Porth's Essentials of Pathophysiology, 4e

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Disorders of the Immune Response

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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

Nonreactive clones

Self-reactive clones

Self-reactive clones

Apoptosis

Activation- induced apoptosis

Failure of antigens to activate lymphocyte

Development of central tolerance

FIGURE 16-5. Development of immunologic  T cell tolerance. (A)

A

Induction of normal immune function with self versus nonself recognition

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.

Clonal anergy

B

Induction of peripheral tolerance

C