Autoantibodies and Autoimmunity
or no effect on the expression of autoim-
munity and autoantibodies. Such negative
effects need to be interpreted carefully as
they may indicate a genetically redundant
process rather than an unimportant gene.
Other gene deletions have been reported to
influence differing aspects of autoimmu-
nity in a gene-speciFc manner, although
the extent of the effect may vary be-
tween experimental models. Some gene
sponses. Thus, deletion of the gene for
the pleiotropic cytokine interferon-
abrogates autoantibody production and
immunopathology in mercury-induced au-
toimmunity of B10.S mice and sponta-
neous autoimmunity in MRL-
The signiFcance of I±N-
in systemic
autoimmunity has been demonstrated in
nonautoimmune-prone mice made trans-
genic for I±N-
expression in the epider-
mis. The increased expression of I±N-
leads to a lupus-like disease characterized
by the production of autoantibodies and
immune complex–mediated tissue dam-
age. ±urther evidence for the importance
of I±N-
has come from an examination of
gene expression in the Nba2 locus of chro-
mosome 1 of the mouse. Nba2 is a genetic
interval identiFed as a locus of genetic
susceptibility for lupus in the NZB strain.
The offspring of Nba2 interval–speciFc
congenic C57BL/6 mice mated with NZW
mice develop autoimmunity similar to the
SLE-prone (NZB
NZW) ±1 mouse. Ex-
amination of gene expression by DNA
array revealed a relationship between in-
creased expression of interferon inducible
gene (
) 202 and features of systemic
autoimmunity. Importantly, the gene for
IF202 lies within the Nba2 interval. ConFr-
mation that increased expression of IF202
occurs in other models of systemic lupus
would signiFcantly enhance its stature as
a lupus susceptibility gene. However, as
susceptibility for SLE maps to multiple ge-
netic loci, it is highly likely that additional
genes contribute to full disease expression
in the (NZB
NZW) ±1 mouse.
A number of other gene deletions are
associated with expression of autoimmu-
nity and autoantibodies. Some of these
such as deFciency of C1q, a component
of the complement system, have particular
relevance as complement deFciencies in
humans and can lead to development of
systemic lupus. SigniFcantly, lack of C1q
is not sufFcient for the development of
murine lupus; this gene deletion must
occur on genetic backgrounds carrying
additional susceptibility genes for autoim-
munity to occur. It must also be noted that
although many knockout and transgenic
models exhibit features of autoimmunity,
they may also exhibit other features that
are not consistent with the known spec-
trum of clinical and immunological facets
of autoimmune diseases. More telling is
the Fnding that many of the genetic mu-
tations that lead to autoimmunity in mice
are not necessary for the development of
human systemic autoimmune disease. As
described above, mutation in the
contributes signiFcantly to the severity of
murine SLE. However, mutations in the
gene are not associated with human
SLE but rather with autoimmune lym-
phoproliferative syndrome (ALPS). ALPS
is characterized by lymphoproliferation of
double-negative T cells and autoantibod-
ies against DNA and cardiolipin, features
found in mice with a
mutation but
without other lupus susceptibility genes.
Similarly, Dnase1-deFcient mice develop
a lupus-like disease with antichromatin
autoantibodies, but deFciency of Dnase1
is not common in human systemic lu-
pus. A nonsense mutation in exon 2 of
gene has been reported in
two apparently unrelated young Japanese
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