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Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002.

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Biochemistry. 5th edition.

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Section 33.6Immune Responses Against Self-Antigens Are Suppressed

The primary function of the immune system is to protect the host from invasion by foreign organisms. But how does the immune system avoid mounting attacks against the host organism? In other words, how does the immune system distinguish between self and nonself? Clearly, proteins from the organism itself do not bear some special tag identifying them. Instead, selection processes early in the developmental pathways for immune cells kill or suppress those immune cells that react strongly with self-antigens. The evolutionary paradigm still applies; immune cells that recognize self-antigens are generated, but selective mechanisms eliminate such cells in the course of development.

33.6.1. T Cells Are Subject to Positive and Negative Selection in the Thymus

T cells derive their name from the location of their production — the thymus, a small organ situated just above the heart. Examination of the developmental pathways leading to the production of mature cytotoxic and helper T cells reveals the selection mechanisms that are crucial for distinguishing self from nonself. These selection criteria are quite stringent; approximately 98% of the thymocytes, the precursors of T cells, die before the completion of the maturation process.

Thymocytes produced in the bone marrow do not express the T-cellreceptor complex, CD4, or CD8. On relocation to the thymus and rearrangement of the T-cell-receptor genes, the immature thymocyte expresses all of these molecules. These cells are first subjected to positive selection (Figure 33.40). Cells for which the T-cell receptor can bind with reasonable affinity to either class I or class II MHC molecules survive this selection; those for which the T-cell receptor does not participate in such an interaction undergo apoptosis and die. The affinities of interaction required to pass this selection are relatively modest, and so contacts between the T-cell receptor and the MHC molecules themselves are sufficient without any significant contribution from the bound peptides (which will be derived from proteins in the thymus). The role of the positive selection step is to prevent the production of T cells that will not bind to any MHC complex present, regardless of the peptide bound.

Figure 33.40. T-Cell Selection.

Figure 33.40

T-Cell Selection. A population of thymocytes is subjected first to positive selection to remove cells that express T-cell receptors that will not bind to MHC proteins expressed by the individual organism. The surviving cells are then subjected to negative (more...)

The cell population that survives positive selection is subjected to a second step, negative selection. Here, T cells that bind with high affinity to MHC complexes bound to self-peptides expressed on the surfaces of antigen-presenting cells in the thymus undergo apoptosis or are otherwise suppressed. Those that do not bind too avidly to any such MHC complex complete development and become mature cytotoxic T cells (which express only CD8) or helper T cells (which express only CD4). The negative selection step leads to self tolerance; cells that bind an MHC-self-peptide complex are removed from the T-cell population. Similar mechanisms apply to developing B cells, suppressing B cells that express antibodies that interact strongly with self-antigens.

33.6.2. Autoimmune Diseases Result from the Generation of Immune Responses Against Self-Antigens

Image caduceus.jpg Although thymic selection is remarkably efficient in suppressing the immune response to self-antigens, failures do occur. Such failures results in autoimmune diseases. These diseases include relatively common illnesses such as insulin-dependent diabetes mellitus, multiple sclerosis, and rheumatoid arthritis. In these illnesses, immune responses against self-antigens result in damage to selective tissues that express the antigen (Figure 33.41).

Figure 33.41. Consequences of Autoimmunity.

Figure 33.41

Consequences of Autoimmunity. Photo-micrographs of an islet of Langerhans (A) in the pancreas of a normal mouse and (B) in the pancreas of a mouse with an immune response against pancreatic β cells, which results in a disease resembling insulin-dependent (more...)

In many cases, the cause of the generation of self-reactive antibodies or T cells in unclear. However, in other cases, infectious organisms such as bacteria or viruses may play a role. Infection leads to the generation of antibodies and T cells that react with many different epitopes from the infectious organism. If one of these antigens closely resembles a self-antigen, an autoimmune response can result. For example, Streptococcus infections sometimes lead to rheumatic fever owing to the production of antibodies to streptococcal antigens that cross-react with exposed molecules in heart muscle.

33.6.3. The Immune System Plays a Role in Cancer Prevention

Image caduceus.jpg The development of immune responses against proteins encoded by our own genomes can be beneficial under some circumstances. Cancer cells have undergone significant changes that often result in the expression of proteins that are not normally expressed. For example, the mutation of genes can generate proteins that do not correspond in amino acid sequence to any normal protein. Such proteins may be recognized as foreign, and an immune response will be generated specifically against the cancer cell. Alternatively, cancer cells often produce proteins that are expressed during embryonic development but are not expressed or are expressed at very low levels after birth. For example, a membrane glycoprotein protein called carcinoembryonic antigen (CEA) appears in the gasterointestinal cells of developing fetuses but is not normally expressed at significant levels after birth. More than 50% of patients with colorectal cancer have elevated serum levels of CEA. Immune cells recognizing epitopes from such proteins will not be subject to negative selection and, hence, will be present in the adult immune repertoire. These cells may play a cancer surveillance role, killing cells that overexpress antigens such as CEA and preventing genetically damaged cells from developing into tumors.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2002, W. H. Freeman and Company.
Bookshelf ID: NBK22378

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