A Reappraisal of Humoral Immunity Based on Mechanisms of Antibody‐Mediated Protection Against Intracellular Pathogens

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Abstract

Sometime in the mid to late twentieth century the study of antibody‐mediated immunity (AMI) entered the doldrums, as many immunologists believed that the function of AMI was well understood, and was no longer deserving of intensive investigation. However, beginning in the 1990s studies using monoclonal antibodies (mAbs) revealed new functions for antibodies, including direct antimicrobial effects and their ability to modify host inflammatory and cellular responses. Furthermore, the demonstration that mAbs to several intracellular bacterial and fungal pathogens were protective issued a serious challenge to the paradigm that host defense against such microbes was strictly governed by cell‐mediated immunity (CMI). Hence, a new view of AMI is emerging. This view is based on the concept that a major function of antibody (Ab) is to amplify or subdue the inflammatory response to a microbe. In this regard, the “damage‐response framework” of microbial pathogenesis provides a new conceptual viewpoint for understanding mechanisms of AMI. According to this view, the ability of an Ab to affect the outcome of a host–microbe interaction is a function of its capacity to modify the damage ensuing from such an interaction. In fact, it is increasingly apparent that the efficacy of an Ab cannot be defined either by immunoglobulin or epitope characteristics alone, but rather by a complex function of Ab variables, such as specificity, isotype, and amount, host variables, such as genetic background and immune status, and microbial variables, such as inoculum, mechanisms of avoiding host immune surveillance and pathogenic strategy. Consequently, far from being understood, recent findings in AMI imply a system with unfathomable complexity and the field is poised for a long overdue renaissance.

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).

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