Class I phosphoinositide3-‐kinases in immunity…
111
models of arthritis, the collagen-‐induced arthritis (CIA) dependent on T-‐cell
dependent cytokines and B cell help, and in the neutrophil-‐dependent arthritis
inducedbyanti-‐collagen IImonoclonal antibodies (104). Similarly, inaneutrophil-‐
dependentmodel of arthritis inducedby serumfromarthritisK/BxNmice, clinical
symptoms were dependent on p110
δ
and p110
γ
, and IC87114 inhibited
progression of the disease (105). In the rat model of adjuvant-‐induced arthritis
(AIA), therapeutic oral administration of the wide spectrumphosphatidylinositol
3-‐kinase inhibitor ZSTK474 ameliorated clinical signs of the disease and inhibited
the production of the effector cytokines IFN-‐
γ
and IL-‐17 by T cells
in vitro
, or the
proliferation and prostaglandin E2 (PGE2) production by fibroblast-‐like
synoviocytes cells (FLS) (106). PI3K
γ
deficiency in amodel 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
γ
-‐specific inhibitor AS252424 also
inhibited invasiveness andmatrixmetalloproteinase 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 aswell as platelet-‐derived growth factor (PDGF)-‐dependent synoviocyte
growth were inhibited by PI3K p110
δ
inhibitors CAL-‐101 or INK007, but not by
p110
α
inhibitors likeA66(108).
12.b. SystemicLupusErythematosus.
Systemic Lupus Erythematosus (SLE) is an autoimmune, chronic,
inflammatory, multisystemic diseasewith a particularly high incidence in females.
SLE is due to tissue and cell damage inducedby autoantibodies generatedby early
expansionof long-‐lived autoreactiveThelpermemory 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
immunecomplexes in thekidney leads to inflammatoryreactionultimately leading
toglomerulonephritis.
There are different animal models that spontaneously develop a SLE-‐
syndrome, including thewidelyusedMRL-‐
lpr
andMRL-‐
gld
micewithamutation in
the expression of the apoptosis-‐signaling Fas molecule or its ligand, respectively.
Roquin
san/san
mice have a mutation that produce disregulated expression of the
PI3Kbinding costimulatorymolecule ICOS, showprogressively enhancednumbers
of Tfh, of germinal centers and autoantibodies, and nephritis (109,110) with a
primerole forTfh IFN-‐
γ
(111,112).
