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U N I T 4
Infection and Immunity
the costimulatory signals that are necessary for its acti-
vation. The peripheral activation of T cells requires two
signals: recognition of the peptide antigen in associa-
tion with the MHC molecules on the APCs, and a set
of secondary costimulatory signals. Because costimula-
tory signals are not strongly expressed on most nor-
mal tissues, the encounter of the autoreactive T cells
and their specific target antigens frequently results in
anergy.
1,2
Another self-tolerance mechanism involves the apop-
totic death of autoreactive T cells.
20,21,24
This type of
apoptosis is mediated by an apoptotic cell surface recep-
tor (called Fas) that is present on the T cell and a soluble
membrane messenger molecule (Fas ligand) that binds
to the apoptotic receptor and activates the death pro-
gram (see Chapter 2). The expression of the apoptotic
Fas receptor is markedly increased in activated T cells;
thus, coexpression of the Fas messenger molecule by the
same cohort of activated autoreactive T cells may serve
to induce their death.
Suppressor T cells with the ability to down-regulate
the function of autoreactive T cells are also thought
to play an essential role in peripheral T-cell tolerance.
These cells are believed to be a distinct subset of CD4
+
and CD8
+
T cells.
25,26
The mechanism by which these
T cells exert their suppressor function is unclear. They
may secrete cytokines that suppress the activity of
self-reactive immune cells, or they may delete the self-reactive T-cell clones.
Mechanisms of Autoimmune Disease
It is not known what triggers autoimmunity, but both
genetic susceptibility and environmental factors, such
as infectious agents, appear to play a role. Moreover,
a number of autoimmune disorders such as SLE
occur more commonly in women than men, suggest-
ing that estrogens may play a role in their develop-
ment. Evidence suggests that estrogens stimulate the
immune response and androgens suppress it.
27,28
For
example, estrogen stimulates a DNA sequence that
promotes the production of interferon-
γ
, which is
thought to assist in the induction of an autoimmune
response.
Genetic Susceptibility
Genetic factors can increase the incidence and sever-
ity of autoimmune diseases, as shown by the famil-
ial clustering of several autoimmune diseases and the
observation that certain inherited HLA types occur
more frequently in persons with a variety of immu-
nologic disorders.
2,22,23
For example, 90% of persons
with ankylosing spondylitis carry the HLA-B27 anti-
gen, compared with 7% of persons without the dis-
ease.
2
Other HLA-associated diseases include Reiter
syndrome with HLA-B27, rheumatoid arthritis with
HLA-DR4, and SLE with HLA-DR3 (see Chapter 44).
The molecular basis for these associations is unknown.
Because autoimmunity does not develop in all persons
with genetic predisposition, it appears that other
factors—such as a “trigger event”—interact to precipi-
tate the altered immune state. The event or events that
trigger the development of an autoimmune response
are unknown. It has been suggested that the “trig-
ger” may be a virus or other microorganism, a chemi-
cal substance, or a self-antigen from a body tissue
that has been hidden from the immune system during
development.
Role of Infections
Viral and bacterial infections may contribute to the
development and exacerbations of autoimmunity. In
many persons, the onset of autoimmunity is associ-
ated with or preceded by infection. In most of these
cases, the infectious microorganisms are not present in
lesions or detectable when autoimmunity develops.
1–3
Therefore, the lesions of autoimmunity are not due to
the infectious agent itself, but to the immune process
that was triggered by the microbe. There are three pro-
posed mechanisms through which infections can trigger
autoimmunity: breakdown of T-cell anergy, molecular
mimicry, and superantigens.
Breakdown of T-Cell Anergy.
Infections of particu-
lar tissues may induce local innate immune responses
that attract leukocytes into the tissue and result in the
activation of antigen-presenting cells. These antigen-
presenting cells begin to express costimulators and
secrete T cell–activating cytokines, resulting in the
breakdown of self-tolerance.
1,2
Most normal tissues
do not express the costimulatory molecules and thus
are protected from autoreactive T cells. However, this
protection can be lost if the cells that do not normally
express the costimulatory molecules are induced to
do so.
Molecular Mimicry.
One proposed link between
infections and autoimmunity is
molecular mimicry,
in which a microbe shares an immunologic epitope
with the host.
29,30
In rheumatic fever and acute glo-
merulonephritis, a protein in the cell wall of group A
β
-hemolytic streptococci has considerable similarity
with antigens in heart and kidney tissue, respectively.
After infection, antibodies directed against the micro-
organism cause a classic case of mistaken identity,
which leads to inflammation of the heart or kidney.
Not everyone exposed to group A
β
-hemolytic strep-
tococci develops an autoimmune reaction. The reason
that only certain persons are targeted for autoimmune
reactions to a particular self-mimicry molecule may
be determined by differences in HLA types. The HLA
type determines exactly which fragments of a pathogen
are displayed on the cell surface for presentation to
T cells. One individual’s HLA may bind self-mimicry
molecules for presentation to T cells, whereas anoth-
er’s HLA type may not. In the spondyloarthropathies,
particularly Reiter syndrome and reactive arthritis,
there is a clear relationship between arthritis and a
