Immunopathogenesis of SLE
Systemic Lupus Erythematosus
(SLE) is a systemic autoimmune disease
with a prevalence of approximately
1/2500 in European populations
affecting mainly females (9
females:1
male)
(1)
.
It's characterized
by a plethora of immunological
and
laboratory abnormalities with
multiple
organ / tissue damage. Almost
all of the key components in the immune system are involved in
the disease pathogenesis which is
largely still unclear
(2)
.
Deficiencies in the recognition
and clearance of apoptotic cells by
phagocytosis have been shown in
patients with SLE
(3,4).
Whether
apoptosis itself is abnormal or merely
an effect of environmental triggers,
such
as U.V. irradiation or viral infection,
is less understood
(5,6)
.
During necrosis or apoptosis nuclear
antigens are subjected to modifications
which allow them to be rec- ognized as non-self. Activation of
TLR7 and TLR9 by self nucleic acids
and immune complexes leads to the
production of IFN-α and proinflammatory
cytokines such as IL-6, TNF?
and IL-12
(7)
.
IFN-α fosters autoimmunity by
several mechanisms; It promotes
dendritic cell maturation, the production
of pro-inflammatory cytokines,
stimulation
of Thl pathways, B-cell
activation
, plasma cell differentiation
and
regulation of apoptosis
. In
SLE the type IFNα can contribute to
loss of tolerance and activation of
autoreactive T and B cells with production
of autoantibodies
(9)
.
The expression of antinuclear
antibodies (ANA) can be divided
to three stages: antibody induction,
maintenance and elimination.
Antigens involved in the first two
stages may not be the same.
Indeed, there is evidence that
viral and bacterial antigens can induce
ANA production while self
molecules
may mediate antibody
maintenance
(10)
.
However, recent studies by
Schroeder et al 2013
(11)
, Detanico
et al 2013
(12)
(8)
argue that ANA arise predominantly from nonautoreactive
B cells that are transformed into autoreactive
cells by the process of somatic
hypermutation , which is normally
associated with affinity
maturation
during the germinal center
reaction.
CD4 T cell differentiation is altered
in SLE presented in the bias
of
TH1/TH2 balance to TH1
(13)
and
subsequently transcriptional factors
T-bet /GATA3 to T-bet
(14)
, and in
the bias of TH17 / Treg to TH17 and
subsequently transcriptional factors
ROR?t/Foxp3 to RORαt
(15,16)
. Besides
the role of follicular helper
(TFH
)
(17)
in providing help to B
cells allowing the formation of germinal
center
(18)
.
CD8 T cell function is impaired in
peripheral blood T cells from patients
with SLE. Double-negative T cells
are also expanded and found within
cellular infiltrates in kidney biopsies
of patients with lupus nephritis with
secretion of IL-1b and IL-17
(19)
SLE susceptibility genes
Here we summarize the con-
firmed genetic risk loci placed in the
context of major SLE disease pathways , where possible