Do B-cell Subsets Play a Role in the Pathogenesis of Tuberculosis

Mycobacterium tuberculosis (M. tb) is a significant global health threat, responsible for approximately 1.6 million deaths annually.[1–6] Over the past four decades, research has predominantly focused on the role of T-cells in M. tb infections. As an airborne pathogen, M. tb primarily targets the lungs, with pulmonary involvement occurring in about 70%–90% of cases.[1,4,7,8] In some instances, the bacteria can become isolated within granulomas, leading to what is referred to as latent tuberculosis (LTB), where individuals are infected but do not display symptoms of active tuberculosis (ATB).[5,7–9] Both CD4+ and CD8+ T-cells are crucial for controlling M. tb infections. Research highlights the protective role of CD8+ T-cells, while CD4+ T-cells are instrumental in immune surveillance and the activation of other immune components.[10–17] Despite this understanding, the role of B-cells in tuberculosis pathogenesis remains poorly defined and often contradictory. While B-cells can reduce the lifespan of various intracellular pathogens, studies on tuberculosis indicate that B-cells may either provide protection,[18–23] be detrimental,[24] or have no significant effect during infection. This inconsistency may arise from the different experimental models and M. tb strains examined. B-cells contribute to immune responses by attracting and activating other immune cells through antigen presentation and cytokine secretion. Although the impact of B-cells on M. tb burden varies, they consistently influence a range of immune responses associated with tuberculosis across different species, from mice to nonhuman primate models.[18,22,25,26] Evidence suggests that B-cells play a significant regulatory role in immune responses during tuberculosis, as recent studies have identified unique humoral signatures and specific antibody (Ab) functionalities in individuals with ATB compared to those with LTB. Furthermore, M. tb-specific Abs produced locally in the lungs may contribute to granuloma formation, a process previously thought to depend solely on macrophages and T-cells. Within granulomas, B-cells produce CXCL13, which recruits CXCR5+ T-cells, facilitating the creation of follicle-like structures essential for granuloma maintenance. The limited protection against tuberculosis indicates that while Th1 cytokines and innate immune responses are beneficial, additional factors must be involved in tuberculosis immunity.[27] Research on B-cells and Ab production has been limited due to the prevailing belief that tuberculosis is primarily a cell-mediated immune response, dominated by T-cells and macrophages.[28,29] Given that M. tb is an intracellular pathogen capable of surviving within host cells, it was assumed that the humoral immunity provided by B-cell-mediated Abs was inadequate for targeting these bacteria.[29] However, recent findings suggest that B-cells may have a more critical role in tuberculosis defense than previously acknowledged. B-lymphocytes can differentiate into plasma cells to produce Abs,[30] which may neutralize pathogens and induce Ab-dependent cellular cytotoxicity. In addition, secreted Abs can activate the complement system, enhancing bacterial phagocytosis and the apoptosis of infected host cells.[31] Certain B-cells, known as memory B-cells, exhibit long-lived characteristics and respond rapidly to previously encountered pathogens.[32,33] Individuals with LTB and ATB exhibit distinct humoral signatures, including unique Ab functionalities and glycosylation patterns.[34] Notably, Abs from LTB patients have been associated with enhanced phagolysosome maturation and improved macrophage killing of M. tb. These findings underscore the importance of understanding humoral immunity in tuberculosis, potentially leading to novel therapeutic strategies. In summary, B-cells play a vital role in the immune response against tuberculosis. Further investigation is necessary to explore the efficacy of targeting specific B-cell subsets for the prevention or mitigation of M. tb infections. Although the role of B-cells in tuberculosis immunity has been a subject of debate, emerging evidence suggests they could be crucial in granuloma formation and local immune responses, paving the way for targeted immunotherapies. Continued research is essential to validate these findings across various models.