476
Autoantibodies and Autoimmunity
BXSB, (NZB
×
NZW
)F
1
,NZM
,MR
L
-
+
/
+
, and MRL-
lpr
/
lpr
,w
h
i
c
hd
e
v
e
l
o
p
forms of SLE that serve as excellent mod-
els of the autoantibody speci±cities and
pathology of the human disease. While
the variety of autoantibodies developed
by these different strains continues to
be investigated, the common autoantibody
response, like human SLE, is against chro-
matin and its subcomponents including
DNA. In the (NZB
×
NZW) F1 strain,
autoimmune disease and autoantibodies
occur earlier and more frequently in fe-
male mice, a ±nding that has been found
to be associated with the presence of
female sex hormones. Because of this
and other features, the (NZB
×
NZW)
F1 strain is considered the best animal
model of human SLE. As noted above,
it is the genetic makeup of these in-
bred strains that has signi±cant potential
to address the genesis of the autoim-
mune response. A much studied aspect
of several of the spontaneous models
of systemic autoimmune disease is the
presence of single-gene defects that ac-
celerate or exacerbate autoimmunity in
these already susceptible mouse strains.
In the MRL substrains, the
lpr
phenotype
is responsible for massive lymphoprolif-
eration of CD4
,CD
8
, and B200
+
T
cells and an accelerated occurrence of au-
toimmune phenomena compared to the
MRL-
+
/
+
. Recent studies have indicated
that the
lpr
defect is due to a mutation
in the
fas
gene that leads to defective
expression of
fas
on T- and B cells,
which allows them to escape apoptotic
elimination and reach the peripheral cir-
culation. Breeding experiments to impart
the
lpr
gene to nonautoimmune genetic
backgrounds have shown that the
fas
de-
fect does influence the development of
autoimmunity and the expression of au-
toantibodies. A dominant role for
fas
in
the initiation of autoimmunity and autoan-
tibodies is questionable, however, because
the MRL-
+
/
+
, which does not have the
fas
defect, does develop a autoantibody
pro±le and immunopathological disease
that is similar to the MRL-
lpr
/
lpr
,a
lb
e
i
t
at a much later age. Other genes that
appear to play a role in acceleration of
autoimmunity include
gld
,thel
igandfo
r
fas
,and
Yaa
, a sex-linked gene that pro-
duces a defect in B cells and is the
accelerator gene of autoimmunity in the
male BXSB mouse. Exposure of lupus-
prone strains to exogenous agents known
to elicit autoimmunity in normal mice
can result in accelerated appearance of
disease features including autoantibod-
ies. In some cases, the exogenous agent
accelerates the appearance of idiopathic
disease, while in others the elicited dis-
ease has features of xenobiotic-induced
disease. Thus, mercury exposure accel-
erates idiopathic disease in BXSB mice
including antichromatin autoantibodies of
the IgG2a subclass, while pristane injec-
tion into (NZB
×
NZW) F1 mice elicits
anti-Sm/RNP and Su autoantibodies that
are not part of the idiopathic disease
of the (NZB
×
NZW) F1 but are found
in pristane-induced autoimmunity. These
observations suggest that not only idio-
pathic and induced autoimmunity may
arise through different mechanisms but
also exogenous triggers can influence dis-
ease expression.
Thefou
r
tht
ypeo
fmode
lin
vo
l
ve
sge
-
netic manipulation in which a gene is
deleted (‘‘knockout’’) or added (‘‘trans-
genic’’) in order to influence the expression
of autoimmunity. Both types of genetic
modi±cation can be used to study the
influence of single genes on the animal
models described above. Perhaps not un-
expectedly, many gene deletions have little
previous page 476 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 478 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off