plasma of patients with autoimmune disease, even
when the disease is mediated by direct T-cell
cytotoxicity (Naparstek and Plotz 1993). The major
reason for the appearance of these autoantibodies is
immune system exposure to sequestered or latent
self-antigens as a consequence of the primary tissue
injury. In patients who suffer a myocardial infarct,
for example, the antimyocardial antibodies that are
sometimes detectable a few weeks after the infarct
are atuoantibodies to latent myocardial self-antigens.
Organ-localized disease.
The laboratory evalu-
ation of organ-localized autoimmune diseases con-
sists primarily of studies of organ function, studies
of organ injury, and the demonstration of auto-
antibodies directed against the organ of interest.
The most specific autoantibodies to use for this
purpose are those directly responsible for the tissue
injury, although the responsible autoantibodies are
known only in some disorders. One of these disor-
ders is Grave’s disease, in which the offending
autoantibodies are directed against the extracellular
domain of the thyroid stimulating hormone receptor
on thyroid cells (Naparstek and Plotz 1993). The
binding of the autoantibodies (called thyroid stimu-
lating immunoglobulins, TSIs) causes activation of
the receptor, leading to hyperthyroidism. Other
autoantibodies are also often found in patients with
Grave’s disease. These include anti-thyroid peroxi-
dase autoantibodies and anti-thyroglobulin autoanti-
bodies. Neither of these autoantibodies is specific
for Grave’s disease, being found with appreciable
frequency in other forms of thyroiditis including
Hashimoto’s autoimmune thyroiditis.
Despite being less specific for Grave’s disease
than the TSIs, anti-thyroid peroxidase autoantibodies
are the autoantibodies that are almost always
measured in the laboratory evaluation of Grave’s
disease (Davies
et al.
1998). This is so because, in
contrast to the TSIs, there exists a widely available,
highly dependable, and inexpensive commercial
assay for anti-thyroid peroxidase autoantibodies
(Miles
et al.
1998). This represents an instance of
the superior practicability of one method out-
weighing the greater diagnostic reliability of another
method.
Systemic disease.
The systemic autoimmune
diseases, which are also called connective tissue
diseases, are characterized by immunologic injury to
multiple organs. The multifocality of injury in these
diseases may be due to a vasculitis that involves
various organs, as in Wegener’s granulomatosis, or
to the deposition of immune complexes in diverse
tissues, as in systemic lupus erythematosus. As
implied by the pattern of injury, the autoantibodies
in systemic disease are not directed against self-
antigens in a specific organ but rather to self-
antigens that are widely distributed. For instance,
antinuclear antibodies, such as those found in
systemic lupus erythematosus, bind to the same
nuclear antigens in different organs. Rheumatoid
factor, the characteristic autoantibody of rheumatoid
arthritis, is directed against IgG which is present
throughout the extracellular fluids.
The laboratory evaluation of the systemic
autoimmune diseases has four components: confirm-
ing an immunologic etiology for an illness present-
ing as a systemic disorder; establishing the diagnosis
from among the various systemic diseases; monitor-
ing the activity of the disease; and monitoring organ
function in those disorders associated which signifi-
cant, progressive organ injury.
The immunologic origin of a systemic disorder
is revealed by the demonstration of the acute phase
response, complement activation, and circulating
autoantibodies (McCarty-Farid 1994).
The acute phase response is a nonspecific
reaction to tissue injury mediated by cytokines. It is
composed of a triad of findings: fever, neutrophilia,
and elevation in the concentrations of certain plasma
proteins, referred to as acute phase proteins (Gabay
and Kushner 1999). All three components of the
triad are usually present when injury is caused by
bacterial infection. Systemic autoimmune diseases
show only the elevation in acute phase protein
concentrations (Table 9.2). The acute phase proteins
can be divided into two groups. The first group
consists of proteins that are normally present in
appreciable concentration in the plasma and which
experience 1.25 to 3-fold elevations in concentration
in an acute phase response. These proteins include
fibrinogen. The second group is made up of
C-reactive protein and amyloid A protein. These
two proteins are normally present in trace quantities
but show up to 1000-fold increases in concentration
during the acute phase response. Only fibrinogen
and C-reactive protein are used clinically as markers
of the acute phase response. Mainly for historical
reasons, fibrinogen is typically not measured directly
but is instead assayed indirectly using the erythro-
cyte sedimentation rate (ESR) or the plasma vis-
cosity. The ESR is the length of the plasma column
that develops when anticoagulated blood sediments
Tissue Injury
9-6
