Autoantibodies and Autoimmunity
461
what constitutes ‘‘self’’ and ‘‘nonself,’’ and
what cellular/molecular mechanisms are
involved. Possible discriminators between
‘‘self’’ and ‘‘nonself’’ include recognition
of infection or identiFcation of danger
signals. The outcome of the debate on
self/nonself discrimination notwithstand-
ing, autoimmunity represents an obvious
disruption of the mechanism by which the
immune system regulates its activities. Im-
portantly, the responsible effector mech-
anisms appear to be no different from
those used to combat exogenous infec-
tive reagents, and include soluble products
such as antibodies (humoral immunity) as
well as direct cell-to-cell contact resulting
in speciFc cell lysis (cell-mediated im-
munity). No single mechanism has been
described that can account for the di-
versity of autoimmune responses or the
production of autoantibodies. ±igure 1 out-
lines the common features of hypothetical
models of autoantibody elicitation. Most
models, particularly those relating to au-
toimmune disease in animals, include a
genetic predisposition. Breeding experi-
ments between inbred strains of mice
have shown that the genetic control of
autoantibody production is complex, in-
volving multiple genes. Although most of
the required genetic elements remain to be
characterized, it appears that both accel-
eration and suppression of autoimmune
responses are under genetic control. The
most frequently observed genetic require-
ment involves the major histocompatibility
complex (MHC) class II genes, which
encode proteins responsible for the pre-
sentation of processed antigen to CD4
+
T
cells via the T-cell receptor.
The most perplexing and challenging
aspect of autoimmunity and autoantibody
elicitation is the identiFcation of the events
involved in the initiation of the response.
Although these early events are poorly un-
derstood for most autoimmune diseases,
it is thought that an exogenous trigger
can provide the Frst step in the initiation
of some autoimmune responses. The best
evidence for this comes from drug- and
Emergence of
autoreactive
T and/or B cells
Availability of
autoantigen
Molecular form
of autoantigen
Exogenous
agent
Genetic
predisposition
APC
CD4
+
T
CD4
+
T
CD4
+
T
T-cell activation
and proliferation
B-cell activation
and proliferation
IL
BB
B
B
Autoantigen presentation
to CD4
+
T cell
(MHC restricted)
T–B–cell interaction
and interleukin
secretion
Autoantibody
secretion
Fig. 1
Hypothetical pathway of autoantibody
elicitation in human disease and experimental
animal models. This model combines features
from the most commonly accepted postulated
mechanisms for autoantibody production.
Genetically predisposed individuals may be
triggered to begin the response by an exogenous
agent such as exposure to a drug, chemical
toxin, or other environmental influence. The
events that follow (listed in large box) are poorly
understood but must involve the emergence of
autoreactive lymphoid cells and the presence of
autoantigen in a molecular form reactive with
autoreactive cells. Once the presentation of
autoantigen has activated autoreactive lymphoid
cells, the production of autoantibody proceeds
essentially as it would for a nonautoimmune
antibody response.
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