A Reappraisal of Humoral Immunity Based on Mechanisms of Antibody‐Mediated Protection Against Intracellular Pathogens
Introduction
The classical view of antibody‐mediated immunity (AMI) is that specific antibody (Ab) produced during the immune response to a microbial infection helps to clear the microbe by enhancing the efficacy of innate immune mechanisms and then confers immunity to subsequent encounters with the microbe. Consistent with this view, historically established mechanisms of AMI include viral and toxin neutralization, complement activation, phagocytosis, and antibody‐dependent cellular cytotoxicity (ADCC) (Janeway et al., 2001). The correlation between a defined amount of serum Ab and immunity against certain viral, bacterial, and toxin‐mediated diseases provided proof that AMI is protective (Robbins et al., 1995). Unfortunately, this tidy view of AMI does not apply to many infectious diseases, particularly those caused by intracellular pathogens such as Mycobacterium tuberculosis and Listeria monocytogenes. In fact, it is difficult to establish a role for AMI in host defense against many pathogenic microbes based on correlations between serum Ab levels and disease prevention and/or efficacy of passive Ab administration (Casadevall, 2004). The difficulty in establishing a role for AMI against intracellular microbes, evidence that the effective tissue response against many intracellular bacteria and fungi is granuloma formation, and that individuals with defects in cell‐mediated immunity (CMI) are at increased risk for disease with such microbes, led to the paradigm that AMI and CMI have dichotomous roles, whereby AMI protected against extracellular and CMI protected against intracellular pathogens, respectively (Casadevall, 2003). However, studies with monoclonal antibodies (mAbs) and mice deficient in B cells and Fc receptors suggest that AMI is remarkably complex and poorly understood and that the time is ripe not only just for a paradigm shift but also for a major rethinking of the role of AMI in health and disease. Consequently, the reevaluation of AMI for intracellular pathogens is serving as a major catalyst for revising certain long‐held concepts in immunological thought.
Section snippets
Intracellular and Extracellular Pathogenic Microbes: How Distinct Are They?
When immunologists consider the relative efficacy of AMI and CMI against a microbe, they often focus on whether it is an intracellular or extracellular pathogen. A major impetus for the classification of microbes as intracellular or extracellular was to ground the understanding of host defense against microbes with different pathogenic strategies in known and emerging immunological mechanisms. Based on what were believed to be fundamental mechanisms of AMI and CMI, AMI was viewed as the
Components of AMI
The term AMI is used here to encompass all the protective effects associated with Ab, including those mediated by “naturally occurring Ab,” passively transferred Ab, and acquired Ab (Ab generated by an immune response). When considering the function of AMI, it is worthwhile to remember that serum contains a high concentration of immunoglobulin proteins that include many different microbial and self‐specificities and isotype compositions. This immunoglobulin pool reflects the host response to
AMI in the Context of the “Damage‐Response Framework”
Given that AMI is a host defense mechanism against pathogenic microbes, an attempt to understand its function should account for Ab action in the context of principles of microbial pathogenesis. Unfortunately, until recently we lacked a unified theory that incorporated the contribution of the host response as well as the microbe into microbial pathogenesis. We have proposed the damage‐response framework (Casadevall 1999, Casadevall 2003) as a unified theory of microbial pathogenesis. This
Abs as Enhancers of Innate Immunity
The importance of naturally occurring Abs, predominantly of the IgM isotype, in enhancing innate immune responses to a multitude of pathogens is being increasingly recognized. In addition to the aforementioned animal models in which microbial virulence is reduced in the absence of serum IgM (see earlier), naturally occurring IgMs enhance complement‐mediated and complement‐independent antimicrobial mechanisms. For example, naturally occurring swine IgM promoted complement‐mediated lysis of
Abs as Direct and Indirect Effector Molecules
Abs can promote host defense by direct or indirect mechanisms (Table 1). Direct Ab functions are those that are manifest when an Ab binds a microbe and/or a microbial component and mediates an antimicrobial or antitoxin effect. Direct Ab functions include those classically associated with AMI such as complement activation, agglutination; toxin and viral neutralization. With the exception of toxin and viral neutralization, these direct effects are facilitated by Abs but mediated in concert with
AMI as a Regulator of the Inflammatory Response
As discussed previously, Ab can be a positive or negative regulator of the inflammatory response. The ability of an Ab to function in a positive or negative regulatory capacity is a function of the Ab isotype, amount, and specificity. Proinflammatory activities of Abs are complement activation, FcR engagement with the release of proinflammatory mediators such as cytokines, chemokines, platelet‐activating factor, and chemokines, neutralization of microbial components that interfere with an
Dose‐Response Conundrum
Early investigators noted that the efficacy of passive Ab therapy did not obey the law of multiple proportions (Goodner and Horsfall, 1935). Classic studies of passive Ab protection against S. pneumoniae revealed that the outcome of a passive Ab protection experiment was critically dependent on the amount of Ab administered (Felton 1928, Goodner 1935). The amount of Ab below which no protection occurred for a given inoculum was known as the “limiting titer zone,” a phenomenon that could be
Ab‐Mediated Protection Against Intracellular Pathogens
By the late twentieth century, the struggle between the cellularists and humoralists that began with the Ehrlich and Metchnikov debate on the relative importance of CMI and AMI nearly a century earlier (Silverstein, 1979) had settled into a sort of détente whereby each arm of the immune response was assigned a specific role in host defense against certain types of microbes. In this dichotomous view of immune function, AMI was considered to have a key role in protection against extracellular
Protective Efficacy of an Ab Molecule
Given that the efficacy of an Ab depends on its specificity, isotype, affinity, and the immune status and genetic background of the host, one cannot classify an Ab as protective, nonprotective, or disease enhancing solely on the basis of Ig structure. In fact, for each microbe Ab‐mediated protection might be thought of as a complex function of: (1) Ab variables such as isotype, specificity, and amount; (2) host variables such as genetic background, immunization status, and immune competence;
Some Emerging Concepts
- 1
Abs are both proinflammatory and anti‐inflammatory and mediate some of their effects by modulating both innate and adaptive cellular responses.
- 2
Protective Abs can probably be made against many if not all pathogens for which current methods cannot demonstrate a clear role for AMI in host defense. The most efficient way to achieve this is to generate mAbs to the microbe in question with the caveat that immunological knowledge is insufficient to predict the Ab characteristics that will be
Acknowledgments
This work was supported by grants from the National Institutes of Health AI 033142, AI 033774, HL 059842 (AC) and AI 035370, AI 045459, AI 044374 (CP).
References (219)
- et al.
Passive transfer of protection against Bacillus anthracis infection in a murine model
Vaccine
(2001) - et al.
Clinical experience with polyclonal IgM‐enriched immunoglobulins in a group of patients affected by sepsis after cardiac surgery
J. Cardiothorac. Vasc. Anesth.
(2005) - et al.
The loss of IgM memory B cells correlates with clinical disease in common variable immunodeficiency
J. Allergy Clin. Immunol.
(2005) The methodology for determining the efficacy of antibody‐mediated immunity
J. Immunol. Methods
(2004)- et al.
Antibody‐mediated regulation of cellular immunity and the inflammatory response
Trends Immunol.
(2003) - et al.
Antibody bound to the surface antigen MPB83 of Mycobacterium bovis enhances survival against high dose and low dose challenge
FEMS Immunol. Med. Microbiol.
(2004) - et al.
The capsule of Mycobacterium tuberculosis and its implications for pathogenicity
Tuber. Lung Dis.
(1999) - et al.
Molecular and cellular determinants of immunity to Histoplasma capsulatum
Res. Immunol.
(1998) - et al.
Intracellular antibody neutralizes Listeria growth
Immunity
(2001) Advances in antibody‐mediated immunity against Mycobacterium tuberculosis: Implications for a novel vaccine strategy
FEMS Immunol. Med. Microbiol.
(2003)
Mycobacterium tuberculosis arabinomannan‐protein conjugates protect against tuberculosis
Vaccine
Mycobacterium tuberculosis aerogenic rechallenge infections in B cell‐deficient mice
Tuber. Lung Dis.
Complex requirements for nascent and memory immunity in pulmonary histoplasmosis
J. Immunol.
Cutting edge: Biasing immune responses by directing antigen to macrophage Fcγ receptors
J. Immunol.
In vivo protection against Leishmania mexicana mediated by monoclonal antibodies
J. Immunol.
Phagosome‐lysosome interactions in cultured macrophages infected with virulent tubercle bacilli. Reversal of the usual nonfusion pattern and observations on bacterial survival
J. Exp. Med.
Potentiation of neutralization of Varicella‐Zoster virus to antibody to immunoglobulin
J. Infect. Dis.
B cells pulsed with Helicobacter pylori antigen efficiently activate memory CD8(+) T cells from H. pylori‐infected individuals
Clin. Immunol.
Antibody prevents the establishment of persistent arenavirus infection in synergy with endogenous T cells
J. Virol.
Both Th1 and Th2 cytokines affect the ability of monoclonal antibodies to protect mice against Cryptococcus neoformans
Infect. Immun.
Relationship of preoperative antiendotoxin core antibodies and adverse outcomes following cardiac surgery
JAMA
A critical role of natural immunoglobulin M in immediate defense against systemic bacterial infection
J. Exp. Med.
Enhanced B‐1 cell development, but impaired IgG antibody responses in mice deficient in secreted IgM
J. Immunol.
Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions
J. Clin. Invest.
Susceptibility to secondary Francisella tularensis live vaccine strain infection in B‐cell‐deficient mice is associated with neutrophila but not with defects in specific T‐cell‐mediated immunity
Infect. Immun.
Infection of B cell‐deficient mice with CDC 1551, a clinical isolate of Mycobacterium tuberculosis: Delay in dissemination and development of lung pathology
J. Immunol.
Outer‐membrane protein‐ and rough lipopolysaccharide‐specific monoclonal antibodies protect mice against Brucella ovis
J. Med. Microbiol.
Antibody‐mediated immunomodulation: A strategy to improve host responses against microbial antigens
Infect. Immun.
Monoclonal antibody‐mediated modulation of the humoral immune response against mucosally applied Streptococcus mutans
Infect. Immun.
Humoral immunity and regulation of intrapulmonary growth of Legionella pneumophila in the immunocompetent host
J. Immunol.
The classical pathway is the dominant complement pathway required for innate immunity to Streptococcus pneumoniae infection in mice
Proc. Natl. Acad. Sci. USA
Correlation of host immune response with quantitative recovery of Chlamydia trachomatis from the human endocervix
Infect. Immun.
Modulation of polymorphonuclear cell interleukin‐8 secretion by human monoclonal antibodies to type 8 pneumococcal capsular polysaccharide
Infect. Immun.
Modulation of the inflammatory response to serotype 8 pneumococcal infection by a human immunoglobulin in monoclonal antibody to serotype 8 capsular polysaccharide
Infect. Immun.
Antibody immunity and invasive fungal infections
Infect. Immun.
Antibody‐mediated protection against intracellular pathogens
Trends Microbiol.
Antibody‐mediated immunity against intracellular pathogens: Two‐dimensional thinking comes full circle
Infect. Immun.
Host‐pathogen interactions: Redefining the basic concepts of virulence and pathogenicity
Infect. Immun.
Host‐pathogen interactions: The basic concepts of microbial commensalism, colonization, infection, and disease
Infect. Immun.
The damage‐response framework of microbial pathogenesis
Nature Microbiol. Rev.
New concepts in antibody‐mediated immunity
Infect. Immun.
Effects of specific monoclonal antibodies to dense granular proteins on the invasion of Toxoplasma gondii in vitro and in vivo
Korean J. Parasitol.
Selective CD27+ (memory) B cell reduction and characteristic B cell alteration in drug‐naive and HAART‐treated HIV type 1‐infected patients
AIDS Res. Hum. Retroviruses
FcgammaRIIb balances efficient pathogen clearance and the cytokine‐mediated consequences of sepsis
J. Exp. Med.
Vaccines and cell‐mediated immunity
Bacteriol. Rev.
Cellular antimicrobial immunity
CRC Crit. Rev. Microbiol.
Cutting edge: The spirochetemia of murine relapsing fever is cleared by complement‐independent bactericidal antibodies
J. Immunol.
Generation of a complement‐independent bactericidal IgM against a relapsing fever Borrelia
J. Immunol.
Mycobactericidal activity of human natural, monoclonal, and recombinant yeast killer toxin‐like antibodies
J. Infect. Dis.
Protective efficacy of major outer membrane protein‐specific immunoglobulin A (IgA) and IgG monoclonal antibodies in a murine model of Chlamydia trachomatis genital tract infection
Infect. Immun.
Cited by (129)
Unlocking the bacterial membrane as a therapeutic target for next-generation antimicrobial amphiphiles
2021, Molecular Aspects of MedicineProtective efficacy of four heat-shock proteins as recombinant vaccines against photobacteriosis in Asian seabass (Lates calcarifer)
2021, Fish and Shellfish ImmunologyCitation Excerpt :It has been well established that cell-mediated immune responses are crucial for providing protection against intracellular pathogens [50]. However, increasing evidence shows that antibodies can provide some protection against this class of pathogens [51,52]. There are several mechanisms by which antibodies can mediate immunity against intracellular pathogens [53].
Skin immune response of rainbow trout (Oncorhynchus mykiss)experimentally exposed to the disease Red Mark Syndrome
2019, Veterinary Immunology and ImmunopathologyDetermination of immunodominant scaffolds of Com1 and OmpH antigens of Coxiella burnetii
2019, Microbial PathogenesisB lymphocytes in anti-mycobacterial immune responses: Pathogenesis or protection?
2019, TuberculosisCitation Excerpt :However, direct evidence for involvement of these cells in protection are lacking. Antibodies (Ab) are prominent players in host interactions with various intracellular pathogens (reviewed in Ref. [92]); however, their role in TB continues to be controversial for many decades [91–94]. For the purposes of this review, it is convenient to split the studies in two general categories: (i) Ab produced by mycobacteria-infected organism itself, and (ii) passive Ab immunization against TB.