C h a p t e r 1 6
Disorders of the Immune Response
355
B-Cell Tolerance
Several mechanisms are available to filter autoreactive
B cells out of the B-cell population: clonal deletion of
immature B cells in the bone marrow; deletion of auto-
reactive B cells in the spleen or lymph nodes; functional
inactivation or anergy; and receptor editing, a process
that changes the specificity of a B-cell receptor when
autoantigen is encountered.
20
There is increasing evi-
dence that B-cell tolerance is predominantly due to
help from T cells. Loss of self-tolerance with develop-
ment of autoantibodies is characteristic of a number of
autoimmune disorders. For example, hyperthyroidism
in Graves disease is due to autoantibodies to the TSH
receptor (see Fig. 16-2 and Chapter 32).
T-Cell Tolerance
The central mechanisms of T-cell tolerance involve the
deletion of self-reactive T cells in the thymus (Fig. 16-5).
T cells develop from bone marrow–derived progenitor
cells that migrate to the thymus, where they encounter
self-peptides bound to MHC molecules. T cells that dis-
play the host’s MHC antigens and T-cell receptors for
a nonself-antigen are allowed to mature in the thymus
(i.e., positive selection). T cells that have a high affinity
for host cells are sorted out and undergo apoptosis or
cell death (i.e., negative selection). The deletion of self-
reactive T cells in the thymus requires the presence of
autoantigens. Because many autoantigens are not pres-
ent in the thymus, self-reactive T cells may escape the
thymus, so peripheral mechanisms that participate in
T-cell tolerance are required.
Several mechanisms are available to control the
responsiveness of self-reactive T cells in the periphery.
Sometimes the host antigens are not available in the
appropriate immunologic form or are separated from
the T cells (e.g., by the blood–brain barrier) so that cor-
responding T cells remain
immunologically ignorant
of
their presence.
20,21
In other cases, the autoreactive T cell
encounters its corresponding antigen in the absence of
Bone marrow
Pre-T cells
Thymus
Self-antigen
not expressed
in thymus
Self-reactive clones
Self-reactive clones
Apoptosis
Development of
central tolerance
Induction of normal
immune function with
self versus nonself
recognition
Failure of
antigens to
activate
lymphocyte
Clonal anergy
Activation-
induced
apoptosis
Induction of peripheral tolerance
A
B
C
Nonreactive clones
FIGURE 16-5.
Development of
immunologic T cell tolerance.
(A)
Development of central tolerance with
deletion of self-reactiveT lymphocytes in
the thymus.
(B)
Nonreactive lymphocytes
with development of normal immune
function.
(C)
Induction of peripheral
tolerance in self-reactive cells that are
not eliminated in the thymus.
