474
Autoantibodies and Autoimmunity
the autoantigen in its native state; only
rarely do they react with the autoantigen
when it is in association with other cellular
subunits that make up its
in vivo
molec-
ular form. Although direct-immunization
antibodies can recognize conformational
epitopes, they do not appear to recognize
conserved epitopes and therefore cannot
exhibit the same lack of species speciFcity
that allows, for example, antiFbrillarin au-
toantibodies to recognize Fbrillarin in all
species that contain this protein. Lack of re-
action against conserved epitopes means
that direct immunization antibodies are
less efFcient at inhibiting the functional
activity of their target autoantigen than
autoantibodies from patients with autoim-
mune diseases. Animal models of other
types, described next, can produce autoan-
tibodies with reactivities that are extremely
difFcult to differentiate from those of hu-
man patients. As a result, such models
more closely approximate their human
counterparts.
The second type of model also involves
the manipulation of normal, nonautoim-
mune animals to produce an autoimmune
response. In these cases, the triggering
event is the introduction of exogenous
material into the animal, which, unlike
the case of direct immunization, may
appear to bear little relationship to the
ensuing autoimmune response. An ex-
ce
l
len
texamp
leo
fth
i
stypeo
fmode
li
s
the autoimmunity induced by heavy met-
als. Administration of mercury by several
different routes and in several different
forms, most notably subcutaneous in-
jection of mercuric chloride, produces
in mice an autoantibody response that
targets the nucleolus. The principal au-
toantigen involved is the 34 kDa protein
Fbrillarin (±ig. 5), a protein component
of the box C/D snoRNP particles. Mer-
cury induces this autoantibody response
in a restricted number of histocompat-
ibility genotypes, most commonly H-2
s
.
Although offspring of crosses between the
autoimmune-sensitive H-2
s
strains and
the autoimmune-resistant strains such as
C57BL/6 (H-2
b
)o
rD
B
A
/
2(H
-
2
d
)a
r
e
sensitive to antiFbrillarin induction fol-
lowing HgCl
2
treatment, the response
does not appear to be solely due to the
product of a dominant
H-2
gene but
involves multiple loci as well. This is sup-
ported by back-crossing of hybrids onto the
autoimmune-sensitive H-2
s
background,
where the HgCl
2
-induced antiFbrillarin re-
sponse is even less frequent, even though
5
0%o
fth
em
i
c
ew
ou
ldb
ee
xp
e
c
t
edt
o
be homozygous for H-2
s
.A
l
th
ou
ghan
-
tiFbrillarin autoantibodies are a marker
for human scleroderma, mercury does not
appear to produce a scleroderma-like dis-
ease in mice; the importance of the model
lies instead in the similarity of this toxin-
induced murine autoantibody’s response
to the spontaneous antiFbrillarin autoan-
tibody in human scleroderma.
Another
example
of
the
exogenous
factor-type model is murine graft-versus-
host disease (GVHD). In this model, the
offspring of the mating of two inbred
nonautoimmune mouse strains are in-
jected (grafted) with lymphocytes from one
of the parental strains. The injected lym-
phocytes recognize genetic differences in
the host strain that are inherited from the
other parental strain and are stimulated
to mount a variety of immune responses
against the host animal; hence the name
‘‘graft versus host.’’ Unlike the case of
direct immunization models, the autoim-
munity produced in this type of model can
lead to severe pathological consequences
including lethal immune-complex disease.
The immunological sequelae that occur
during a GVHD response depend on the
murine inbred strains used. Injection of
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