Autoantibodies and Autoimmunity
system is apoptotic cell death. The im-
petus for this hypothesis is the Fnding
that many autoantigens undergo prote-
olytic cleavage during apoptotic cell death
and that apoptotic bodies (debris from dy-
ing cells) contain multiple autoantigens.
Processing and presentation of such ma-
terial by antigen-presenting cells (APC)
has been suggested as a means of pro-
viding antigen to autoreactive T cells.
However, uptake of apoptotic cellular ma-
terial does not lead to the activation of
APCs, which is necessary if APCs are to
activate T cells. Inability of apoptotic ma-
terial to activate APCs may stem from the
observation that apoptosis is a descriptor
for programmed cell death (PCD), which
is a physiological process. This contrasts
sharply with necrotic cell death, which is
a nonphysiological process that produces
cellular material that activates APCs. Also
of note is that necrotic cell death induced
by mercury leads to proteolytic cleavage
of the autoantigen Fbrillarin. Immuniza-
tion with the N-terminal fragment of such
cleavage leads to autoantibodies against
Fbrillarin that possess some of the char-
acteristics of the antiFbrillarin response
elicited by mercury alone. In contrast,
the antibody response elicited by immu-
nization with full-length Fbrillarin does
not mimic the mercury-induced response,
suggesting that processing and presen-
tation of fragmented autoantigens may
allow loss of self/nonself discrimination.
Examination of the molecular forms of
autoantigens during and after cell death
and their roles in activating both APC
and T cells will be fruitful areas of fu-
ture research.
Roles in autoantibody production have
been argued for pathways that either are
or are not dependent on the presence of
T cells. A T cell–dependent response is
processed antigen to CD4
T cells. An
essential element in any model of au-
toantibody elicitation is the emergence
of antibody-secreting B cells, which rec-
ognize material derived from the host.
The antibody secreted by a B cell is di-
rected against a single region (or epitope)
on an antigen. An autoantibody response
can target a number of epitopes on any
one antigen, clearly showing that multi-
ple autoreactive B-cell clones are activated
during an autoimmune response. In the
systemic autoimmune diseases, many au-
toantigens are complexes of nucleic acid
and/or protein, and an autoimmune re-
sponse may target several of the compo-
nents of a complex. It is unknown whether
the autoantibody responses to the compo-
nents of a complex arise simultaneously,
sequentially, independently, or through in-
terrelated mechanisms.
In only a few diseases have autoanti-
bodies been shown to be the causative
agents of pathogenesis (e.g. antiacetyl-
choline receptor autoantibodies in myas-
thenia gravis, antithyroid stimulating hor-
mone receptor autoantibodies in Graves’
disease). It is noteworthy not only that
these diseases are organ speciFc but also
that their autoantigens are extracellular or
on the surface of cell membranes and
are therefore easily targeted by the im-
mune system. In some individuals, the
largest organ, the skin, can suffer insult
from several blistering conditions now
known to be autoimmune diseases charac-
terized by autoantibodies against products
of keratinocytes. The autoantigens in-
volved are cell adhesion molecules that
are important in maintaining the integrity
of the skin by cell–cell contact between
the various cell layers in the epidermis
and at the dermal–epidermal junction. In
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