells
that
trigger
polyclonal

hyperactivity
of
B
lymphocyte
responses
and
hypergammaglobulinemia;

expansion
of
autoreactive
B
cells
leads
to
enhanced
levels
of
antibodies
against
a

variety
of
self
antigens,
particularly
nuclear
antigens
and
DNA.
Accumulation
of

immune
complexes
in
the
kidney
leads
to
inflammatory
reaction
ultimately
leading

to
glomerulonephritis.

There
are
different
animal
models
that
spontaneously
develop
a
SLE-­-
syndrome,
including
the
widely
used
MRL-­-lpr
and
MRL-­-gld
mice
with
a
mutation
in

the
expression
of
the
apoptosis-­-signaling
Fas
molecule
or
its
ligand,
respectively.

Roquinsan/san
mice
have
a
mutation
that
produce
disregulated
expression
of
the

PI3K
binding
costimulatory
molecule
ICOS,
show
progressively
enhanced
numbers

of
Tfh,
of
germinal
centers
and
autoantibodies,
and
nephritis
(109,110)
with
a

prime
role
for
Tfh
IFN-­-?
(111,112).

111