472
Autoantibodies and Autoimmunity
intriguing features of some autoantibodies
have added new dimensions to the biolog-
ical usefulness of these proteins and have
suggested that functionally active macro-
molecular complexes may play a role in the
elicitation of the autoantibody response.
Thep
resenceo
fmu
l
t
ip
leau
toan
t
ibody
speciFcities in the blood of individual
human patients with autoimmune dis-
eases poses a limitation on their use
in studies involving a single autoanti-
gen. Only infrequently are patients found
whose autoantibody response is so re-
stricted that they express autoreactivity
to a single autoantigen or autoantigenic
complex; such autoantibodies are termed
monospecifc
. ±or some autoantibody speci-
Fcities, this condition has been overcome
by the production of hybridomas secret-
ing a monoclonal autoantibody. Some
hybridomas have been produced by fu-
sion of B cells from human patients, but
most have come from fusion of lymphoid
cells from animal models of autoimmu-
nity, particularly inbred murine strains.
Monoclonal antibody speciFcities include
reactivity against the nucleic acids DNA
and RNA, subunits of chromatin, protein
components of snRNP particles, Fbril-
larin, and immunoglobulin.
4
Autoantibodies in Experimental Models of
Autoimmunity
Research into the mechanisms of autoim-
munity and the antigenic speciFcity, and
possible pathogenic role, of autoantibod-
ies has been signiFcantly advanced by the
availability of animal models. ±our dif-
ferent types of models have been used
(Table 4). SpeciFc antigen immunization
models
are
produced
by
direct
injec-
tion of puriFed antigen into animals to
elicit autoantibody. Direct immunization
has proven most useful when the au-
toantigen is extracellular or is on the
cell membrane. In such examples, the
elicited autoantibody response can pro-
duce pathological consequences such as
the myasthenia gravis–like disease pro-
duced in rodents following immunization
with puriFed acetylcholine receptor. The
animals used in this type of model are
most often healthy, normal individuals
with fully functional immune systems and
are able to downregulate the autoimmune
response produced by the immunization
of autoantigen. As a result, direct immu-
nization models often produce transient
autoimmune responses and the animals
return to a healthy state.
Comparison of the autoantigenic reactiv-
ities of antibodies raised by immunization,
especially to intracellular autoantigens, has
revealed distinct differences in compari-
son to autoantibodies found in human au-
toimmune disease. Direct immunization
requires a puriFed antigen, which means
subjecting the antigen to rigorous bio-
physical, biochemical, and sometimes im-
munological separation techniques. The
resulting preparation may therefore be par-
tially or totally denatured and no longer in
association with other cellular components
that constitute its
in vivo
molecular form.
Even if the native
in vivo
macromolecular
complex can be puriFed, direct immu-
nization experiments are ‘‘best guess’’
attempts to mimic the natural autoimmu-
nization process because the molecular
structure of the putative autoimmunogen
that contains the autoantigen of interest
is unknown. A further complication is the
use of adjuvants to boost the immune
response. As a result, direct immuniza-
tion produces antibodies that, although
they react with the autoantigen, usually
recognize a denatured form rather than
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