C h a p t e r 1 6
Disorders of the Immune Response
357
prior bacterial infection, combined with the inherited
HLA-B27 antigens.
Superantigens.
Superantigens are a family of related
substances, including staphylococcal and streptococcal
exotoxins, that can short-circuit the normal sequence of
events in an immune response, leading to inappropriate
activation of CD4
+
helper T cells. Superantigens do not
require the typical processing and presentation of anti-
gen by APCs to induce a T-cell response.
31
Instead, they
are able to interact with a T-cell receptor outside the
normal antigen-binding site. This distinctive mode of
activation, combined with the ability of superantigens
to bind to a wide variety of MHC class II molecules, can
lead to the activation of large numbers of T cells regard-
less of their MHC/peptide specificity. Superantigens are
involved in several diseases, including food poisoning
and toxic shock syndrome.
Release of Sequestered Antigens
Normally the body does not produce antibodies
against self-antigens. Thus, any self-antigen that was
completely sequestered during development and then
reintroduced to the immune system is likely to be
regarded as foreign. Among the sequestered tissues
that could be regarded as foreign are spermatozoa and
ocular antigens such as those found in uveal tissue.
Posttraumatic uveitis and orchiditis after vasectomy
may fall into this category.
Changes in antigen structure or release of hidden
antigens may also account for the persistence of auto-
immune disorders. Once an autoimmune disorder has
been induced, it tends to be progressive, sometimes
with sporadic relapses and remissions. A possible
mechanism for the persistence and evolution of auto-
immunity is the phenomenon called
epitope spreading
.
2
Infections, and even the initial autoimmune episode,
may expose self-antigens that have been hidden from
the immune system, resulting in continued activation
of new lymphocytes that recognize the previously hid-
den epitopes.
Diagnosis andTreatment of
Autoimmune Disease
Suggested criteria for determining whether a disor-
der is an autoimmune disease include the following:
evidence of an autoimmune reaction, determination
that the immunologic findings are not secondary to
another condition, and no other identifiable causes
for the disorder. Currently, the diagnosis of autoim-
mune disease is based primarily on clinical findings
and serologic testing.
The basis for most serologic assays is the demon-
stration of antibodies directed against tissue antigens
or cellular components. For example, an individual
with a history of fever, arthritis, and a macular rash
and who has high levels of antinuclear antibody
has a probable diagnosis of SLE. The detection of
autoantibodies in the laboratory usually is accom-
plished by one of three methods: indirect fluorescent
antibody assay (IFA), enzyme-linked immunosorbent
assay (ELISA), or particle agglutination of some kind.
The rationale behind each of these methods is similar:
the patient’s serum is diluted and allowed to react with
an antigen-coated surface (e.g., whole, fixed cells for
the detection of antinuclear antibodies). In the case of
IFA and ELISA, a second “labeled” antibody is added,
which binds to the patient’s antibody and can induce
a visible reaction. Particle agglutination assays are
much simpler—the binding of the patient’s antibody to
antigen-coated particles causes a visible agglutination
reaction. For most serologic assays, the patient’s serum
is serially diluted until it no longer produces a visible
reaction (e.g., 1:100 dilution). This is called a
posi-
tive titer.
Healthy persons sometimes have low titers
of antibody against cellular and tissue antigens, but
their titers usually are far lower than in patients with
autoimmune disease.
Treatment of autoimmune disease is based on the
tissue or organ that is involved, the effector mecha-
nism involved, and the magnitude and chronicity of
the effector processes. Ideally, treatment should focus
on the mechanism underlying the autoimmune disor-
der. Corticosteroids and immunosuppressive drugs
may be used to arrest or reverse the downhill course of
some autoimmune disorders. Purging autoreactive cells
from the immune repertoire through the use of plas-
mapheresis is also an option in some severe cases of
autoimmunity.
Recent research has focused on the cytokines
involved in the inflammatory response that accom-
panies many of the autoimmune disorders (e.g.,
interferon-
β
for multiple sclerosis and tumor necrosis
factor-
α
[TNF-
α
] antibodies for rheumatoid arthritis
and Crohn disease).
SUMMARY CONCEPTS
■■
Autoimmune diseases represent a disruption
in self-tolerance that results in damage to body
tissues by the immune system.
■■
Self-tolerance is maintained through central and
peripheral mechanisms that delete autoreactive
B or T cells or otherwise suppress or inactivate
immune responses that would be destructive
to host tissues. Defects in any of these
mechanisms could impair self-tolerance and
predispose to the development of autoimmune
disease.
■■
Autoimmunity results from a failure of tolerance.
Autoimmune disorders may be triggered by
environmental stimuli, such as infections, in a
genetically predisposed individual.
