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FIGURE 14-1 Central and peripheral tolerance to self antigens. Immature lymphocytes specific for self antigens may encounter these antigens in the generative lymphoid organs and are deleted, change their specificity (B cells only), or (in the case of CD4+ T cells) develop into regulatory lymphocytes (central tolerance). Some self-reactive lymphocytes may mature and enter peripheral tissues and may be inactivated or deleted by encounter with self antigens in these tissues or are suppressed by the regulatory T cells (peripheral tolerance). (Note that T cells recognize antigens presented by antigen-presenting cells, which are not shown.)

Suppression |

Apoptosis (deletion)

Suppression |

FIGURE 14-1 Central and peripheral tolerance to self antigens. Immature lymphocytes specific for self antigens may encounter these antigens in the generative lymphoid organs and are deleted, change their specificity (B cells only), or (in the case of CD4+ T cells) develop into regulatory lymphocytes (central tolerance). Some self-reactive lymphocytes may mature and enter peripheral tissues and may be inactivated or deleted by encounter with self antigens in these tissues or are suppressed by the regulatory T cells (peripheral tolerance). (Note that T cells recognize antigens presented by antigen-presenting cells, which are not shown.)

engage antigen receptors. In experimental models, some self antigens are recognized by lymphocytes but, for unknown reasons, fail to elicit any response and are functionally ignored.

• Foreign antigens in the absence of costimulatory signals may inhibit immune responses by inducing tolerance in specific lymphocytes. Many of the mechanisms of tolerance to foreign antigens are similar to those of self-tolerance in mature lymphocytes. Effective immunization methods are designed to enhance the immunogenicity of antigens by administering them in ways that promote lymphocyte activation and prevent tolerance induction. Some microbes and tumors may also evade immune attack by inducing unresponsiveness in specific lymphocytes.

• The induction of immunologic tolerance may be exploited as a therapeutic approach for preventing harmful immune responses. A great deal of effort is being devoted to the development of strategies for inducing tolerance to treat autoimmune and allergic diseases and to prevent the rejection of organ transplants. Tolerance induction may also be useful for preventing immune reactions to the products of newly expressed genes in gene therapy protocols, for preventing reactions to injected proteins in patients with deficiencies of these proteins (e.g., hemophiliacs treated with factor VIII), and for promoting acceptance of stem cell transplants.

We do not know which self antigens induce central or peripheral tolerance (or are ignored). It is technically difficult to identify rare cells that may be specific for natural self antigens because reagents for detecting antigen-specific lymphocytes are not widely used and few self antigens are defined for which such reagents could even be produced. Experimental approaches, especially the creation of genetically modified mice, have provided valuable models for analysis of self-tolerance, and many of our current concepts are based on studies with such models. Furthermore, by identifying genes that may be associated with autoimmunity in mice and humans, it has been possible to deduce some of the critical mechanisms of self-tolerance. In the sections that follow, we will discuss central and peripheral tolerance first in T cells and then in B lymphocytes, but many aspects of the processes are common to both lineages.

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