Editorial: Tuberculosis and humoral immunity

As a result, observations derived from the TB field are typically generalized to other areas of immunopathology and vaccinology. One of such generalization is the assumption that T cell responses (a very destructive weapon of the immune system) are the chief protective mechanism against intracellular bacteria. Thus, TB research has emphasized the role of cell-mediated immunity (CMI), particularly CD4+ and CD8+ T cells, in combating Mtb (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). However, vaccine candidates designed to promote class one T helper (TH1) cell responses have failed to control this infection (15)(16)(17), suggesting that other components of the immune system are essential for protection. Indeed, emerging evidence (18)(19)(20)(21)(22)(23)(24)(25)(26)(27), including our own findings (28)(29)(30), is reshaping this perspective by underscoring the critical contributions of humoral immunity in host defense against TB. This editorial synthesizes the current understanding of humoral immunity in TB, its potential to enhance diagnostics and vaccine strategies, and the interplay between cellular and humoral responses. Our aim was to provide a collection of selected manuscripts contributing to clarify the misconception that B cells and antibodies are ineffective against intracellular pathogens like Mtb, an assumption that has been challenged by recent studies demonstrating that humoral immunity is not only relevant but also potentially protective in TB.A provoking reflection necessary to challenge current dogmas in TB research is the idea of tissues as crucial orchestrators of the class of immune response deployed against invading microorganisms (31). As such, the lungs must determine the ultimate combination of effector mechanisms more suitable to ensure bacilli clearance while preserving the local architecture of the tissue. With this in mind, what is the benefit of evoking such a destructive stereotyped response like CMI within a local microenvironment so delicate to allow the vital function of gas exchange? Perhaps other immune components at the site of encounter with Mtb [including mucosal antibodies and B cells of bronchial-associated lymphoid tissue (BALT)] are better at controlling the infection while preserving the structure of the lungs due to their less harmful effects. B cells, for instance, can act as antigen-presenting cells, modulate T cell responses, and produce antibodies that neutralize Mtb or mediate effector functions. Notably, B-cell aggregates in Mtbinfected lungs have been correlated with reduced bacterial burden and improved outcomes of TB disease (20,23,30). Antibodies have been shown to enhance macrophage uptake and intracellular killing of Mtb via Fc receptor-mediated pathways (18,32). Furthermore, Mtb-specific IgA and IgG antibodies contribute to mucosal immunity and bacterial clearance in experimental models (33,34).The research highlighted in this special issue further emphasizes some of these ideas and provide proof-of-concept evidence. First, Flores-Gonzalez et al. demonstrated distinct alterations in B cell subsets and reduced cytokine production, such as IFN-γ and IL-10, in patients with active TB, particularly drug-resistant cases. These findings suggest that phenotypical alterations of B cells may serve as readouts of the failure of lung tissue-instructed defenses to eliminate Mtb. Also, in their review article, McIntyre et al. highlighted increasing evidence supporting the role of antibody-mediated immunity in TB, demonstrating that antibodies contribute to pathogen neutralization, promote phagocytosis, and mediate antibody-dependent cellular cytotoxicity (ADCC). These effector mechanisms of antibodies might be pivotal at the early stages of the disease when first contact with Mtb occurs. Especially during early childhood and adolescence, social factors like breastfeeding, undernutrition, hygiene, poverty, exposure to environment mycobacteria, and respiratory infection history might influence the repertoire of antibodies available in the respiratory tract. Thus, analyzing humoral immunity to TB in distinct age groups is of significant relevance, as here represented by studies on maternal and infant immunity by Hjelmar et al., which suggest that antibodies against Mtb antigens, such as lipoarabinomannan (LAM), may offer protection against disease progression during early childhood. Although significant progress has been made, the diversity of TB-specific antibodies presents challenges for As we continue to unravel the complexities of the immune response to TB, a more comprehensive approach that incorporates both cellular and humoral immunity will be essential. Such an approach not only broadens our understanding of TB pathogenesis but also paves the way for more effective vaccines and therapies, ultimately bringing us closer to the goal of TB eradication.