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Eur J Immunol. Author manuscript; available in PMC Oct 12, 2009.
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How B cells Shape the Immune Response against Mycobacterium tuberculosis

Abstract

Extensive work illustrating the importance of cellular immune mechanisms for protection against Mycobacterium tuberculosis has largely relegated B cell biology to an afterthought within the tuberculosis (TB) field. However, recent studies have illustrated that B lymphocytes, through a variety of interactions with the cellular immune response, play previously underappreciated roles in shaping host defense against nonviral intracellular pathogens, including M. tuberculosis. Work in our laboratory has recently shown that, by considering these lymphocytes more broadly within their variety of interactions with cellular immunity, B cells have a significant impact on the outcome of airborne challenge with M. tuberculosis as well as the resultant inflammatory response. In this review, we advocate for a revised view of TB immunology in which roles of cellular and humoral immunity are not mutually exclusive. In the context of our current understanding of host defense against nonviral intracellular infections, we review recent data supporting a more significant role of B cells during M. tuberculosis infection than previously thought.

Keywords: tuberculosis, mycobacteria, B cells, humoral, Fcγ receptors

Introduction

Though vital to immunological protection and vaccination against a broad range of microbial pathogens, B cells remain an enigma in the TB field. Classically, B cells and antibodies are thought to offer no significant contribution towards protection against M. tuberculosis [1]. Though providing early evidence that humoral immunity may affect mycobacterial infection, the inconsistent results of passive immune therapies (likely due to variability in the preparation of antisera) conducted in the late nineteenth century [2] had led to its replacement by safer and more consistent antibiotic treatment for TB by the 1950s [3]. Within time the efforts of founding immunologists such as Albert Calmette and Elie Metchnikoff elevated cellular immunity to the forefront of host defense in the twentieth century [4-6], where it has dominated research efforts in the TB field ever since [7]. The more recent rise of molecular genetics has only further relegated B cells towards irrelevance in the TB field, as studies of B cell immunodeficiency in both humans [8, 9] and mice [10, 11] have questioned whether these lymphocytes impart a protective effect against M. tuberculosis.

Immunological advances in the twenty-first century have led researchers to not only consider natural immunity to infection, which itself can be variable in terms of protection [12], but also novel ways to rationally improve vaccination strategies against infectious agents [13-15]. Moreover, immunoglobulin research has advanced to produce safer and more effective antibody therapies, allowing passive immunization to be reconsidered for infectious disease treatment [16]. Seeing immunology within these ever unraveling complexities of host defense has brought us once again back to B cells, in the hopes of unlocking previously underappreciated potentials of these lymphocytes to improve immunity against M. tuberculosis.

B and T cells collaborate to repel infectious challenge

The first components of host defense to encounter pathogens that have breeched anatomical barriers constitute innate immunity, which includes mononuclear phagocytes, natural killer cells and other innate cells of lymphoid origin, neutrophils, and serum factors including complement and natural antibodies [17-19]. Encounter with foreign microbes through conserved pattern-recognition receptors activates innate sentinels known as dendritic cells to stimulate T lymphocytes, which in turn provide help to B cells and orchestrate adaptive immune responses [20, 21]. Adaptive immunity has evolved in vertebrates to include both cellular and humoral components, with T cells and B cells mediating these effects respectively. T cells target and promote apoptotic killing of pathogen-infected cells either directly or through cytokine activation of neighboring immune cells, while B cells make antibodies that neutralize invasion and target infectious agents for destruction [22]. The lungs are particularly vulnerable to infection due to limitations in anatomical barriers allowing for airflow, making effective, but non-pathologic, pulmonary immunity vital for successful host defense [23].

Paramount amongst the properties of immunity is memory, which, through the differentiation of long-lived and highly specialized lymphocytes, results in decidedly effective secondary responses upon subsequent pathogen exposure. Edward Jenner is credited with first realizing this phenomenon when devising a smallpox vaccine over 200 years ago [24]. Vaccination harnesses immunological memory by priming the immune system with an attenuated version of the targeted pathogen, bypassing the risk of primary infection while maintaining the immunological benefits against future exposure with the virulent pathogen [25]. As an effective means of preventing pathogen entry and neutralizing microbial toxins, antibodies are of particular importance to nearly all vaccines currently in use [26]. Bacillus Calmette-Guérin (BCG) is the only vaccine administered to prevent TB, and while it is thought to be protective against pediatric TB meningitis its efficacy against adult pulmonary TB is limited [27]. Efficacy of BCG immunization against TB correlated with specific antibodies in one study [28], however it is conventionally accepted that cellular immunity plays the predominant role. With immune correlates of protection against M. tuberculosis remaining incompletely defined [29], much remains to be understood regarding ways to enhance host defense against M. tuberculosis. We remain hopeful that greater understanding of both B and T cells will contribute to improved strategies of harnessing the complementary functions of these lymphocytes.

The role of B cells in immunity against non-viral intracellular pathogens

Protection against intracellular pathogens is often generalized as exclusively T cell-mediated, with B cells and antibodies playing a much more limited role than they are perceived to play during extracellular infections [30]. This follows the concept that antibodies, flowing through the serum, are specialized for targeting extracellular microbes, while only T cells, which use antigen-presentation as a means to look within cells, can specifically target intracellular microbes for killing. Exceptions to these rules exist, however, as antibodies confer long-lived protection against many obligate intracellular viruses [31-34], presumably by targeting the extracellular phase of the virion, and T cells are activated by antigen-presentation to stimulate defense against extracellular helminthes [35]. Directly relevant to the present review, emerging experimental evidence suggest that B cells play a role in defense against a wide variety of intracellular bacterial, fungal, and parasitic pathogens (see below). Immunity likely did not evolve as two disconnected arms of defense that separately deal with intracellular and extracellular pathogens, rather a far more resourceful means of host defense is one developed to achieve maximally adaptive, cooperative, and versatile infection containment.

As mentioned previously, B and T cell responses function complementarily to repel natural infection, and can likewise both contribute to long-lived protection as a result of vaccination [36, 37]. For example, collaboration between cellular and humoral immunity protects young children against Haemophilus influenzae type b, as conjugation of the T cell-independent carbohydrate antigen polyribosylribitol phosphate to a T cell-dependent protein immunogen stimulates long-lived antibody protection [38, 39]. T helper cells greatly impact the development and specialization of B cell responses [40], and B cells conversely impact T cell activation by acting as or upon antigen-presenting cells [41]. Within this intricate relationship between both arms of immunity, cellular and humoral responses together determine the outcome of intracellular infection.

Viruses often rely on limited means of cellular entry, and antibodies that neutralize the molecular interactions mediating infection allow for long-term immunity against viral pathogen [42]. Intracellular bacteria, such as mycobacteria, and parasites, like malaria, present a much more complicated picture by utilizing multiple potential modes of cell entry [43], expanding the epitope requirements for neutralizing antibodies. Given this complexity, it is likely that successful antibody responses against intracellular bacteria tend to prevent disease rather than infection [44], through activation of complement pathways and cellular immunity [45]. Further research efforts are necessary to understand how protective antibodies can be incorporated into successful vaccines against intracellular bacterial pathogens, such as M. tuberculosis, that continue to cause significant global morbidity and mortality.

Limitation of single-gene knockout mouse studies in infectious diseases

The small size, limited expense, available genetics and laboratory reagents, and an immune system that significantly mirrors that of humans maintain the mouse as the preferred choice for infectious disease study. Mice with targeted deletions that ‘knockout’ specific genes are useful tools for immunologists, and can be utilized to garner much information regarding the roles of individual immune components within the host response to specific pathogens. Knockout mice have been useful for examining the effects of B cell-deficiency upon disease progression and survival for a wide range of intracellular bacteria and parasites. Enhanced susceptibility of B cell-deficient mice to infections with Chlamydia trachomatis, Francisella tularensis, Leishmania major, Plasmodium chabaudi chabaudi, Pneumocystis carinii, and Salmonella enterica serovar Typhimurium have all been reported [46-52], demonstrating that B lymphocytes mediate optimal immunity against many intracellular pathogens in addition to viruses.

Studies of M. tuberculosis infection in B cell-deficient mice have been variable, with reports of immunity being diminished, pathologic progression being delayed, or no apparent effects from the genetic ablation of B cells [10, 11, 53-55]. This broad range of results emphasizes the limitations and variances inherent to mouse models of infectious disease, particularly TB. Single knockout studies in M. tuberculosis-infected mice may yield results whose interpretation are not straightforward because of functionally overlapping immune components [56, 57], may not account for potential host response differences between mice and humans [58], and do not provide any information regarding the potential effects of augmenting the particular immune component in question. Consequently, knockout mouse studies can lead to premature conclusions regarding the role of a particular component of immunity, if not interpreted thoroughly. Additionally, experimental conditions can have marked effects on results. For example, increasing the infection inoculum exposed a requirement for B cells in the optimal TB host response in mice [53, 54]. Supporting a role for B cells in host immune response to M. tuberculosis, genetic ablation of the polymeric Ig receptor heightened susceptibility of mice, implicating a role for secretory IgA within optimal TB immunity [59]. Finally, protective effects of intravenous immunoglobulin (IVIG) suggest further impact of humoral components upon host defense in TB [60]. Though the results of certain knockout mouse studies and the IVIG experiment indicate that B cells and their products mediate protection against M. tuberculosis, the important question that remains is whether B cell responses can be augmented to improve immunity against M. tuberculosis through immunotherapy or vaccination.

Ectopic B cell aggregates as a consequence of chronic inflammation and infection

Our renewed interest in B lymphocytes emerged from observations of follicle-like B cell aggregates in the lungs of TB patients [61, 62]. These B cell aggregates are the predominant foci of cellular proliferation in human TB lungs [61], and are characteristics of TB granulomatous progression in mice [11, 62, 63]. B cell aggregates are noted pathological findings of many chronic inflammatory diseases, including multiple sclerosis and rheumatoid arthritis [64, 65]. Similar B cell clusters have been observed in other infections, such as with influenza virus and Helicobacter [66, 67]. Certain pathogens have evolved means of promoting expansion and inhibiting apoptosis of B cells [68, 69], which may contribute to the accumulation of these lymphocytes during infection.

What are the effects of these ectopic B cell aggregates upon immunity to M. tuberculosis? It has been hypothesized that these follicle-like structures function to perpetuate local host responses, with the majority of proliferative activity occurring in the proximity of B cell aggregates [61]. T cells can be scattered throughout these B cell clusters [62], making these potential sites of both antigen presentation and B cell maturation. It is also notable that these B cell aggregates are components of tertiary lymphoid tissue within TB lungs [70], containing markers of germinal centers [54]. Further suggesting that B cells foster localized architecture of the immune response, we noted that B cell-deficient mice had exacerbated pulmonary pathology and disruption of granulomatous organization in the lungs [54]. Much remains to be understood regarding the significance of lymphoid neogenesis in TB, but it has been demonstrated that these inducible lymphoid structures can prime protective immunity in the lungs and memory responses against pulmonary influenza virus challenge in the absence of secondary lymphoid organs [66, 71].

T cell activation is strongly influenced by B cells

B cells are professional antigen-presenting cells with notable impact upon T cell responses. By capturing antigens via cell surface receptors, B lymphocyte activation is initiated. Subsequent progression through cellular interactions with CD4+ helper T cells includes antigen-presentation events which stimulate T cells to produce the cytokines that reciprocally regulate the antibody responses of B cells [72]. Though the significance of B cell-mediated antigen-presentation varies with antigen and immunological conditions [73], these lymphocytes can be targeted to present antigen to T cells by specific vaccination strategies [74, 75]. In fact, one such B cell-targeting vaccine vector has been effective in boosting BCG primed immunity against M. tuberculosis [76]. In a recently published example, the presence of B cells, but not specific antibody, protected against reactivation of chronic virus infection, presumably through antigen-presentation to T cells [77]. An antibody-independent function of B cells in priming optimal primary and secondary immune responses against the intracellular bacterial pathogen Francisella tularensis has also been reported [78]. Furthermore, activated B cells serving as antigen-presenting cells have been utilized to enhance anti-tumor immunity [79]. It has also been noted that antigen-presentation by B cells can help perpetuate autoimmunity [80], while resting B cells are thought to mediate immune tolerance [81, 82]. By studying B cells as targets for immune augmentation as well as in the suppression of autoimmunity [83], future research will likely expose creative means of targeting this often overlooked pathway of antigen-presentation. Finally, accumulating evidence suggests that B cells are required to prime memory T cell responses [52, 84], placing the B and T cell relationship in particularly relevant context to vaccine biology.

B cells can also act upon other antigen-presenting cells, thus influencing the evolution of T cell responses in a more indirect manner. T cells are stimulated to clonally expand by antigen-presenting cells that concurrently express costimulatory molecules on their surface while presenting antigen [85]. This illustrates the two-signal hypothesis for T cell activation in which engagement of both the antigen receptor and CD28 on the surface of T cells are required to initiate adaptive immune responses, with lymphocyte tolerance a consequence of an absent second signal [86]. Antigen-presenting cells upregulate surface expression of costimulatory proteins, such as those of the B7 family, during a maturation process that follows the activation of innate immunity [17]. These costimulatory molecules then interact with CD28 or other co-receptors to promote activation of T cells [87]. B cells can modulate this maturation process through the production of antibodies and cytokines, which can either enhance or suppress immune responses [88-93]. B cells have been reported to polarize T cell responses through the production of cytokines [94], and the provision of IL-10 is thought to be a means by which B cells can promote Th2 differentiation in mice [95]. Additionally, natural antibodies can modulate antigen-presentation by binding to and altering the activity of the costimulatory molecules B7 and CD40 [41, 96, 97].

Much has been uncovered regarding antibody regulation of antigen-presentation through Fcγ receptors [98], and this immunological pathway has garnered interest as a potential means of improving vaccination against intracellular pathogens [99]. Fcγ receptors are divided into stimulatory and inhibitory types based upon the presence of intracellular ITAM or ITIM-motifs, respectively [100, 101]. FcγRIIB, the lone inhibitory Fcγ receptor, has an intricate involvement in T cell activation by limiting dendritic cell maturation and subsequent antigen-presentation while the stimulatory Fcγ receptors appear to promote both processes [89, 90]. FcγRIIB also plays a significant role in mediating peripheral tolerance of T cell responses in murine autoimmunity models [102]. Furthermore, selective blockade of FcγRIIB leads to enhanced T cell activity in experimental tumor models [89-91]. Stimulatory Fcγ receptors appear to promote T cell responses, the polarization of which is shaped by the prevailing inflammatory context and can be either Th1 or Th2 dominated [103]. Fcγ receptor engagement can be strongly influenced by antibody isotype [104], and immunization methods that preferentially target stimulatory Fcγ receptors have the potential effects of enhancing cellular immunity against intracellular pathogens [99, 105]. Interestingly, it has been reported that FcγRIII mediates immune suppressive effects in an IVIG model, illustrating that association with an ITAM motif may not restrict function to proinflammatory activity [106].

Genetic disruption of Fcγ receptor function in mice has implicated a role for these receptors in microbial infection [107]. In particular, specific ablation of the shared stimulatory Fcγ-chain compromises optimal immunity against a variety of intracellular pathogens, including influenza virus, Leishmania species, Plasmodium berghei, and Salmonella enterica [49, 108-112]. Passive immunization against Cryptococcus neoformans with IgG1 mAb was also dependent upon functional stimulatory Fcγ receptors [113], further implicating the stimulatory Fcγ receptors in cellular host defense against intracellular pathogens. We have found that disruption of stimulatory Fcγ receptor activity heightens susceptibility to M. tuberculosis Erdman, corresponding with compromised bacterial containment and worsened immunopathology [114]. Conversely, genetic deletion of inhibitory FcγRIIB improves mycobacterial containment, with increases in IFN-γ production and Th1 polarization detected in the lungs [114]. Efforts are underway to study how these apparent effects of Fcγ receptors can be harnessed to improve immunity against M. tuberculosis.

These immune-enhancing effects from specific targeting of Fcγ receptors may provide mechanisms of improving vaccine-induced immunity against intracellular pathogens [99, 105]. For example, viral vectors can be targeted to Fcγ receptor-bearing cells through antibody-dependent infection enhancement [115], providing a means by which antigen-presenting cells can potentially be manipulated for activation and immunization. Interestingly, a Plasmodium falciparum merozoite surface antigen has been identified that preferentially induces isotype class-switching to IgG2b in mice [116], a cytophilic immunoglobulin subtype with preferential affinity for stimulatory Fcγ receptors [104]. Future research should further expose how Fcγ receptors can be targeted and utilized to enhance immunity against intracellular pathogens.

Are antibodies protective against M. tuberculosis, an intracellular pathogen

Contrary to the generally accepted notion that humoral immunity is insignificant in protection against the tubercle bacillus, passive administration of antibodies had reported efficacy against M. tuberculosis since the late nineteenth century [2]. However, serum therapy for TB fell out of favor when efficacy of treatment and reagent preparations were found to be inconsistent [117], and the advent of pharmacologic antimycobacterials, such as streptomycin, by the middle of the twentieth century, offered a far more reliable option [118]. Excellent reviews exist regarding the history and recent developments of antibody-mediated immunity to M. tuberculosis [2, 119]. Recently, monoclonal antibodies against mycobacterial arabinomannan, heparin-binding hemagglutinin and 16 kDa α-crystallin have all demonstrated efficacy in mouse models of TB [120-124]. These antibodies mediate protection in different manners, some by diminishing tissue mycobacterial burden while others enhance animal survival through apparent decreases in inflammatory progression [119]. Notable, however, is the fact that an M. tuberculosis arabinomannan-protein conjugate vaccine has been reported to induce more robust antibody responses than BCG, but without an apparent survival improvement in mice [125]. Question remains as to whether the mouse is an optimal modality to measure enhanced protection, given the chronically inflammatory and persistent infectious burden of the model and limited correlations of the pathology with that of human disease. Thus, future studies are required to unravel antibody correlates of protection in humans and animal models if effectively protective immunization-induced B cell responses against M. tuberculosis are to be generated. Finally, it is noteworthy that virtually nothing is known of the impact of innate or natural antibody responses [126-128] upon mycobacterial infection. Given that complex lipids are a major constituents of the hydrophobic cell wall of mycobacteria, it would be interesting to examine the significance of T-independent antibody responses, most notably of B1 and marginal zone B cells, in the defense against M. tuberculosis.

Looking beyond antigen-specific neutralization, antibodies also have notable general effects upon inflammation, including complement activation, Fcγ receptor cross-linking, and release of microbial products due to direct antimicrobial activity [45]. In regards to pulmonary host responses, antibodies can modulate architectural changes in airway epithelium and vessels, as in response to mycoplasma infection [129]. In our own studies, we found that adoptive transfer of B cells resolved the inflammatory exacerbation in B cell-deficient mice upon airborne challenge with M. tuberculosis Erdman [54]. Suggesting a role of immunoglobulin-mediated “endocrine” immune regulation, this reduction in pathology occurred in conjunction with detectable levels of antibodies in the serum but without the presence of B cells locally within lungs [54]. It is quite apparent that antibodies can have a variety of protective effects during infection with intracellular pathogens, which includes limiting inflammatory pathology [130] in addition to well-established roles in neutralizing and opsonizing microbes.

How B cells shape the immune response against M. tuberculosis

The correlates of vaccine-mediated protection against M. tuberculosis are incompletely defined, but most evidence suggests that T cells are of paramount importance [7]. Consequently, the aim of all the novel TB vaccines currently in development is to enhance cellular immune responses against the pathogen [131]. As reminded by recent failure in a clinical trial of a T cell vaccine against HIV [132], it is prudent not to limit vaccine research too narrowly. It is quite likely that protective antibody responses will be required for optimally successful immunization against M. tuberculosis in the future [44], and further research designed to uncover how humoral immunity can best be harnessed to mediate this protection seems warranted. In this direction, efforts to understand B cell biology and its relationship with TB have demonstrated that these often over-looked lymphocytes can significantly influence cytokine production, bacillary containment, and immunopathologic progression during M. tuberculosis infection. As one possible mechanism by which B cells shape the immune response, we hypothesize that immunoglobulin, acting upon Fcγ receptors, influences antigen-presenting cell maturation to produce the noted phenotypes of gene-deficient mice challenged with M. tuberculosis (Figure 1). However, this is but one pathway by which B lymphocytes modulate the host response in tuberculosis infection. B cells can conceivably shape anti-tuberculous immunity through a variety of means including direct effects of antibody upon the pathogen, antigen presentation, cytokine production, as well as influencing the intracellular killing mechanisms of leukocytes.

Figure 1
Schematic of how B cells shape the immune response against M. tuberculosis

As addressed earlier, T cell activation is achieved through antigen-presentation by specialized cells that must undergo a maturation process in order to serve this function [17]. We previously described how B cells can have a significant impact upon antigen-presenting cell maturation through the engagement of Fcγ receptors by antibodies. Using mice deficient in inhibitory FcγRIIB receptor function, we found that the absence of FcγRIIB enhanced containment of M. tuberculosis Erdman in mice [114]. Pulmonary IFN-γ production and Th1 cell frequency were correspondingly increased in FcγRIIB-deficient mice. Conversely, genetic ablation of the common γ-chain shared amongst stimulatory Fcγ receptors impaired M. tuberculosis containment and worsened overall survival (110). Thus, B cells can significantly impact host immunity and disease outcome by engagement of Fcγ receptors during TB, influencing both Th1 activation and mycobacterial containment.

Murine studies of M. tuberculosis infection also indicate that B cells have a significant impact upon the production of IL-10 in the lungs. IL-10 is produced by a broad range of leukocytes, including B cells, dendritic cells, macrophages, and T cells, imparting mostly anti-inflammatory functions upon host responses [133]. Heightened production of IL-10 in the lungs during M. tuberculosis infection has been reported in two different murine models of B cell deficiency [54, 134]. We also observed an IL-10 increase in the lungs of stimulatory-Fcγ-chain-deficient mice infected with M. tuberculosis Erdman [114].

The cellular source of this IL-10 increase is unclear as intracellular cytokine staining techniques to detect IL-10 are not optimally sensitive for detecting significant quantities of these cells in mice. The recent development of IL-10 reporter mice may facilitate such studies in the future [135, 136]. IL-10 production is a characteristic of incompletely activated dendritic cells that have not undergone complete maturation [137]. Thus, by influencing cellular activation via immune complex engagement of Fcγ receptors, B cells may influence the production of IL-10 by these antigen-presenting cells. It has also been reported that B cells can activate or inhibit regulatory T cells, a significant cellular source of IL-10 [138, 139]. Finally, the increase in IL-10 may be in reaction to the exacerbated immunopathology induced during M. tuberculosis infection of B cell -/- and Fcγ-chain -/- mice [54], as the production of anti-inflammatory cytokines, like IL-10, may be a compensatory attempt to limit excessive inflammation. More work is needed to assess the relationship of B cells and cytokines during TB, particularly given that B cells themselves can be a source of the vital anti-mycobacterial cytokine IFN-γ [94].

As also described previously in this article, B cells are prominent components of TB pulmonary granulomatous inflammation, with large aggregates of these lymphocytes as prominent histological characteristics of the infection [61-63]. The absence of B cells, while compromising optimal immunity leading to exacerbated pulmonary pathology upon acute M. tuberculosis infection [54], leads paradoxically to a delay in inflammatory progression during chronic infection in mice [55]. One possible explanation for this paradox is that B cell function during the course of tuberculous infection is infection phase-specific: During acute infection, B cells are required for an optimal granulomatous response and effective immunity against pulmonary challenge with M. tubeculosis, and in their absence, dysregulation of granuloma formation results and increased pulmonary inflammation is required to contain infection. In contrast, during chronic phase of infection when persistent bacilli are contained, the immunologically active B cell clusters [54, 61, 62] likely promote the perpetuation of local host immunity against M. tuberculosis and may aid in prevention of reactivation disease. This perpetuation of inflammation may occur in part through B cells acting as antigen-presenting cells. Indeed, T cells have been observed to be associated with B cell nodules in both human and mouse tuberculous lung tissues ([62], P. Maglione and J. Chan, unpublished). In this regard, antigen uptake may occur in a specific manner via the BCR, though it has been shown that B cells can load MHC with peptide not in line with their receptor specificity [140]. Such “non-specific” antigens could be the result of Toll-like receptor uptake [141]. Thus, the inflammatory paradox of B cell-deficient mice seems to reflect the role of B cells shifting from optimizing host defense during acute challenge to perpetuating the chronic inflammatory response during persistent infection.

TB morbidity and mortality results from an aberrant and damaging host response [142, 143]: one that is both excessive in pathologic consequence yet ineffective in containing the pathogen. This apparent paradox may be viewed as a product of ineffective immune containment of the tubercle bacillus leading to excessive compensatory recruitment of leukocytes within the lungs. This is best evidenced in patients with reactivation TB. Rather than being devoid of immune activity, which could explain the reemergence of a dormant pathogen, the lungs of patients with reactivation diseases contain areas of intense pulmonary infiltrate [143]. Prior to treatment, active TB pulmonary infiltrate is dominated by neutrophils [61], an innate immune cell that aids in early protection but promotes inflammatory damage in a variety of acute pulmonary diseases [144]. Similar to humans, susceptibility to TB is associated with increased pulmonary neutrophil influx in mice [145]. In contrast, incidental findings of Ghon complex pathology in humans emphasize how successful containment of M. tuberculosis needs not have significant immunopathology as a by-product. Existing data strongly suggest that B cells play a role in modulating the inflammatory response during TB infection [54,55]

Concluding Remarks

Even if host bacillary containment succeeds without symptoms of disease, M. tuberculosis infection persists in a latent state that can reactivate later in life, often as a result of immunodeficiency. Given this observation that M. tuberculosis infection persists even in those with successful disease-preventing immunity, it is clear that a vaccine that prevents TB must invoke an immune response that is superior to that induced by natural infection [44]. Rational design of such a vaccine will require extensive study of the basic immunology underlying protective immunity, and will likely benefit from understanding how immunological pathways that may be modestly protective during natural infection can be optimized to achieve neutralization through vaccination.

As this is a review aiming to expand interest in the relationship of B cell biology and TB, it is important to highlight key questions that beg to be answered. For example, what type of memory B cells develops, if any at all, as a result of natural M. tuberculosis infection? How do these memory B cells compare to those induced by BCG vaccination? Do T-independent memory B cells develop against non-protein antigens of M. tuberculosis, and are these better targets for immunization than protein antigens? Furthermore, can antibodies be identified that prevent mycobacterial infection in human subjects, and can these neutralization targets be incorporated into a vaccine? Conversely, are there specific antibodies that adversely modulate anti-tuberculosis immunity? Are the ectopic germinal centers identified in TB lungs important sites of memory B cell or long-lived plasma cell development? What is the pathology of latent infection and are germinal centers present throughout the course of chronic TB? As an alternative to sterile eradication, can B cells be stimulated to maintain chronic containment and prevent TB reactivation? Or conversely, can B cell depletion treatments be utilized to diminish inflammatory pathology in patients with chronic TB? What antibody-independent functions of B cells participate in shaping the host immune response to M. tuberculosis?

Many questions remain unanswered regarding the role of B cells but hopefully further studies of these lymphocytes will reveal more about how they can be harnessed to optimize immunity against M. tuberculosis. Given the global significance of TB, it is imperative that we investigate all possibilities that may help design better treatments and develop effective vaccines. Despite decades-long perceptions of B cell futility towards M. tuberculosis infection, recent data suggest that this powerful arm of immunity should not be overlooked.

Acknowledgments

This work was supported by National Institutes of Health Grants R01 HL071241, R01 AI50732, P01 AI063537, and Albert Einstein College of Medicine/Montefiore Medical Center for AIDS Research Grants P30 AI051519, and T32 AI007506, and by a Seed Grant from the American Medical Association Foundation (to P.J.M.).

Abbreviations

TB
tuberculosis
IVIG
intravenous immunoglobulin
Ig
immunoglobulin

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