Frazer, J. K., and J. D. Capra. 1999. Immunoglobulins: structure and function. In Fundamental Immunology, 4th ed. W. E. Paul, ed. Philadelphia, Lippincott-Raven.
Kohler, G., and C. Milstein. 1975. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495.
Kraehenbuhl, J. P., and M. R. Neutra. 1992. Transepithelial transport and mucosal defence II: secretion of IgA. Trends Cell Biol. 2:134.
Immunology Today, The Immune Receptor Supplement, 2nd ed. 1997. Elsevier Trends Journals, Cambridge, UK (ISSN 13651218).
Newman, J. 1995. How breast milk protects newborns. Sci. Am. 273(6):76.
Reth, M. 1995. The B-cell antigen receptor complex and core-ceptor. Immunol. Today 16:310.
Stanfield, R. L., and I. A. Wilson. 1995. Protein-peptide interactions. Curr. Opin. Struc. Biol. 5:103.
Wedemayer, G. J., P. A. Patten, L. H. Wang, P. G. Schultz, and R. C. Stevens. 1997. Structural insights into the evolution of an antibody combining site. Science, 276:1665.
Wentworth, P., and Janda, K. 1998. Catalytic Antibodies. Curr. Opin. Chem. Biol. 8:138.
Wilson, I. A., and R. L. Stanfield. 1994. Antibody-antibody interactions: new structures and new conformational changes. Curr. Opin. Struc. Biol. 4:857.
USEFUL WEB SITES
The Kabat Database of Sequences of Proteins of Immunolog-ical Interest: This site has the amino acid and DNA sequences of many antibodies and other proteins that play important roles in immunology.
Antibodies—Structure and Sequence: This Web site summarizes useful information on antibody structure and sequence. It provides general information on antibodies and crystal structures and links to other antibody-related information.
National Center for Biotechnology Information (NCBI): A unique and comprehensive resource of computerized databases of bibliographic information, nucleic acid sequences, protein sequences, and sequence analysis tools created and maintained by the National Library of Medicine.
The Molecular Modeling Database (MMDB) contains 3-di-mensional structures determined by x-ray crystallography and NMR spectroscopy. The data for MMDB are obtained from the Protein Data Bank (PDB). The National Center for Biotechnology Information (NCBI) has structural data crosslinked to bibliographic information, to databases of protein and nucleic acid sequences, and to the NCBI animal taxonomy database. The NCBI has developed a 3D structure viewer, Cn3D, for easy interactive visualization of molecular structures.
Protein Explorer is a molecular visualization program created by Eric Martz with the support of the National Science Foundation to make it easier for students, educators, and scientists to use interactive and dynamic molecular visualization techniques. Many will find it easier to use than Chime and Rasmol.
IMGT, the international ImMunoGeneTics database created by Marie-Paule Lefranc, is a well organized, powerful, and comprehensive information system that specializes in im-munoglobulins, T-cell receptors and major histocompatibility complex (MHC) molecules of all vertebrate species.
Clinical Focus Question Two pharmaceutical companies make IVIG. Company A produces their product from pools of 100,000 donors drawn exclusively from the population of the United States. Company B makes their IVIG from pools of 60,000 donors drawn in equal numbers from North America, Europe, Brazil, and Japan.
a. Which product would you expect to have the broadest spectrum of pathogen reactivities? Why?
b. Assume the patients receiving the antibody will (1) never leave the USA, or (2) travel extensively in many parts of the world. Which company's product would you choose for each of these patient groups? Justify your choices.
1. Indicate whether each of the following statements is true or false. If you think a statement is false, explain why.
a. A rabbit immunized with human IgG3 will produce antibody that reacts with all subclasses of IgG in humans.
b. All immunoglobulin molecules on the surface of a given B cell have the same idiotype.
c. All immunoglobulin molecules on the surface of a given B cell have the same isotype.
d. All myeloma protein molecules derived from a single myeloma clone have the same idiotype and allotype.
e. Although IgA is the major antibody species that undergoes transcytosis, polymeric IgM, but not monomeric IgA, can also undergo transcytosis.
f. The hypervariable regions make significant contact with the epitope.
g. IgG functions more effectively than IgM in bacterial agglutination.
h. Although monoclonal antibodies are often preferred for research and diagnostic purposes, both monoclonal and polyclonal antibodies can be highly specific.
i. All isotypes are normally found in each individual of a species.
j. The heavy-chain variable region (VH) is twice as long as the light-chain variable region (VL).
2. You are an energetic immunology student who has isolated protein X, which you believe is a new isotype of human im-munoglobulin.
a. What structural features would protein X have to have in order to be classified as an immunoglobulin?
b. You prepare rabbit antisera to whole human IgG, human k chain, and human 7 chain. Assuming protein X is, in fact, a new immunoglobulin isotype, to which of these antisera would it bind? Why?
c. Devise an experimental procedure for preparing an antiserum that is specific for protein X.
3. According to the clonal selection theory, all the im-munoglobulin molecules on a single B cell have the same antigenic specificity. Explain why the presence of both IgM and IgD on the same B cell does not violate the unispecificity implied by clonal selection.
4. IgG, which contains 7 heavy chains, developed much more recently during evolution than IgM, which contains ^ heavy chains. Describe two advantages and two disadvantages that IgG has in comparison with IgM.
5. Although the five immunoglobulin isotypes share many common structural features, the differences in their structures affect their biological activities.
a. Draw a schematic diagram of a typical IgG molecule and label each of the following parts: H chains, L chains, interchain disulfide bonds, intrachain disulfide bonds, hinge, Fab, Fc, and all the domains. Indicate which domains are involved in antigen binding.
b. How would you have to modify the diagram of IgG to depict an IgA molecule isolated from saliva?
c. How would you have to modify the diagram of IgG to depict serum IgM?
6. Fill out the accompanying table relating to the properties of IgG molecules and their various parts. Insert a (+) if the molecule or part exhibits the property; a ( —) if it does not; and a (+/—) if it does so only weakly.
Gotowww.whfreeman.com/immunology : Self-Test
Review and quiz of key terms
Whole H L Property IgG chain chain Fab F(ab')2 Fc
Bivalent antigen binding
Binds to Fc receptors
Fixed complement in presence of antigen
Has V domains
Has C domains
7. Because immunoglobulin molecules possess antigenic determinants, they themselves can function as immunogens, inducing formation of antibody. For each of the following immunization scenarios, indicate whether antiimmunoglobulin antibodies would be formed to isotypic (IS), allotypic (AL), or idiotypic (ID) determinants:
a. Anti-DNP antibodies produced in a BALB/c mouse are injected into a C57BL/6 mouse.
b. Anti-BGG monoclonal antibodies from a BALB/c mouse are injected into another BALB/c mouse.
c. Anti-BGG antibodies produced in a BALB/c mouse are injected into a rabbit.
d. Anti-DNP antibodies produced in a BALB/c mouse are injected into an outbred mouse.
e. Anti-BGG antibodies produced in a BALB/c mouse are injected into the same mouse.
8. Write YES or NO in the accompanying table to indicate whether the rabbit antisera listed at the top react with the mouse antibody components listed at the left.
9. The characteristic structure of immunoglobulin domains, termed the immunoglobulin fold, also occurs in the numerous membrane proteins belonging to the immunoglobulin superfamily.
a. Describe the typical features that define the im-munoglobulin-fold domain structure.
b. Consider proteins that belong to the immunoglobulin superfamily. What do all of these proteins have in common? Describe two different Ig superfamily members that bind antigen. Identify four different Ig superfamily members that do not bind antigen.
10. Where are the CDR regions located on an antibody molecule and what are their functions?
11. The variation in amino acid sequence at each position in a polypeptide chain can be expressed by a quantity termed the variability. What are the largest and smallest values of variability possible?
12. You prepare an immunotoxin by conjugating diphtheria toxin with a monoclonal antibody specific for a tumor antigen.
a. If this immunotoxin is injected into an animal, will any normal cells be killed? Explain.
b. If the antibody part of the immunotoxin is degraded so that the toxin is released, will normal cells be killed? Explain.
13. An investigator wanted to make a rabbit antiserum specific for mouse IgG. She injected a rabbit with purified mouse IgG and obtained an antiserum that reacted strongly with mouse IgG. To her dismay, however, the antiserum also reacted with each of the other mouse isotypes. Explain why she got this result. How could she make the rabbit antiserum specific for mouse IgG?
14. You fuse spleen cells having a normal genotype for immunoglobulin heavy chains (H) and light chains (L) with three myeloma-cell preparations differing in their im-munoglobulin genotype as follows: (a) H+,L+; (b) H_, L+; and (c) H_, L_. For each hybridoma, predict how many unique antigen-binding sites, composed of one H and one L chain, theoretically could be produced and show the chain structure of the possible antibody molecules. For each possible antibody molecule indicate whether the chains would originate from the spleen (S) or from the myeloma (M) fusion partner (e.g., HsLs/HmLm).
15. For each immunoglobulin isotype (a-e) select the description^) listed below (1-12) that describe that isotype. Each description may be used once, more than once, or not at all; more than one description may apply to some isotypes.
7 k IgG Fab IgG Fc J chain chain fragment fragment chain
Mouse 7 chain
Mouse k chain
Mouse IgM whole
Mouse IgM Fc fragment
(1) Secreted form is a pentamer of the basic H2L2 unit
(2) Binds to Fc receptors on mast cells
(3) Multimeric forms have a J chain
(4) Present on the surface of mature, unprimed B cells
(5) The most abundant isotype in serum
(6) Major antibody in secretions such as saliva, tears, and breast milk
(7) Present on the surface of immature B cells
(8) The first serum antibody made in a primary immune response
(9) Plays an important role in immediate hypersensitivity
(10) Plays primary role in protecting against pathogens that invade through the gut or respiratory mucosa
(11) Multimeric forms may contain a secretory component
(12) Least abundant isotype in serum
16. Describe four distinct roles played by Fc receptors. In what ways is signal transduction from Fc receptors similar to signal transduction from the B-cell receptor?
17. What is IVIG and what are some of the mechanisms by which it might protect the body against infection? Suppose one had the option of collecting blood for the manufacture of IVIG from the following groups of healthy individuals: 35-year-old men who had lived all of their lives in isolated villages in the mountains of Switzerland, or 45-55-year-old men who had been international airline pilots for 20 years. Which group would provide the better pool of blood? Justify your answer.
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