Autoantibodies and Autoimmunity
chemical-induced autoimmunity, which
has been described in both human dis-
ease and animal models of autoimmunity.
However, even in exogenously induced
autoimmunity, many of the events bet-
ween the administration of a chemical or
a drug and the appearance of autoantibod-
ies remain to be unveiled. Induction of
autoantibodies by exogenous agents can
take from several weeks to many months.
Drug-induced systemic autoimmunity in
humans can take prolonged periods of
time to develop and can be provoked by
a large number of chemically unrelated
drugs. The autoantibody response, how-
ever, appears quite restricted, targeting
histones and histone–DNA complexes, the
components of chromatin. Complexes of
drug and autoantigen are not the immuno-
gens responsible for the autoantibody
response, since the drug is not required for
autoantibody interaction with the autoanti-
gen. Withdrawal of the drug often leads
to cessation of clinical symptoms, clearly
implicating the participation of the drug
in some mechanism inciting the autoim-
mune response, although the autoantibody
may persist for months in the absence of
the drug. In several animal models, expo-
sure to chemicals, particularly inorganic
forms of heavy metals such as mercury,
silver, or gold, can lead to autoantibody
expression within weeks. In these murine
models, the autoantibody response is again
restricted, but here the predominant tar-
gets are nonchromatin components of the
nucleolus. The development of restricted
autoantibody speciFcities in humans given
many different drugs or in mice given
heavy metals suggests that it is not the
parent molecule that is important but
rather the metabolic products of these
compounds that lead on the one hand
to antichromatin autoantibodies and on
the other to antinucleolar antibodies. In
human drug-induced autoimmunity, a
common pathway of oxidative metabolism
via the ubiquitous neutrophil has been
suggested as a means of producing re-
active drug metabolites that may perturb
immune regulation sufFciently to produce
autoimmune disease. Another mechanism
that has been proposed is disruption by
drug metabolites of positive selection of
T cells during their development in the
thymus. This mechanism has been shown
to result in mature CD4
T cells that are
able to respond to self-antigen leading to
T-cell proliferation as well as autoantibody
production by B cells.
In ±ig. 1, the large boxed area highlights
several concepts that form pivotal points
in many hypothetical postulates of autoan-
tibody elicitation but about which little
is known. How do B- and T cells, with
receptors for autoantigen, emerge from
and escape the regulatory mechanisms
that normally keep them in check, then
make their way to the secondary lymphoid
tissues? Studies involving transgenic mice
possessing neoautoantigens suggest that
possible mechanisms include avoidance of
apoptotic elimination, escape from toler-
ance induction, and reversal of an anergic
state. Molecular identiFcation of autoanti-
gens, their presence in macromolecular
complexes, the occurrence of autoantibod-
ies in different components of the same
complex, and the appearance of somatic
mutations in the variable regions of au-
toantibodies have suggested that it is the
autoantigen that drives the autoimmune
response. It remains unclear how autoanti-
gens, particularly intracellular autoanti-
gens, are made available to autoreactive
lymphoid cells, and what molecular forms
of these complex macromolecular struc-
tures interact with autoreactive lymphoid
cells. One mechanism that has been pro-
posed as a means by which autoantigens
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