How B Cells Shape the Immune Response Against Mycobacterium Tuberculosis

676 Paul J. Maglione and John Chan DOI 10.1002/eji.200839148 Eur. J. Immunol. 2009. 39: 676–686 Mini-Review

How B cells shape the immune response against Mycobacterium tuberculosis

Paul J. Maglione and John Chan

Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, USA

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 non-viral 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 non-viral intracellular infections, we review recent data supporting a more significant role of B cells during M. tuberculosis infection than previously thought.

Key words: B cells . Fcc receptors . Humoral . Mycobacteria . Tuberculosis

Introduction toward irrelevance in the TB field, as studies of B-cell immunodeficiency in both humans [8, 9] and mice [10, 11] Though vital to immunological protection and vaccination have questioned whether these lymphocytes impart a protective against a broad range of microbial pathogens, B cells remain an effect against M. tuberculosis. enigma in the tuberculosis (TB) field. Classically, B cells and Immunological advances in the twenty-first century have led antibodies are thought to offer no significant contribution toward researchers to not only consider natural immunity to infection, protection against Mycobacterium tuberculosis [1]. Though which itself can be variable in terms of protection [12], but also providing early evidence that humoral immunity may affect novel ways to rationally improve vaccination strategies against mycobacterial infection, the inconsistent results of passive infectious agents [13–15]. Moreover, Ig research has advanced to immune therapies (likely due to variability in the preparation produce safer and more effective antibody therapies, allowing of antisera) conducted in the late nineteenth century [2] had led passive immunization to be reconsidered for infectious disease to its replacement by safer, and more consistent antibiotic treatment [16]. Seeing immunology within these ever unraveling treatment for TB by the 1950s [3]. Within time, the efforts of complexities of host defense has brought us once again back to founding immunologists such as Albert Calmette and Elie B cells, in the hopes of unlocking previously underappreciated Metchnikoff elevated cellular immunity to the forefront of host potentials of these lymphocytes to improve immunity against defense in the twentieth century [4–6], where it has dominated M. tuberculosis. research efforts in the TB field ever since [7]. The more recent rise of molecular genetics has only further relegated B cells B and T cells collaborate to repel infectious challenge

The ﬁrst components of host defense to encounter pathogens that Correspondence: Professor John Chan e-mail: [email protected] have breeched anatomical barriers constitute innate immunity,

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which includes mononuclear phagocytes, natural killer cells and specifically target intracellular microbes for killing. Exceptions to other innate cells of lymphoid origin, neutrophils, and serum these rules exist, however, as antibodies confer long-lived factors including complement and natural antibodies [17–19]. protection against many obligate intracellular viruses [31–34], Encounter with foreign microbes through conserved pattern- presumably by targeting the extracellular phase of the virion, and recognition receptors activates innate sentinels known as T cells are activated by antigen-presentation to stimulate defense dendritic cells to stimulate T lymphocytes, which in turn provide against extracellular helminthes [35]. Directly relevant to the help to B cells and orchestrate adaptive immune responses present review, emerging experimental evidence suggests that B [20, 21]. Adaptive immunity has evolved in vertebrates to include cells play a role in defense against a wide variety of intracellular both cellular and humoral components, with T cells and B cells bacterial, fungal, and parasitic pathogens (see Limitation of mediating these effects, respectively. T cells target and promote single-gene knockout mouse studies in infectious diseases). Immu- apoptotic killing of pathogen-infected cells either directly or nity likely did not evolve as two disconnected arms of defense through cytokine activation of neighboring immune cells, that separately deal with intracellular and extracellular patho- whereas B cells make antibodies that neutralize invasion and gens, rather a far more resourceful means of host defense is one target infectious agents for destruction [22]. The lungs are developed to achieve maximally adaptive, cooperative, and particularly vulnerable to infection due to limitations in versatile infection containment. anatomical barriers allowing for airflow, making effective, but As mentioned previously, B- and T-cell responses function non-pathologic, pulmonary immunity vital for successful host complementarily to repel natural infection, and can likewise both defense [23]. contribute to long-lived protection as a result of vaccination Paramount among the properties of immunity is memory, [36, 37]. For example, collaboration between cellular and which, through the differentiation of long-lived and highly humoral immunity protects young children against Haemophilus specialized lymphocytes, results in decidedly effective secondary influenzae type b, as a conjugation of the T-cell-independent responses upon subsequent pathogen exposure. Edward Jenner is carbohydrate antigen polyribosylribitol phosphate to a T-cell- credited with first realizing this phenomenon when devising a dependent protein immunogen stimulates long-lived antibody smallpox vaccine over 200 years ago [24]. Vaccination harnesses protection [38, 39]. Th cells greatly impact the development and immunological memory by priming the immune system with an specialization of B-cell responses [40], and B cells conversely attenuated version of the targeted pathogen, bypassing the risk of impact T-cell activation by acting as or upon antigen-presenting primary infection while maintaining the immunological benefits cells [41]. Within this intricate relationship between both arms of against future exposure with the virulent pathogen [25]. As an immunity, cellular and humoral responses together determine the effective means of preventing pathogen entry and neutralizing outcome of intracellular infection. microbial toxins, antibodies are of particular importance to Viruses often rely on limited means of cellular entry, and nearly all vaccines currently in use [26]. BCG is the only vaccine antibodies that neutralize the molecular interactions mediating administered to prevent TB, and although it is thought to be infection allow for long-term immunity against viral pathogens protective against pediatric TB meningitis, its efficacy against [42]. Intracellular bacteria, such as mycobacteria, and parasites, adult pulmonary TB is limited [27]. Efficacy of BCG immuniza- like malaria, present a much more complicated picture by tion against TB correlated with specific antibodies in one study utilizing multiple potential modes of cell entry [43], expanding [28]: however it is conventionally accepted that cellular immu- the epitope requirements for neutralizing antibodies. Given this nity plays a predominant role. With immune correlates of complexity, it is likely that successful antibody responses against protection against M. tuberculosis remaining incompletely defined intracellular bacteria tend to prevent disease rather than infec- [29], much remains to be understood regarding ways to enhance tion [44], through activation of complement pathways and host defense against M. tuberculosis. We remain hopeful that cellular immunity [45]. Further research efforts are necessary to greater understanding of both B and T cells will contribute to understand how protective antibodies can be incorporated into improved strategies of harnessing the complementary functions successful vaccines against intracellular bacterial pathogens, such of these lymphocytes. as M. tuberculosis, that continue to cause significant global morbidity and mortality.

The role of B cells in immunity against non-viral intracellular pathogens Limitation of single-gene knockout mouse studies in infectious diseases Protection against intracellular pathogens is often generalized as exclusively T-cell mediated, with B cells and antibodies playing a The small size, limited expense, available genetics and laboratory much more limited role than they are perceived to play during reagents, and an immune system that significantly mirrors that of extracellular infections [30]. This follows the concept that humans maintain the mouse as the preferred choice for infectious antibodies, flowing through the serum, are specialized for disease study. Mice with targeted deletions that ‘‘knockout’’ targeting extracellular microbes, whereas only T cells, which specific genes are useful tools for immunologists, and can be use antigen-presentation as a means to look within cells, can utilized to garner much information regarding the roles of

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individual immune components within the host response to expansion and inhibiting apoptosis of B cells [68, 69], which may specific pathogens. Knockout mice have been useful for examin- contribute to the accumulation of these lymphocytes during ing the effects of B-cell deficiency upon disease progression and infection. survival for a wide range of intracellular bacteria and parasites. What are the effects of these ectopic B-cell aggregates upon Enhanced susceptibility of B-cell-deficient mice to infections with immunity to M. tuberculosis? It has been hypothesized that these Chlamydia trachomatis, Francisella tularensis, Leishmania major, follicle-like structures function to perpetuate local host responses, Plasmodium chabaudi chabaudi, Pneumocystis carinii, and Salmo- with the majority of proliferative activity occurring in the proxi- nella enterica serovar Typhimurium have all been reported mity of B-cell aggregates [61]. T cells can be scattered throughout [46–52], demonstrating that B lymphocytes mediate optimal these B-cell clusters [62], making these potential sites of both immunity against many intracellular pathogens in addition to antigen-presentation and B-cell maturation. It is also notable that viruses. these B-cell aggregates are components of tertiary lymphoid Studies of M. tuberculosis infection in B-cell-deficient mice tissue within TB lungs [70], containing markers of germinal have been variable, with reports of immunity being diminished, centers [54]. Further suggesting that B cells foster localized pathologic progression being delayed, or no apparent effects from architecture of the immune response, we noted that B-cell-defi- the genetic ablation of B cells [10, 11, 53–55]. This broad range cient mice had exacerbated pulmonary pathology and disruption of results emphasizes the limitations and variances inherent to of granulomatous organization in the lungs [54]. Much remains mouse models of infectious disease, particularly TB. Single to be understood regarding the significance of lymphoid knockout studies in M. tuberculosis-infected mice may yield neogenesis in TB, but it has been demonstrated that these indu- results, whose interpretations are not straightforward because of cible lymphoid structures can prime protective immunity in the functionally overlapping immune components [56, 57], may not lungs and memory responses against pulmonary influenza account for potential host response differences between mice and virus challenge in the absence of secondary lymphoid organs humans [58], and do not provide any information regarding the [66, 71]. 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 T-cell activation is strongly influenced by B cells component of immunity, if not interpreted thoroughly. Addi- tionally, experimental conditions can have marked effects on B cells are professional antigen-presenting cells with notable impact results. For example, increasing the infection inoculum exposed a upon T-cell responses. By capturing antigens via cell-surface requirement for B cells in the optimal TB host response in mice receptors, B lymphocyte activation is initiated. Subsequent progres- [53, 54]. Supporting a role for B cells in host immune response to sion through cellular interactions with CD41 helper T cells includes M. tuberculosis, genetic ablation of the polymeric Ig receptor antigen-presentation events, which stimulate T cells to produce the heightened susceptibility of mice, implicating a role for secretory cytokines that reciprocally regulate the antibody responses of B cells IgA within optimal TB immunity [59]. Finally, protective effects [72]. Though the significance of B-cell-mediated antigen-presenta- of intravenous Ig (IVIG) suggest further impact of humoral tion varies with antigen and immunological conditions [73], these components upon host defense in TB [60]. Though the results of lymphocytes can be targeted to present antigen to T cells by specific certain knockout mouse studies and the IVIG experiment indicate vaccination strategies [74, 75]. In fact, one such B-cell-targeting that B cells and their products mediate protection against vaccine vector has been effective in boosting BCG primed immunity M. tuberculosis, the important question that remains is whether against M. tuberculosis [76]. In a recently published example, the B-cell responses can be augmented to improve immunity against presence of B cells, but not specific antibody, protected against M. tuberculosis through immunotherapy or vaccination. 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 Ectopic B-cell aggregates as a consequence of chronic against the intracellular bacterial pathogen F. tularensis has also inflammation and infection been reported [78]. Furthermore, activated B cells serving as antigen-presenting cells have been utilized to enhance anti-tumor Our renewed interest in B lymphocytes emerged from observa- immunity [79]. It has also been noted that antigen-presentation by tions of follicle-like B-cell aggregates in the lungs of TB patients B cells can help perpetuate autoimmunity [80], whereas resting B [61, 62]. These B-cell aggregates are the predominant foci of cells are thought to mediate immune tolerance [81, 82]. By studying cellular proliferation in human TB lungs [61], and are character- B cells as targets for immune augmentation as well as in the istics of TB granulomatous progression in mice [11, 62, 63]. suppression of autoimmunity [83], future research will likely expose B-cell aggregates are noted pathological findings of many chronic creative means of targeting this often over-looked pathway of inflammatory diseases, including multiple sclerosis and rheuma- antigen-presentation. Finally, accumulating evidence suggests that toid arthritis [64, 65]. Similar B-cell clusters have been observed B cells are required to prime memory T-cell responses [52, 84], in other infections, such as with influenza virus and Helicobacter placing the B- and T-cell relationship in particularly relevant context [66, 67]. Certain pathogens have evolved means of promoting to vaccine biology.

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B cells can also act upon other antigen-presenting cells, was also dependent upon functional stimulatory Fcg receptors thus influencing the evolution of T-cell responses in a more [113], further implicating the stimulatory Fcg receptors in indirect manner. T cells are stimulated to clonally expand by cellular host defense against intracellular pathogens. We have antigen-presenting cells that concurrently express co-stimulatory found that disruption of stimulatory Fcg receptor activity molecules on their surface while presenting antigen [85]. This heightens susceptibility to M. tuberculosis Erdman, corresponding illustrates the two-signal hypothesis for T-cell activation in which with compromised bacterial containment and worsened immu- engagement of both the antigen receptor and CD28 on the nopathology [114]. Conversely, genetic deletion of inhibitory surface of T cells is required to initiate adaptive immune FcgRIIB improves mycobacterial containment, with increases in responses, with lymphocyte tolerance a consequence of an absent IFN-g production and Th1 polarization detected in the lungs second signal [86]. Antigen-presenting cells up-regulate surface [114]. Efforts are underway to study how these apparent effects expression of co-stimulatory proteins, such as those of the B7 of Fcg receptors can be harnessed to improve immunity against family, during a maturation process that follows the activation of M. tuberculosis. innate immunity [17]. These co-stimulatory molecules then These immune-enhancing effects from specific targeting of interact with CD28 or other co-receptors to promote activation of Fcg receptors may provide mechanisms of improving vaccine- T cells [87]. B cells can modulate this maturation process through induced immunity against intracellular pathogens [99, 105]. For the production of antibodies and cytokines, which can either example, viral vectors can be targeted to Fcg receptor-bearing enhance or suppress immune responses [88–93]. B cells have cells through antibody-dependent infection enhancement [115], been reported to polarize T-cell responses through the production providing a means by which antigen-presenting cells can poten- of cytokines [94], and the provision of IL-10 is thought to be a tially be manipulated for activation and immunization. Interest- means by which B cells can promote Th2 differentiation in mice ingly, a P. falciparum merozoite surface antigen has been [95]. Additionally, natural antibodies can modulate antigen- identified that preferentially induces isotype class-switching to presentation by binding to and altering the activity of the co- IgG2b in mice [116], a cytophilic Ig subtype with preferential stimulatory molecules B7 and CD40 [41, 96, 97]. affinity for stimulatory Fcg receptors [104]. Future research Much has been uncovered regarding antibody regulation of should further expose how Fcg receptors can be targeted and antigen-presentation through Fcg receptors [98], and this utilized to enhance immunity against intracellular pathogens. immunological pathway has garnered interest as a potential means of improving vaccination against intracellular pathogens [99]. Fcg receptors are divided into stimulatory and inhibitory Are antibodies protective against M. tuberculosis,an types based on the presence of intracellular ITAM or ITIM motifs, intracellular pathogen? respectively [100, 101]. FcgRIIB, the lone inhibitory Fcg receptor, has an intricate involvement in T-cell activation by limiting Contrary to the generally accepted notion that humoral immunity dendritic cell maturation and subsequent antigen-presentation, is insignificant in protection against the tubercle bacillus, passive whereas the stimulatory Fcg receptors appear to promote both administration of antibodies had reported efficacy against processes [89, 90]. FcgRIIB also plays a significant role in M. tuberculosis since the late nineteenth century [2]. However, mediating peripheral tolerance of T-cell responses in murine serum therapy for TB fell out of favor when efficacy of treatment autoimmunity models [102]. Furthermore, selective blockade of and reagent preparations were found to be inconsistent [117], FcgRIIB leads to enhanced T-cell activity in experimental tumor and the advent of pharmacologic anti-mycobacterials, such as models [89–91]. Stimulatory Fcg receptors appear to promote streptomycin, by the middle of the twentieth century, offered a T-cell responses, the polarization of which is shaped by the far more reliable option [118]. Excellent reviews exist regarding prevailing inflammatory context and can be either Th1 or Th2 the history and recent developments of antibody-mediated dominated [103]. Fcg receptor engagement can be strongly immunity to M. tuberculosis [2, 119]. Recently, mAb against influenced by antibody isotype [104], and immunization methods mycobacterial arabinomannan, heparin-binding hemagglutinin that preferentially target stimulatory Fcg receptors have the and 16 kDa a-crystallin have all demonstrated efficacy in mouse potential effects of enhancing cellular immunity against intra- models of TB [120–124]. These antibodies mediate protection in cellular pathogens [99, 105]. Interestingly, it has been reported different manners, some by diminishing tissue mycobacterial that FcgRIII mediates immune suppressive effects in an IVIG burden while others enhance animal survival through apparent model, illustrating that association with an ITAM motif may not decreases in inflammatory progression [119]. Notable, however, restrict function to pro-inflammatory activity [106]. is the fact that an M. tuberculosis arabinomannan–protein Genetic disruption of Fcg receptor function in mice has conjugate vaccine has been reported to induce more robust implicated a role for these receptors in microbial infection [107]. antibody responses than BCG, but without an apparent survival In particular, specific ablation of the shared stimulatory Fcg-chain improvement in mice [125]. The question remains as to whether compromises optimal immunity against a variety of intracellular the mouse is an optimal modality to measure enhanced pathogens, including influenza virus, Leishmania species, protection, given the chronically inflammatory and persistent Plasmodium berghei, and S. enterica [49, 108–112]. Passive infectious burden of the model and limited correlations of the immunization against Cryptococcus neoformans with IgG1 mAb pathology with that of human disease. Thus, future studies are

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required to unravel antibody correlates of protection in humans in TB infection. B cells can conceivably shape anti-tuberculous and animal models if effectively protective immunization- immunity through a variety of means, including direct effects of induced B-cell responses against M. tuberculosis are to be antibody upon the pathogen, antigen-presentation, cytokine generated. Finally, it is noteworthy that virtually nothing is production, as well as influencing the intracellular killing known of the impact of innate or natural antibody responses mechanisms of leukocytes. [126–128] upon mycobacterial infection. Given that complex As addressed earlier, T-cell activation is achieved through lipids are major constituents of the hydrophobic cell wall of antigen-presentation by specialized cells that must undergo a mycobacteria, it would be interesting to examine the significance maturation process in order to serve this function [17]. We of T-independent antibody responses, most notably of B1 and previously described how B cells can have a significant impact marginal zone B cells, in the defense against M. tuberculosis. upon antigen-presenting cell maturation through the engagement Looking beyond antigen-specific neutralization, antibodies of Fcg receptors by antibodies. Using mice deficient in inhibitory also have notable general effects upon inflammation, including FcgRIIB receptor function, we found that the absence of FcgRIIB complement activation, Fcg receptor cross-linking, and release of enhanced containment of M. tuberculosis Erdman in mice [114]. microbial products due to direct anti-microbial activity [45]. With Pulmonary IFN-g production and Th1 cell frequency were regards to pulmonary host responses, antibodies can modulate correspondingly increased in FcgRIIB-deficient mice. Conversely, architectural changes in airway epithelium and vessels, as in genetic ablation of the common g-chain shared among stimula- response to mycoplasma infection [129]. In our own studies, we tory Fcg receptors impaired M. tuberculosis containment and found that adoptive transfer of B cells resolved the inflammatory worsened overall survival [110]. Thus, B cells can significantly exacerbation in B-cell-deficient mice upon airborne challenge impact host immunity and disease outcome by engagement of Fcg with M. tuberculosis Erdman [54]. Suggesting a role of Ig-medi- receptors during TB, influencing both Th1 activation and myco- ated ‘‘endocrine’’ immune regulation, this reduction in pathology bacterial containment. occurred in conjunction with detectable levels of antibodies in the Murine studies of M. tuberculosis infection also indicate that serum but without the presence of B cells locally within lungs B cells have a significant impact upon the production of IL-10 in [54]. It is quite apparent that antibodies can have a variety of the lungs. IL-10 is produced by a broad range of leukocytes, protective effects during infection with intracellular pathogens, including B cells, dendritic cells, macrophages, and T cells, which includes limiting inflammatory pathology [130] in addi- imparting mostly anti-inflammatory functions upon host tion to well-established roles in neutralizing and opsonizing responses [133]. Heightened production of IL-10 in the lungs microbes. 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-Fcg-chain- How B cells shape the immune response against deficient mice infected with M. tuberculosis Erdman [114]. M. tuberculosis The cellular source of this IL-10 increase is unclear as intracellular cytokine-staining techniques to detect IL-10 are not The correlates of vaccine-mediated protection against optimally sensitive for detecting significant quantities of these M. tuberculosis are incompletely defined, but most evidence cells in mice. The recent development of IL-10 reporter mice may suggests that T cells are of paramount importance [7]. Conse- facilitate such studies in the future [135, 136]. IL-10 production quently, the aim of all the novel TB vaccines currently in is a characteristic of incompletely activated dendritic cells that development is to enhance cellular immune responses against the have not undergone complete maturation [137]. Thus, by influ- pathogen [131]. As reminded by recent failure in a clinical trial of encing cellular activation via immune complex engagement of a T-cell vaccine against HIV [132], it is prudent not to limit Fcg receptors, B cells may influence the production of IL-10 by vaccine research too narrowly. It is quite likely that protective these antigen-presenting cells. It has also been reported that B antibody responses will be required for optimally successful cells can activate or inhibit regulatory T cells, a significant immunization against M. tuberculosis in the future [44], and cellular source of IL-10 [138, 139]. Finally, the increase in IL-10 further research designed to uncover how humoral immunity can may be in reaction to the exacerbated immunopathology induced best be harnessed to mediate this protection seems warranted. In during M. tuberculosis infection of B cell/ and Fcg-chain/ this direction, efforts to understand B-cell biology and its mice [54], as the production of anti-inflammatory cytokines, such relationship with TB have demonstrated that these often over- as IL-10, may be a compensatory attempt to limit excessive looked lymphocytes can significantly influence cytokine produc- inflammation. More work is needed to assess the relationship of B tion, bacillary containment, and immunopathologic progression cells and cytokines during TB, particularly given that B cells during M. tuberculosis infection. As one possible mechanism by themselves can be a source of the vital anti-mycobacterial cyto- which B cells shape the immune response, we hypothesize that Ig, kine IFN-g [94]. acting upon Fcg receptors, influences antigen-presenting cell As also described previously in this article, B cells are maturation to produce the noted phenotypes of gene-deficient prominent components of TB pulmonary granulomatous inflam- mice challenged with M. tuberculosis (Fig. 1). However, this is but mation, with large aggregates of these lymphocytes as prominent one pathway by which B lymphocytes modulate the host response histological characteristics of the infection [61–63]. The absence

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Response to Acute Infection: Stimulatory • Diminished mycobacterial burden Fcγ receptors • Infection containment likely requires recruitment IFN-γ of fewer immune cells resulting in less pathology B cell Response During Chronic Infection: Effector T cells • Perpetuation of inflammatory response may lead to greater immunopathology over time antigen presenting cell

Inhibitory Response to Acute Infection: FcγRIIB receptor • Infection containment likely requires recruitment of more immune cells resulting in more pathology IL-10

B cell Response During Chronic Infection: Effector T cells • Increased mycobacterial burden • Diminished survival antigen presenting cell

Response to Acute Infection: • Increased mycobacterial burden in higher dose models IL-10 • Dysregulation of the graunulomatous reaction. Infection containment requires recruitment of more Absence of B cells immune cells resulting in more pathology Effector T cells Response During Chronic Infection: antigen presenting cell • Decreased perpetuation of inflammatory response leads to less immunopathology than wildtype mice with B cells

Figure 1. Schematic of how B cells shape the immune response against M. tuberculosis. B cells modulate the murine host response against M. tuberculosis in a variety of ways. Upon acute infection, selective engagement of stimulatory Fcg receptors by antibody complexes heightens the Th1 response and promotes mycobacterial containment with minimal inﬂammation. Conversely, engagement of inhibitory FcgRIIB increases IL-10 production and compromises immunity against M. tuberculosis. Interestingly, an immunosuppressive phenotype in the absence of B cells subverts optimal containment of acute M. tuberculosis challenge initially, but delays inﬂammatory progression during chronic TB.

of B cells, while compromising optimal immunity leading to culous lung tissues ([62], P. Maglione and J. Chan, unpublished). exacerbated pulmonary pathology upon acute M. tuberculosis In this regard, antigen uptake may occur in a specific manner via infection [54], leads paradoxically to a delay in inflammatory the BCR, though it has been shown that B cells can load MHC progression during chronic infection in mice [55]. One possible with peptide not in line with their receptor specificity [140]. Such explanation for this paradox is that B-cell function during the ‘‘non-specific’’ antigens could be the result of Toll-like receptor course of TB is infection phase-specific: During acute infection, uptake [141]. Thus, the inflammatory paradox of B-cell-deficient B cells are required for an optimal granulomatous response mice seems to reflect the role of B cells shifting from optimizing and effective immunity against pulmonary challenge with host defense during acute challenge to perpetuating the chronic M. tuberculosis, and in their absence, dysregulation of granuloma inflammatory response during persistent infection. formation results and increased pulmonary inflammation is TB morbidity and mortality results from an aberrant and required to contain infection. In contrast, during chronic phase of damaging host response [142, 143]: one that is both excessive in infection when persistent bacilli are contained, the immunologi- pathologic consequence yet ineffective in containing the patho- cally active B-cell clusters [54, 61, 62] likely promote the gen. This apparent paradox may be viewed as a product of perpetuation of local host immunity against M. tuberculosis and ineffective immune containment of the tubercle bacillus leading may aid in prevention of reactivation disease. This perpetuation to excessive compensatory recruitment of leukocytes within the of inflammation may occur in part through B cells acting as lungs. This is best evidenced in patients with reactivation TB. antigen-presenting cells. Indeed, T cells have been observed to be Rather than being devoid of immune activity, which could associated with B-cell nodules in both human and mouse tuber- explain the re-emergence of a dormant pathogen, the lungs of

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patients with reactivation diseases contain areas of intense help design better treatments and develop effective vaccines. pulmonary infiltrate [143]. Prior to treatment, active TB Despite decades long perceptions of B-cell futility toward pulmonary infiltrate is dominated by neutrophils [61], an innate M. tuberculosis infection, recent data suggest that this powerful immune cell that aids in early protection but promotes inflam- arm of immunity should not be over-looked. matory 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 need Acknowledgements: This work was supported by National not have significant immunopathology as a by-product. Existing Institutes of Health Grants R01 HL071241, R01 AI50732, P01 data strongly suggest that B cells play a role in modulating the AI063537, and Albert Einstein College of Medicine/Montefiore inflammatory response during TB infection [54, 55]. 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.). Concluding remarks Conflict of interest: The authors declare no financial or Even if host bacillary containment succeeds without symptoms of commercial conflict of interest. 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 References in those with successful disease-preventing immunity, it is clear that a vaccine that prevents TB must invoke an immune response 1 Kumararatne, D. 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