8536d_ch03_057-075 8/6/02 10:28 AM Page 62 mac79 Mac 79: 45_Bw Glasby et al. Immunology 5e 62 PART I Generation of B-Cell and T-Cell Response TABLE 3-3 Postulated mode of action of some commonly used adjuvants POSTULATED MODE OF ACTION Enhances Stimulates costimulator granuloma lymphocytes persistence formation nonspecifically Freunds incomplete adjuvant Freund's complete adjuvant +++ Aluminum potassium sulfate(alum) Mycobacterium tuberculosis ???+? +一 Bordetella pertussis Bacterial lipopolysaccharide( LPS) +++ Synthetic polynucleotides(poly IC/poly AU) Freunds complete adjuvant far more potent than the in- terminal portion, whereas the T cells responded only to epi- complete form. Activated macrophages are more phago- topes in the carboxyl-terminal portion cytic than unactivated macrophages and express higher Lymphocytes may interact with a complex antigen on sev- levels of class II MHC molecules and the membrane mole- eral levels of antigen structure. An epitope on a protein anti ules of the B7 family. The increased expression of class iI gen may involve elements of the primary, secondary, tertiary, MHC increases the ability of the antigen-presenting cell to and even quaternary structure of the protein(see Figure 3-1) present antigen to TH cells. B7 molecules on the antigen- In polysaccharides, branched chains are commonly present, presenting cell bind to CD28, a cell-surface protein on TH and multiple branches may contribute to the conformation cells, triggering co-stimulation, an enhancement of the T- of epitopes cell immune response. Thus, antigen presentation and the The recognition of antigens by t cells and B cells is funda requisite co-stimulatory signal usually are increased in the mentally different(Table 3-4). B cells recognize soluble anti- presence of adj gen when it binds to their membrane-bound antibody. Alum and Freund's adjuvants also stimulate a local, Because B cells bind antigen that is free in solution, the epi- chronic inflammatory response that attracts both phagocytes topes they recognize tend to be highly accessible sites on the and lymphocytes. This infiltration of cells at the site of the exposed surface of the immunogen. As noted previousl adjuvant injection often results in formation of a dense, most T cells recognize only peptides combined with MHC macrophage-rich mass of cells called a granuloma. Because molecules on the surface of antigen-presenting cells and al the macrophages in a granuloma are activated, this mecha- tered self-cells; T-cell epitopes, as a rule, cannot be consid nism also enhances the activation of TH cell ered apart from their associated MHC molecules Other adjuvants (e.g, synthetic polyribonucleotides and bacterial lipopolysaccharides)stimulate the nonspecific pro- Properties of B-Cell Epitopes Are Determined liferation of lymphocytes and thus increase the likelihood of by the Nature of the Antigen-Binding Site antigen-induced clonal selection of lymphocytes Several generalizations have emerged from studies in which the molecular features of the epitope recognized by B cells Epitopes have been established The ability to function as a B-cell epitope is determined by As mentioned in Chapter 1, immune cells do not interact the nature of the antigen-binding site on the antibody molecul with, or recognize, an entire immunogen molecule; instead, displayed by B cells. Antibody binds to an epitope by weak lymphocytes recognize discrete sites on the macromolecule noncovalent interactions operate only over called epitopes, or antigenic determinants. Epitopes are the tances. For a strong bond, the antibodys binding site and the mmunologically active regions of an immunogen that bind epitope must have complementary shapes that place the in- to secreted antibodies. Studies with small antigens have or teracting groups near each other. This requirement poses to antigen-specific membrane receptors on lymphocytes some restriction on the properties of the epitope. The size of realed that B and T cells recognize different epitopes on the the epitope recognized by a B cell can be no larger than the same antigenic molecule. For example, when mice were im- size of the antibody s binding site. For any given antigen-an munized with glucagon, a small human hormone of 29 tibody reaction, the shape of the epitope that can be recog amino acids, antibody was elicited to epitopes in the amino- nized by the antibody is determined by the shape assumed byFreund’s complete adjuvant far more potent than the in￾complete form. Activated macrophages are more phago￾cytic than unactivated macrophages and express higher levels of class II MHC molecules and the membrane mole￾cules of the B7 family. The increased expression of class II MHC increases the ability of the antigen-presenting cell to present antigen to TH cells. B7 molecules on the antigen￾presenting cell bind to CD28, a cell-surface protein on TH cells, triggering co-stimulation, an enhancement of the T￾cell immune response. Thus, antigen presentation and the requisite co-stimulatory signal usually are increased in the presence of adjuvant. Alum and Freund’s adjuvants also stimulate a local, chronic inflammatory response that attracts both phagocytes and lymphocytes. This infiltration of cells at the site of the adjuvant injection often results in formation of a dense, macrophage-rich mass of cells called a granuloma. Because the macrophages in a granuloma are activated, this mecha￾nism also enhances the activation of TH cells. Other adjuvants (e.g., synthetic polyribonucleotides and bacterial lipopolysaccharides) stimulate the nonspecific pro￾liferation of lymphocytes and thus increase the likelihood of antigen-induced clonal selection of lymphocytes. Epitopes As mentioned in Chapter 1, immune cells do not interact with, or recognize, an entire immunogen molecule; instead, lymphocytes recognize discrete sites on the macromolecule called epitopes, or antigenic determinants. Epitopes are the immunologically active regions of an immunogen that bind to antigen-specific membrane receptors on lymphocytes or to secreted antibodies. Studies with small antigens have re￾vealed that B and T cells recognize different epitopes on the same antigenic molecule. For example, when mice were im￾munized with glucagon, a small human hormone of 29 amino acids, antibody was elicited to epitopes in the amino￾terminal portion, whereas the T cells responded only to epi￾topes in the carboxyl-terminal portion. Lymphocytes may interact with a complex antigen on sev￾eral levels of antigen structure. An epitope on a protein anti￾gen may involve elements of the primary, secondary, tertiary, and even quaternary structure of the protein (see Figure 3-1). In polysaccharides, branched chains are commonly present, and multiple branches may contribute to the conformation of epitopes. The recognition of antigens by T cells and B cells is funda￾mentally different (Table 3-4). B cells recognize soluble anti￾gen when it binds to their membrane-bound antibody. Because B cells bind antigen that is free in solution, the epi￾topes they recognize tend to be highly accessible sites on the exposed surface of the immunogen. As noted previously, most T cells recognize only peptides combined with MHC molecules on the surface of antigen-presenting cells and al￾tered self-cells; T-cell epitopes, as a rule, cannot be consid￾ered apart from their associated MHC molecules. Properties of B-Cell Epitopes Are Determined by the Nature of the Antigen-Binding Site Several generalizations have emerged from studies in which the molecular features of the epitope recognized by B cells have been established. The ability to function as a B-cell epitope is determined by the nature of the antigen-binding site on the antibody molecules displayed by B cells. Antibody binds to an epitope by weak noncovalent interactions, which operate only over short dis￾tances. For a strong bond, the antibody’s binding site and the epitope must have complementary shapes that place the in￾teracting groups near each other. This requirement poses some restriction on the properties of the epitope. The size of the epitope recognized by a B cell can be no larger than the size of the antibody’s binding site. For any given antigen-an￾tibody reaction, the shape of the epitope that can be recog￾nized by the antibody is determined by the shape assumed by 62 PART II Generation of B-Cell and T-Cell Responses TABLE 3-3 Postulated mode of action of some commonly used adjuvants POSTULATED MODE OF ACTION Prolongs Enhances Induces Stimulates antigen co-stimulatory granuloma lymphocytes Adjuvant persistence signal formation nonspecifically Freund’s incomplete adjuvant  Freund’s complete adjuvant  Aluminum potassium sulfate (alum) ?  Mycobacterium tuberculosis  ?  Bordetella pertussis  ?  Bacterial lipopolysaccharide (LPS)  Synthetic polynucleotides (poly IC/poly AU)  ?  8536d_ch03_057-075 8/6/02 10:28 AM Page 62 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: