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Chapter 8 : Antigens, Antigenicity, and Immunogenicity

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Abstract:

The initiation of an immune response requires the interaction between T cells, B cells, and antigen-presenting cells (APCs), which form central components of almost all immune responses, and antigens, substances recognized as foreign by the immune system. The ability of an antigen to combine with antibody reflects the property of antigenicity. The distinction between antigenicity and immunogenicity can be seen by examining antigen-antibody reactions; a substance that is antigenic but not immunogenic would likely bind to a B-cell membrane immunoglobulin receptor but fail to provoke subsequent antibody production by that B cell. Researchers have determined the three-dimensional structure of major histocompatibility complex (MHC) class I and class II proteins bound to peptide. This work provided important insights into the nature of T-cell epitopes. To elucidate the differences between antigenicity and immunogenicity, K. Landsteiner, in the 1920s, synthesized numerous small organic compounds that, by themselves, could not induce antibodies but, after coupling or conjugation to a larger molecule, could induce antibodies capable of binding the free compound. Adjuvants enhance immunity, usually by provoking a more intense and prolonged immune response. Common T-cell mitogens include concanavalin A, phytohemagglutinin, and pokeweed mitogen. These mitogens bind surface carbohydrates on cells and may also promote cellular agglutination. Although mitogens are an experimentally useful surrogate for measuring lymphocyte responses to antigens, the results of such experiments must be interpreted with caution since the responses may deviate considerably from the true in vivo situation.

Citation: Pier G. 2004. Antigens, Antigenicity, and Immunogenicity, p 185-206. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch8

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Figures

Image of Figure 8.1
Figure 8.1

Demonstration of the locations of epitopes and paratopes in the interactions of antigens with the TCR and B-cell receptor . The epitope is a portion of the antigen that makes physical contact with the receptor. Ab, antibody; Ag, antigen.

Citation: Pier G. 2004. Antigens, Antigenicity, and Immunogenicity, p 185-206. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch8
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Image of Figure 8.2
Figure 8.2

Illustration of the difference between sequential epitopes and conformational epitopes. Sequential epitopes (blue regions) are composed of amino acids that are contiguous in a primary amino acid sequence of the protein antigen (e.g., amino acids 15 to 21). Adapted from M. Z. Atassi and A. L. Kazim, 19–40, 1978, with permission. In contrast, a conformational epitope is composed of amino acids that are separated from each other in the primary structure of the protein antigen but are brought together in the native, folded structure of the antigen. The ball-and-stick portions of the model highlight amino acids in three different regions of the antigen's primary sequence (color coded in blue, red, and white) that together form one conformational epitope. Adapted from W. G. Laver et al., 553–556, 1990, with permission.

Citation: Pier G. 2004. Antigens, Antigenicity, and Immunogenicity, p 185-206. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch8
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Image of Figure 8.3
Figure 8.3

Binding of a TCR to its cognate antigenic peptide requires the simultaneous interaction of the peptide with both the TCR (on the T cell) and the MHC (on either a target cell or an APC). The physical region of the peptide that contacts the MHC is termed the agretope, and the region that contacts the TCR is termed the epitope. Side view of peptide. The antigenic peptide is depicted in a helical configuration, with the amino acid side chains making contact with either the MHC or the TCR. Endon view of peptide showing that both chains of TCR and MHC are involved in interaction with antigen.

Citation: Pier G. 2004. Antigens, Antigenicity, and Immunogenicity, p 185-206. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch8
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Image of Figure 8.4
Figure 8.4

Antigenic peptides bound to MHC class I and MHC class II proteins. In both cases, the antigenic peptide lies in a groove that is situated between two α-helical regions of the MHC protein. The MHC class I molecule (white) is shown with a peptide antigen (red) from human immunodeficiency virus reverse transcriptase (amino acids 309 to 317). β-Microglobulin is shown in blue. The MHC class II diagram shows a DR molecule with the α chain in white, the β chain in blue, and the embedded red peptide lying in a pocket with open ends. Reprinted with permission from D. A. A. Vignali and J. L. Strominger, 112–118, 1994.

Citation: Pier G. 2004. Antigens, Antigenicity, and Immunogenicity, p 185-206. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch8
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Image of Figure 8.5
Figure 8.5

Schematic representation of peptide bound to both MHC and TCR, showing amino acids of the peptide that make significant contributions to TCR binding. The amino acid side chain that makes the most extensive interaction with the TCR is colored red, while the side chains of two amino acids that make lesser (although still significant) interactions are colored orange.

Citation: Pier G. 2004. Antigens, Antigenicity, and Immunogenicity, p 185-206. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch8
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Image of Figure 8.6
Figure 8.6

Demonstration of how an antigen-binding site on an antibody molecule undergoes conformational changes to accommodate antigen upon binding. Comparison of the loop in the third CDR of the heavy chain in the unligated and ligated state. Note in particular the different positions of amino acids 99 and 100 (aspartic acid and asparagine, respectively). Shape of the antigen-binding pocket in the unligated and ligated state. The peptide is positioned in panel B as it is in the ligated state but without the antigen-binding pocket undergoing the conformational change. Reprinted from J. M. Rini et al., 959–965, 1992, with permission.

Citation: Pier G. 2004. Antigens, Antigenicity, and Immunogenicity, p 185-206. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch8
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Image of Figure 8.7
Figure 8.7

The idiotype–anti-idiotype network for generating B-cell responses to related epitopes. An epitope on an antigen stimulates an antibody response (antibody 1) that binds to the antigen.Within the antigen-binding site of antibody 1 are new antigenic determinants, not previously present in the host at a high level, that form the idiotopes. Antibody 2 responds to an idiotope on antibody 1, binding to the antigen-binding site in much the same way as the immunizing antigenic epitope. The result is that the antigen-binding site (or idiotype) of antibody 2 is closely related to the three-dimensional shape of the original immunizing epitope. Antibody 2 can now be used as a surrogate for the original antigen.

Citation: Pier G. 2004. Antigens, Antigenicity, and Immunogenicity, p 185-206. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch8
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Image of Figure 8.8
Figure 8.8

Use of hapten-carrier conjugates to study the factors affecting immunogenicity and antigenicity of an antigen. Covalent conjugation of the hapten, diazoarsanilic acid, to the tyrosine-containing carrier protein forms the hapten-carrier conjugate. The hapten-carrier conjugate (immunogen) gives rise to the antibodies of different specificities, which are determined by testing sera against the indicated structure. Some antibodies generated against the conjugate recognize epitopes on the carrier, while other antibodies recognize the hapten portion of the conjugate. Still other antibodies recognize that comprise both hapten and carrier structures.

Citation: Pier G. 2004. Antigens, Antigenicity, and Immunogenicity, p 185-206. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch8
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Image of Figure 8.9
Figure 8.9

Aspects of protein structure affecting immunogenicity.

Citation: Pier G. 2004. Antigens, Antigenicity, and Immunogenicity, p 185-206. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch8
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Image of Figure 8.10
Figure 8.10

Dose dependency of the immune response of mice to BSA. Mice were given an initial dose of BSA ranging from 10 picograms (10 g) to 1 g. Fourteen days later they were given the optimal dose of 10 mg of BSA, and antibody titers were measured 7 days later. Animals given suboptimal (10 to 10 g) or supraoptimal (1 [or 10°] g) doses had a lower secondary response, indicating that these doses interfered with and suppressed the secondary response to the optimal 10-mg dose. Responses of <100% indicate inhibition of secondary antibody production, whereas responses of >100% indicate that priming has occurred for an increased secondary booster response. Adapted from N. A.Mitchison, 275, 1964, with permission.

Citation: Pier G. 2004. Antigens, Antigenicity, and Immunogenicity, p 185-206. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch8
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Image of Figure 8.11
Figure 8.11

Antigens involved in the host response to viruses. Viral-envelope antigens can be the targets of antibodies, which can either block host-cell infection or trigger complement-mediated killing of free virions. Viral infection of a host cell will result in the production of viral proteins within the infected cell. Some of these viral proteins may be processed and presented to cytotoxic T lymphocytes on MHC class I. Alternatively, the infection may induce overproduction of host proteins such as stress-response proteins or may alter the production or peptide loading of MHC class I, resulting in killing of the infected cell by cytotoxic T lymphocytes or natural killer cells. Finally, viral envelope proteins are expressed on the cell membrane of the infected cell and can be the targets of antibodymediated killing by either cell-mediated or complement-mediated killing.

Citation: Pier G. 2004. Antigens, Antigenicity, and Immunogenicity, p 185-206. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch8
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Image of Figure 8.12
Figure 8.12

Architecture of the gram-positive and gram-negative bacterial cell wall. Prominent structures often involved in provoking immune responses are displayed. All bacteria have an inner cytoplasmic membrane and cell well, composed of peptidoglycan, surrounding the cytoplasmic membrane. Gram-negative bacteria have an additional outer membrane that contains proteins and lipopolysaccharide. Often capsular polysaccharides surround bacterial cells. The antigens most commonly used for immunologic diagnosis and as targets for protective antibodies are found on the outer surface, where they can readily interact with immunologic effectors such as antibody. Reprinted from G. B. Pier, p. 767–774, K. J. Isselbacher et al. (ed)., 7th ed. (McGraw-Hill, New York, N.Y., 2001), with permission.

Citation: Pier G. 2004. Antigens, Antigenicity, and Immunogenicity, p 185-206. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch8
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Image of Figure 8.13
Figure 8.13

Life cycle of the cause of African sleeping sickness. Crosssection of showing structural features. The variant surface glycoprotein is a major antigen seen by the immune system. The parasite has more than 103 genes for this glycoprotein and changes the antigenic structure to evade host defenses. Reprinted from P. Borst, A29–A33, 1991, and Anonymous, A46–A47, 1991, with permission from Elsevier.

Citation: Pier G. 2004. Antigens, Antigenicity, and Immunogenicity, p 185-206. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch8
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Image of Figure 8.14
Figure 8.14

Difference between normal antigenic stimulation of T cells and stimulation by a superantigen . Unlike the normal antigen, which must be processed and presented by an APC, a superantigen (SA) remains intact and binds to nonpolymorphic portions of the MHC class II protein and to β chains of the TCR from a particular family of V chains. Some superantigens bind to cell adhesion molecules (CAM) and β chains of the TCR.

Citation: Pier G. 2004. Antigens, Antigenicity, and Immunogenicity, p 185-206. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch8
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References

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1. Cox, J. C.,, and A. R. Coulter. 1997. Adjuvants—a classification and review of their modes of action. Vaccine 15:248256.
2. Fremont, D. H.,, W. A. Hendrickson,, P. Marrack,, and J. Kappler. 1996. Structures of an MHC class II molecule with covalently bound single peptides. Science 272:10011004.
3. Hudecz, F. 2001. Manipulation of epitope function by modification of peptide structure: a minireview. Biologicals 29:197207.
4. Kaisho, T.,, and S. Akira. 2002. Toll-like receptors as adjuvant receptors. Biochim. Biophys. Acta 589:113.
5. Llewelyn, M.,, and J. Cohen. 2002. Superantigens: microbial agents that corrupt immunity. Lancet Infect. Dis. 2:156162.
6. Marchalonis, J. J.,, M. K. Adelman,, I. F. Robey,, S. F. Schluter,, and A. B. Edmundson. 2001. Exquisite specificity and peptide epitope recognition promiscuity, properties shared by antibodies from sharks to humans. J. Mol. Recognit. 14:110121.
7. Ramsland, P. A.,, E. Yuriev,, and A. B. Edmundson. 2001. Immunoglobulin cross-reactivity examined by library screening, crystallography and docking studies. Comb. Chem. High Throughput Screen. 4:397408.
8. Regner, M. 2001. Cross-reactivity in T-cell antigen recognition. Immunol. Cell Biol. 79:91100.
9. Rini, J. M.,, U. Schulze-Gahmen,, and I. A. Wilson. 1992. Structural evidence for induced fit as a mechanism for antibody- antigen recognition. Science 255:959965.
10. Rubin, B.,, L. Alibaud,, A. Huchenq-Champagne,, J. Arnaud,, M. L. Toribio,, and J. Constans. 2002. Some hints concerning the shape of T-cell receptor structures. Scand. J. Immunol. 55:111118.
11. Rudolph, M. G.,, J. G. Luz,, and I. A. Wilson. 2002. Structural and thermodynamic correlates of T cell signaling. Annu. Rev. Biophys. Biomol. Struct. 31:121149.
12. Rudolph, M. G.,, and I. A. Wilson. 2002. The specificity of TCR/pMHC interaction. Curr. Opin. Immunol. 14:5265.
13. Thomas, J.W. 2001.Antigen-specific responses in autoimmunity and tolerance. Immunol. Res. 23:235244.
14. Van Regenmortel, M. H. 2001. Antigenicity and immunogenicity of synthetic peptides. Biologicals 29:209213.

Tables

Generic image for table
Table 8.1

Type of adjuvants currently used or under investigation

Citation: Pier G. 2004. Antigens, Antigenicity, and Immunogenicity, p 185-206. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch8
Generic image for table
Table 8.2

Toxic proteins of bacteria causing disease

Citation: Pier G. 2004. Antigens, Antigenicity, and Immunogenicity, p 185-206. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch8

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