This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Casadevall, A. Search for Related Content PubMed PubMed Citation Articles by Casadevall, A.

Next Article 

Infection and Immunity, August 2003, p. 4225-4228, Vol. 71, No. 8
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.8.4225-4228.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Antibody-Mediated Immunity against Intracellular Pathogens: Two-Dimensional Thinking Comes Full Circle

Departments of Medicine and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461

	INTRODUCTION

Top Introduction Deconstructing a paradigm Interpretation of negative... Lesson from erhlichia... References

 
The view that antibody-mediated immunity against many prokaryotic and eukaryotic intracellular pathogens is not important was popular until recently (6). The concept of a division of labor whereby antibody-mediated immunity protected against extracellular pathogens and cell-mediated immunity protected against intracellular pathogens may have had its intellectual origins in the great debate between the advocates of humoral and cellular immunity at the turn of the 20th century. The humoralists, championed by Paul Ehrlich, viewed immunity as being conferred by soluble substances in the blood and the generation of an effective antibody response, with phagocytic cells functioning primarily to clean up microbial debris (42). The cellularists, championed by Elie Metchnikoff, viewed immunity as being conferred by macrophages and other phagocytic cells, with the role of humoral factors being to provide opsonins (42). This debate was fueled by the success and difficulties associated with demonstrating antibody-mediated protection against certain pathogens in passive immunization studies. Administration of immune serum protected against toxin-mediated diseases such as tetanus and diphtheria and a certain subset of bacterial pathogens exemplified by the organisms now known as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. However, passive immunization provided little or no protection against other microbes such as Mycobacterium tuberculosis (reviewed in reference 19).

By the 1960s, classical studies with facultative intracellular pathogens such as Listeria monocytogenes had shown that effective control of infection depended on cellular immunity, as manifested by granuloma formation and participation of T lymphocytes (28). The microbes for which passive antibody was not protective and cell-mediated immunity appeared to be paramount for host defense were often facultative intracellular pathogens. This association gave credence to the concept of an immunological division of labor whereby humoral and cellular immunity provided effective control for extracellular and intracellular pathogens, respectively (3, 8, 28). Furthermore, this division of labor was conceptually consistent with a large body of experimental observations that indicated an inverse and mutually antagonistic relationship between humoral and cellular immunity (35). In recent years, the view that antibody-mediated immunity protects against extracellular pathogens and cell-mediated immunity protects against intracellular pathogens has been modified and extended by the Th1/Th2 paradigm, which posits a division of labor at the level of T-cell differentiation. According to this view, Th1-polarized responses result in granulomatous inflammation that effectively controls intracellular pathogens, whereas Th2-polarized responses result in the production of antibodies that control extracellular pathogens and parasites.

The fact that a microbe inside a cell is separated from serum antibody has contributed to the belief that serum antibody cannot be effective against an intracellular pathogen. However, the two-dimensional separation and categorization of microbes as either intracellular and extracellular pathogens was never absolute, since tissue examination often revealed that pathogens classified as intracellular could be found in the extracellular space and vice versa. Furthermore, at some point in the infectious cycle, most intracellular pathogens reside in the extracellular space, where they are vulnerable to antibody action, and Fc receptor cross-linking can have profound effects in the intracellular milieu through signal transduction.

In this issue of Infection and Immunity, we have an example of how the investigation of mechanisms by which passive antibody protects against the obligate intracellular pathogen Ehrlichia chaffensis led to the discovery of an extracellular phase that may include replication (27). Hence, the wheel has turned full circle, since an investigation to explain how antibody protects against an obligate intracellular pathogen has revealed that it may not always reside in the intracellular space and thus could become accessible to serum antibody.

	DECONSTRUCTING A PARADIGM

Top Introduction Deconstructing a paradigm Interpretation of negative... Lesson from erhlichia... References

 
The notion of an immunological duality whereby immunity to intracellular pathogens is conferred by cell-mediated mechanisms and immunity to extracellular pathogens is conferred by antibody-mediated mechanisms was a reigning paradigm in the closing decades of the 20th century and still has wide credence. However, this view is problematic because it is not universally applicable to all pathogens and because the induction of antibody mediated-immunity is sufficient to prevent infection with some intracellular pathogens. For example, the major childhood viral diseases and smallpox were drastically reduced in incidence or eradicated by vaccines that elicited antibody-mediated immunity despite the fact that all viruses are obligate intracellular pathogens. For some intracellular bacterial pathogens, such as Salmonella enterica serovar Typhimurium, it was clear that antibody responses were protective in certain hosts (13). The concept of an immunological division of labor based on whether or not a microbe assumed intracellular residence defied the common-sense view that the most effective immune response was one that combined both humoral and cellular components.

Perhaps the most important advance in suggesting a resolution to the cellular versus humoral controversy was the application of hybridoma technology to investigate the potential of antibody-mediated immunity against certain pathogens for which immune serum did not manifest efficacy. In contrast to immune serum, which varied greatly in the composition, isotype, and specificity of microbe-binding antibodies, monoclonal antibodies provided a homogenous preparation or defined reagents with which to investigate the variables that contributed to antibody-mediated protection. Studies with monoclonal antibodies have now demonstrated passive protection for several microbes where experiments with immune serum had provided negative or inconsistent results, including Candida albicans (20), Cryptococcus neoformans (9, 17, 32, 40), Listeria monocytogenes (11), Leishmania mexicana (1), Mycobacterium tuberculosis (45), and Histoplasma capsulatum (J. D. Nosanchuk, A. Casadevall, and G. Deepe, Abstr. Annu. Meet. Am. Soc. Microbiol., 2001, abstr. F-143). For these pathogens, the identification of protective monoclonal antibodies established the precedent that antibody could be effective and dispelled the notion that humoral immunity was ineffective due to an inherent limitation in the activity of this arm of the immune system. The list of intracellular pathogens for which antibody has been shown to modify the course of infection to the benefit of the host is extensive (Table 1).

	INTERPRETATION OF NEGATIVE RESULTS

Top Introduction Deconstructing a paradigm Interpretation of negative... Lesson from erhlichia... References

A dramatic example of the limitations of passive antibody transfer experiments is provided by the observation that transfer of either too little or too much antibody can result in no protection. In 1987, Dromer et al. generated a protective immunoglobulin G1 (IgG1) monoclonal antibody to Cryptococcus neoformans and demonstrated that a certain amount of immunoglobulin was necessary to observe protection in a murine model of cryptococcosis (9). This observation suggested that the inability to protect with immune serum may have been a consequence of inadequate amounts of protective antibody. Similarly, it was noted that a monoclonal antibody to listeriolysin O was protective against Listeria monocytogenes if administered in large doses but that antibodies with that specificity were not common in immune serum (11). More recently, my group has shown prozone-like effects with protective IgM and IgG, such that the administration of large amounts of immunoglobulin can result in reduced or abolished protective effects (43, 44). Consequently, too much or too little antibody can yield a negative result in a passive protection experiment despite the fact that antibody can be protective against the relevant pathogen.

Apart from antibody amount, immunoglobulin-related variables such as antibody specificity (31), isotype (49), and idiotype (39) can have profound effects on antibody protective efficacy. However, host-related variables can also determine the outcome of passive protection experiments. For example, the protective efficacy of passive antibody to Salmonella enterica serovar Typhimurium is dependent on the mouse strain used (13). For some pathogens, the efficacy of passive antibody is dependent on the presence of intact cellular immunity (48). Adding to the uncertainty associated with negative results in passive transfer experiments is the observation that antibody efficacy can depend on the microbial strain used despite the presence of the target antigen (33).

Clearly, negative results in passive protection experiments do not exclude the existence of protective antibodies. Conversely, the discovery that it is possible to make protective monoclonal antibodies against several intracellular pathogens does not necessarily imply that antibody immunity plays a major role in natural resistance, since the antibodies that mediate protection may be absent or rare in the immune response to natural infection. Experimental variables that can lead to a negative result in passive protection experiments are listed in Table 2.

	LESSON FROM ERHLICHIA CHAFFEENSIS

Top Introduction Deconstructing a paradigm Interpretation of negative... Lesson from erhlichia... References

The efficacy of passive antibody against E. chaffensis in SCID mice suggests that antibody-mediated protection was independent of T cells and implied that other mechanisms must be operative. In pursuit of that question, Li and Winslow now describe an extracellular phase for E. chaffensis during which the bacteria are potentially susceptible to serum antibody (27). Although it has not been proven that antibody-mediated protection against E. chaffensis occurs in the extracellular phase, this observation suggests a mechanism that is fundamentally different from that reported for Listeria monocytogenes (12), where antibody is active intracellularly. Ironically, the finding that E. chaffensis has an extracellular phase that is presumably susceptible to serum antibody is consistent with the older view that antibodies are active only against extracellular microbes. Nonetheless, antibody may be effective against E. chaffensis when a threshold portion of the microbial pool is extracellular and accessible to antibody. This discovery suggests that other obligate intracellular pathogens may also have extracellular phases during which they are susceptible to humoral immunity. This elegant study illustrates the connectivity of scientific thought in that pursuing an explanation for an observation that defied one paradigm led to findings that undermined another and, in so doing, provided new insights into microbial pathogenesis and immunology.

	FOOTNOTES

 
* Mailing address: Dept. of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-4259. Fax: (718) 430-4259. E-mail: casadeva{at}aecom.yu.edu.

The views expressed in this Commentary do not necessarily reflect the views of the journal or of ASM. Editor: T. R. Kozel

	REFERENCES

Top Introduction Deconstructing a paradigm Interpretation of negative... Lesson from erhlichia... References

 

1.	Anderson, S., J. R. David, and D. McMahon-Pratt. 1983. In vivo protection against Leishmania mexicana mediated by monoclonal antibodies. J. Immunol. 131:1616-1618.[Medline]
2.	Bowden, R. A., S. M. Estein, M. S. Zygmunt, G. Dubray, and A. Cloeckaert. 2000. Identification of protective outer membrane antigens of Brucella ovis by passive immunization of mice with monoclonal antibodies. Microbes Infect. 2:481-488.[CrossRef][Medline]
3.	Bretscher, P. A. 1992. An hypothesis to explain why cell-mediated immunity alone can contain infections by certain intracellular parasites and how immune class regulation of the response can be subverted. Immunol. Cell. Biol. 70:343-351.
4.	Brieland, J. K., L. A. Heath, G. B. Huffnagle, D. G. Remick, M. S. McClain, M. C. Hurley, R. K. Kunkel, J. C. Fantone, and C. Engleberg. 1996. Humoral immunity and regulation of intrapulmonary growth of Legionella pneumophila in the immunocompetent host. J. Immunol. 157:5002-5008.[Abstract]
5.	Briles, D. E., C. Forman, and M. Crain. 1992. Mouse antibody to phosphocholine can protect mice from infection with mouse-virulent human isolates of Streptococcus pneumoniae. Infect. Immun. 60:1957-1962.[Abstract/Free Full Text]
6.	Casadevall, A. 1998. Antibody-mediated protection against intracellular pathogens. Trends Microbiol. 6:102-103.[CrossRef][Medline]
7.	Casadevall, A., and M. D. Scharff. 1994. "Serum Therapy" revisited: Animal models of infection and the development of passive antibody therapy. Antimicrob. Agents Chemother. 38:1695-1702.[Free Full Text]
8.	Collins, F. M. 1979. Cellular antimicrobial immunity. Crit. Rev. Microbiol 7:27-91.
9.	Dromer, F., J. Charreire, A. Contrepois, C. Carbon, and P. Yeni. 1987. Protection of mice against experimental cryptococcosis by anti-Cryptococcus neoformans monoclonal antibody. Infect. Immun. 55:749-752.[Abstract/Free Full Text]
10.	Dromer, F., C. Perrone, J. Barge, J. L. Vilde, and P. Yeni. 1989. Role of IgG and complement component C5 in the initial course of experimental cryptococcosis. Clin. Exp. Immunol. 78:412-417.[Medline]
11.	Edelson, B. T., P. Cossart, and E. R. Unanue. 1999. Cutting edge: paradigm revisited: antibody provides resistance to Listeria infection. J. Immunol. 163:4087-4090.[Abstract/Free Full Text]
12.	Edelson, B. T., and E. R. Unanue. 2001. Intracellular antibody neutralizes Listeria growth. Immunity 14:503-512.[CrossRef][Medline]
13.	Eisenstein, T. K., L. M. Millar, and B. M. Sultzer. 1984. Immunity to infection with Salmonella typhimurium: mouse strain differences in vaccine- and serum-mediated protection. J. Infect. Dis. 150:425-435.[Medline]
14.	Eisenstein, T. K., R. Tamada, J. Meissler, A. Flesher, and H. C. Oels. 1984. Vaccination against Legionella pneumophila: serum antibody correlates with protection induced by heat-killed or acetone-killed cells against intraperitoneal but not aerosol infection in guinea pigs. Infect. Immun. 45:685-691.[Abstract/Free Full Text]
15.	Elzer, P. H., R. H. Jacobason, S. M. Jones, K. H. Nielsen, J. T. Douglas, and A. J. Winter. 1994. Antibody-mediated protection against Brucella abortus in BALB/c mice at successive periods after infection: variation between virulent strain 2308 and attenuated vaccine strain 19. Immunology 82:651-658.[Medline]
16.	Feldmesser, M., and A. Casadevall. 1997. Effect of serum IgG1 against murine pulmonary infection with Cryptococcus neoformans. J. Immunol. 158:790-799.[Abstract]
17.	Fleuridor, R., Z. Zhong, and L. Pirofski. 1998. A human IgM monoclonal antibody prolongs survival of mice with lethal cryptococcosis. J. Infect. Dis. 178:1213-1216.[Medline]
18.	Fulop, M., P. Mastroeni, M. Green, and R. W. Titball. 2001. Role of antibody to lipopolysaccharide in protection against low- and high-virulence strains of Francisella tularensis. Vaccine 19:4465-4472.[CrossRef][Medline]
19.	Glatman-Freedman, A., and A. Casadevall. 1998. Serum therapy for tuberculosis revisited: a reappraisal of the role of antibody-mediated immunity against Mycobacterium tuberculosis. Clin. Microbiol. Rev. 11:514-532.[Abstract/Free Full Text]
20.	Han, Y., and J. E. Cutler. 1995. Antibody response that protects against disseminated candidiasis. Infect. Immun. 63:2714-2719.[Abstract]
21.	Joiner, K. A., R. Scales, K. A. Warren, M. M. Frank, and P. A. Rice. 1985. Mechanism of action of blocking immunoglobulin G for Neisseria gonorrhoeae. J. Clin. Investig. 76:1765-1772.
22.	Kang, H., J. S. Remington, and Y. Suzuki. 2000. Decreased resistance of B-cell-deficient mice to infection with Toxoplasma gondii despite unimpaired expression of IFN-gamma, TNF-alpha, and inducible nitric oxide synthase. J. Immunol. 164:2629-2634.[Abstract/Free Full Text]
23.	Kaylor, P. S., T. B. Crawford, T. F. McElwain, and G. H. Palmer. 1991. Passive transfer of antibody to Ehrlichia risticii protects mice from ehrlichiosis. Infect. Immun. 59:2058-2062.[Abstract/Free Full Text]
24.	Koesling, J., T. Aebischer, C. Falch, R. Schülein, and C. Dehio. 2001. Cutting Edge: Antibody-mediated cessation of hemotropic infection by the intraerythrocytic mouse pathogen Bartonella grahamii. J. Immunol. 167:11-14.[Abstract/Free Full Text]
25.	Lee, E., and Y. Rikihisa. 1997. Anti-Ehrlichia chaffeensis antibody complexed with E. chaffeensis induces potent proinflammatory cytokine mRNA expression in human monocytes through sustained reduction of IB- and activation of NF-B. Infect. Immun. 2890:2897.
26.	Li, J. S., F. Chu, A. Reilly, and G. M. Winslow. 2002. Antibodies highly effective in SCID mice during infection by the intracellular bacterium Ehrlichia chaffeensis are of picomolar affinity and exhibit preferential epitope and isotype utilization. J. Immunol. 169:1419-1425.[Abstract/Free Full Text]
27.	Li, J. S., and G. M. Winslow. 2003. Survival, replication, and antibody susceptibility of Ehrlichia chaffeensis outside of host cells. Infect. Immun. 71:4229-4237.[Abstract/Free Full Text]
28.	Mackaness, G. B. 1971. Resistance to intracellular infection. J. Infect. Dis. 123:439-445.[Medline]
29.	Mackaness, G. B. 1977. Cellular immunity and the parasite. Adv. Exp. Med. Biol. 93:65-73.[Medline]
30.	Messick, J. B., and Y. Rikihisa. 1994. Inhibition of binding, entry, or intracellular proliferation of Erhlichia risticii in P388D1 cells by anti-E. risticii serum, immunoglobulin G, or Fab fragment. Infect. Immun. 62:3156-3161.[Abstract/Free Full Text]
31.	Mukherjee, J., G. Nussbaum, M. D. Scharff, and A. Casadevall. 1995. Protective and non-protective monoclonal antibodies to Cryptococcus neoformans originating from one B-cell. J. Exp. Med. 181:405-409.[Abstract/Free Full Text]
32.	Mukherjee, J., M. D. Scharff, and A. Casadevall. 1992. Protective murine monoclonal antibodies to Cryptococcus neoformans. Infect. Immun. 60:4534-4541.[Abstract/Free Full Text]
33.	Mukherjee, J., M. D. Scharff, and A. Casadevall. 1995. Variable efficacy of passive antibody administration against diverse Cryptococcus neoformans strains. Infect. Immun. 63:3353-3359.[Abstract]
34.	Pal, S., I. Theodor, E. M. Peterson, and L. de la Maza. 1997. Monoclonal immunoglobulin A antibody the major outer membrane protein of the Chlamydia trachomatis mouse pneumonitis biovar protects mice against a chlamydial genital challenge. Vaccine 15:575-582.[CrossRef][Medline]
35.	Parish, C. R. 1972. The relationship between humoral and cell-mediated immunity. Transplant. Rev. 13:35-66.[Medline]
36.	Peterson, E. M., X. Cheng, V. L. Motin, and L. de la Maza. 1997. Effect of immunoglobulin G isotype on the infectivity of Chlamydia trachomatis in a mouse model of intravaginal infection. Infect. Immun. 65:2693-2699.[Abstract]
37.	Pethe, K., S. Alonso, F. Biet, G. Delogu, M. J. Brennan, and F. D. Menozzi. 2001. The heparin-binding haemagglutinin of M. tuberculosis is required for extrapulmonary dissemination. Nature 412:190-194.[CrossRef][Medline]
38.	Phalipon, A., M. Kaufmann, P. Michetti, J. Cavaillon, M. Huerre, P. Sansonetti, and J. Kraehenbuhl. 1995. Monoclonal immunoglobulin A antibody directed against serotype-specific epitope of Shigella flexneri lipopolysaccharide protects against murine experimental shigellosis. J. Exp. Med. 182:769-778.[Abstract/Free Full Text]
39.	Pirofski, L. 2001. Polysaccharides, mimotopes and vaccines for fungal and encapsulated pathogens. Trends Microbiol. 9:445-451.[CrossRef][Medline]
40.	Sanford, J. E., D. M. Lupan, A. M. Schlagetter, and T. R. Kozel. 1990. Passive immunization against Cryptococcus neoformans with an isotype-switch family of monoclonal antibodies reactive with cryptococcal polysaccharide. Infect. Immun. 58:1919-1923.[Abstract/Free Full Text]
41.	Sayles, P. C., G. W. Gibson, and L. L. Johnson. 2000. B cells are essential for vaccination-induced resistance to virulent Toxoplasma gondii. Infect. Immun. 68:1026-1033.[Abstract/Free Full Text]
42.	Silverstein, A. M. 1979. History of immunology. Cellular versus humoral immunity: determinants and consequences of an epic 19th century battle. Cell. Immunol. 48:208-221.[CrossRef][Medline]
43.	Taborda, C. P., and A. Casadevall. 2001. Immunoglobulin M efficacy against Cryptococcus neoformans: mechanism, dose dependence and prozone-like effects in passive protection experiments. J. Immunol. 66:2100-2107.
44.	Taborda, C. P., J. Rivera, O. Zaragoza, and A. Casadevall. 2003. More is not necessarily better: prozone-like effects in passive immunization with immunoglobulin G. J. Immunol. 170:3621-3630.[Abstract/Free Full Text]
45.	Teitelbaum, R., A. Glatman-Freedman, B. Chen, J. B. Robbins, E. R. Unanue, A. Casadevall, and B. R. Bloom. 1998. A monoclonal antibody recognizing a surface antigen of Mycobacterium tuberculosis enhances host survival. Proc. Natl. Acad. Sci. USA 95:15688-15693.[Abstract/Free Full Text]
46.	Usinger, W. R., and A. H. Lucas. 1999. Avidity as a determinant of the protective efficacy of human antibodies to pneumococcal capsular polysaccharides. Infect. Immun. 67:2366-2370.[Abstract/Free Full Text]
47.	Winslow, G. M., E. Yager, K. Shilo, E. Volk, A. Reilly, and F. K. Chu. 2000. Antibody-mediated elimination of the obligate intracellular bacterial pathogen Erhlichia chaffeensis during active infection. Infect. Immun. 68:2187-2195.[Abstract/Free Full Text]
48.	Yuan, R., A. Casadevall, J. Oh, and M. D. Scharff. 1997. T cells cooperate with passive antibody to modify Cryptococcus neoformans infection in mice. Proc. Natl. Acad. Sci. USA 94:2483-2488.[Abstract/Free Full Text]
49.	Yuan, R., A. Casadevall, G. Spira, and M. D. Scharff. 1995. Isotype switching from IgG3 to IgG1 converts a non-protective murine antibody to C. neoformans into a protective antibody. J. Immunol. 154:1810-1816.[Abstract]

This article has been cited by other articles:

• Huntley, J. F., Conley, P. G., Rasko, D. A., Hagman, K. E., Apicella, M. A., Norgard, M. V. (2008). Native Outer Membrane Proteins Protect Mice against Pulmonary Challenge with Virulent Type A Francisella tularensis. Infect. Immun. 76: 3664-3671 [Abstract] [Full Text]  
• Racine, R., Chatterjee, M., Winslow, G. M. (2008). CD11c Expression Identifies a Population of Extrafollicular Antigen-Specific Splenic Plasmablasts Responsible for CD4 T-Independent Antibody Responses during Intracellular Bacterial Infection. J. Immunol. 181: 1375-1385 [Abstract] [Full Text]  
• Huntley, J. F., Conley, P. G., Hagman, K. E., Norgard, M. V. (2007). Characterization of Francisella tularensis Outer Membrane Proteins. J. Bacteriol. 189: 561-574 [Abstract] [Full Text]  
• Rivera, J., Casadevall, A. (2005). Mouse Genetic Background Is a Major Determinant of Isotype-Related Differences for Antibody-Mediated Protective Efficacy against Cryptococcus neoformans. J. Immunol. 174: 8017-8026 [Abstract] [Full Text]  
• Sable, S. B., Kumar, R., Kalra, M., Verma, I., Khuller, G. K., Dobos, K., Belisle, J. T. (2005). Peripheral Blood and Pleural Fluid Mononuclear Cell Responses to Low-Molecular-Mass Secretory Polypeptides of Mycobacterium tuberculosis in Human Models of Immunity to Tuberculosis. Infect. Immun. 73: 3547-3558 [Abstract] [Full Text]  
• Sable, S. B., Verma, I., Behera, D., Khuller, G. K. (2005). Human immune recognition-based multicomponent subunit vaccines against tuberculosis. Eur Respir J 25: 902-910 [Abstract] [Full Text]  
• Brady, L. J. (2005). Antibody-Mediated Immunomodulation: a Strategy To Improve Host Responses against Microbial Antigens. Infect. Immun. 73: 671-678 [Full Text]  
• Rivera, J., Zaragoza, O., Casadevall, A. (2005). Antibody-Mediated Protection against Cryptococcus neoformans Pulmonary Infection Is Dependent on B Cells. Infect. Immun. 73: 1141-1150 [Abstract] [Full Text]  
• Casadevall, A., Pirofski, L.-a. (2004). New Concepts in Antibody-Mediated Immunity. Infect. Immun. 72: 6191-6196 [Full Text]  

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Casadevall, A. Search for Related Content PubMed PubMed Citation Articles by Casadevall, A.