Antibodies and Tuberculosis: Finally Coming of Age?
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PERSPECTIVES clusters that express proliferation-associated OPINION markers and secrete M. tuberculosis- specific antibodies14. However, depletion of B cells Antibodies and tuberculosis: using the therapeutic monoclonal antibody rituximab resulted in highly heterogeneous effects in local granuloma immune finally coming of age? modulation, perhaps owing to the variety of antibody and non-antibody Hao Li and Babak Javid functions of B cells, but had no effect on disease outcome15. Abstract | Are antibodies important for protection against tuberculosis? The jury While these studies did not by has been out for more than 100 years. B cell depletion in experimental themselves prove a lack of B cell or Mycobacterium tuberculosis infection failed to identify a major role for these cells antibody involvement in immunity to in immunity to tuberculosis. However, recent identification of naturally occurring M. tuberculosis, they did cast doubt on antibodies in humans that are protective during M. tuberculosis infection has the potential importance of B cells and reignited the debate. Here, we discuss the evidence for a protective role for antibodies in animal models of TB infection. In parallel, however, studies using antibodies antibodies in tuberculosis and consider the feasibility of designing novel in passive immunization suggested that tuberculosis vaccines targeting humoral immunity. certain antibodies are protective against TB. Administration of monoclonal antibodies The role of humoral immunity in vaccine strategy in TB and discuss the key raised against M. tuberculosis antigens or tuberculosis (TB) is controversial. Almost all questions that still need to be addressed in pooled mouse or human immunoglobulins clinical and preclinical vaccine candidates this field. could ameliorate disease in animal models for TB that are in development target in most16–23, although not all24, cases. Perhaps cell-mediated immunity1. As an intracellular Antibodies in tuberculosis owing to caution in interpretation of some pathogen, it has been assumed that Why is antibody-mediated immunity of the data — antibodies mixed with Mycobacterium tuberculosis, which is the controversial? Koch’s 1882 discovery of M. tuberculosis in vitro before infection, causative agent of TB, would be inaccessible M. tuberculosis as the causative agent of TB as in some of the experiments, might have to circulating antibodies; however, cells stimulated an interest in specific therapies, induced clumping and exaggerated the infected with M. tuberculosis would be including serum therapy, which had shown degree of offered protection — there was vulnerable to killing by the effector arm considerable success in the treatment of greater enthusiasm for the development of the cell-mediated immune response. other infectious diseases (reviewed in REF.8). of recombinant vaccines that elicited Several publications have stimulated However, dozens of studies using serum potent cell- mediated immune responses a re- evaluation of the contribution of therapy in TB showed highly variable in animal models. antibody- mediated immunity to protection results, partly owing to differences in against M. tuberculosis2–5, but a number antigens, antibody titres in serum and host Antibodies back in vogue. In 2013, the first of important questions remain. Why has animals (reviewed in REF.9). As such, late- stage clinical trial in the modern era antibody- mediated immunity been largely interest in serum therapy waned rapidly for a new vaccine against TB was reported; overlooked for vaccine development? and came to a halt following the more disappointingly, it showed no efficacy over Which approaches led to the recent series promising discoveries of the BCG and above routine BCG immunization25. of high- profile papers re- examining the vaccine strain and streptomycin, the first The vaccine, known as MVA85A, delivered role of antibodies in human immunity to anti- tubercular antibiotic. a recombinant immunodominant epitope, TB? How do antibodies offer protection There was also increasing evidence for antigen 85A, via modified vaccinia Ankara against M. tuberculosis? As the only licensed the importance of cell-mediated responses virus. MVA85A performed as engineered: vaccine for TB, bacillus Calmette–Guerin in protection against TB. Mice lacking key it elicited a potent response of CD4+ T cells (Mycobacterium bovis- BCG or BCG) elements of cell-mediated immunity, such secreting IFNγ25,26. Therefore, its failure offers highly variable protection against as IFNγ, tumour necrosis factor (TNF) or (though unsurprising27 to some) led to TB6 and almost no protection against the T cells, and patients with HIV are highly a re- evaluation of what may constitute a transmissible form of the disease, there is an susceptible to TB10,11. This contrasted with protective immune response against urgent need for a new TB vaccine if we are the relatively modest disease phenotypes M. tuberculosis. Some questioned whether to interrupt the current TB emergency; in seen when mice lacking B cells were infected IFNγ- secreting CD4+ T cells were the key 2016 M. tuberculosis claimed more lives than with M. tuberculosis12,13. It was shown to cell- mediated immunity28, and there was any other single pathogen7. In this Opinion in experimentally infected cynomolgus also renewed interest in the potential role, piece, we consider whether antibody-based macaques that M. tuberculosis- containing if any, of antibody-mediated immunity in vaccines could show promise as a new granulomata are surrounded by B cell M. tuberculosis infection. NATURE REVIEWS | IMMUNOLOGY VOLUME 18 | SEPTEMBER 2018 | 591 PERSPECTIVES Important lessons had been learnt in were infected with M. tuberculosis, HEBUI) with no evidence of prior infection the interim. The focus shifted to studying antibodies from the individuals with LTBI by M. tuberculosis may represent human naturally elicited human antibody responses. were better at restricting intracellular ‘restrictors’ that can control M. tuberculosis It was also clear from the renaissance in growth of the pathogen than antibodies infection — although an alternative broadly neutralizing antibodies in the HIV from patients with active TB4. explanation might be that current tests for field that not all HIV-infected individuals Our own group and the groups of LTBI merely fail to identify the mediators made these protective antibody responses29. Kaufmann and Wardemann chose to of immune exposure in these individuals33. As such, pooling antibodies from multiple compare antibody responses between By contrast, no patients with active TB made donors might drown out signals of patients with active TB and health-care protective antibody responses3. Intriguingly, protection within the noise of the majority workers (HCWs) who had potential M. tuberculosis growth restriction owing of donors that did not make protective occupational exposure to M. tuberculosis3,5. to antibodies from protective donors was responses. Below, we focus on four Zimmermann et al. identified M. tuberculosis- completely abrogated both in vivo and key papers published since 2016 that specific antibody responses in both patients in vitro in the absence of CD4+ T cells and applied these principles to advance with active TB and HCWs. Approximately required formation of immune complexes the field2–5. 40% of monoclonal antibodies isolated for full efficacy, suggesting that protection A low titre of antibodies against from the plasmablasts of these individuals was not due simply to neutralization of lipoarabinomannan (LAM), which is a recognized mycobacterial antigens, with M. tuberculosis by antibodies3. key glycolipid found on the surface of the majority of M. tuberculosis- specific Together, these studies revived interest Mycobacterium spp., had been associated antibodies targeting surface-exposed in humoral immunity to TB and suggested with disseminated TB in children30, antigens: either binding intact bacteria that subjects with high exposure to and passive immunization of mice with or surface antigens5. It was found that M. tuberculosis but without active TB monoclonal antibodies against the sugar 7 of 12 isolated immunoglobulin A (IgA) represent the ideal population in which to component of LAM, arabinomannan, had monoclonal antibodies but 0 of 16 isolated study and isolate protective antibodies. been demonstrated to be protective in IgG monoclonal antibodies were able to One further study deserves highlighting. mouse infection models19,21. Achkar restrict M. tuberculosis growth within the Unlike the preceding four studies, it focused and colleagues obtained serum from lung epithelial cell line A549. However, on BCG- elicited immunity in murine TB 30 healthy volunteers immunized with BCG, although HCWs had slightly higher titres of and did not involve human antibodies. which stimulates both cell-mediated and M. tuberculosis-specific IgA, both restrictive Casadevall and colleagues showed that when humoral immunity2. They demonstrated and ineffective M. tuberculosis- specific mice were immunized with BCG grown with that BCG elicited antibody responses monoclonal antibodies were isolated from an intact capsule, they were better able to against both arabinomannan and LAM and patients with active TB and the healthy resist subsequent infection with pathogenic that post- vaccination serum was able to HCWs. Therefore, it could not be inferred M. tuberculosis34. Importantly, encapsulated opsonize M. tuberculosis for phagocytosis from these studies how important