Alterations in the peripheral blood B cell subpopulations of multidrug-resistant tuberculosis patients

Abreu, Marconi; Carvalheiro, Helena; Rodrigues-Sousa, Tiago; Domingos, António; Segorbe-Luís, A.; Rodrigues-Santos, Paulo; Souto-Carneiro, Margarida

doi:10.1007/s10238-013-0258-1

Cited by 16 publications

(12 citation statements)

References 32 publications

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“…To identify MTB-reactive memory B cells among all circulating memory B cells, we focused our analysis on HBHA as representative MTB antigen and performed flow cytometry with fluorescently labeled HBHA to detect HBHA-reactive memory B cells in these donors compared with TB patients (Fig 2D and E). Although TB patients showed significantly reduced overall memory B-cell frequencies compared with HD, we identified individual TB patients and MTB-exposed HCW with anti-HBHA memory B-cell responses (Fig 2E and F;Abreu et al, 2014). To determine the somatic mutation levels and the isotype distribution in these cells, we amplified and sequenced the Ig genes of single HBHA-reactive memory B cells from four HCW and four TB patients with anti-HBHA serum titers ( Fig 2G).…”

Section: Embo Molecular Medicinementioning

confidence: 98%

Human isotype‐dependent inhibitory antibody responses against Mycobacterium tuberculosis

et al. 2016

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Accumulating evidence from experimental animal models suggests that antibodies play a protective role against tuberculosis (TB). However, little is known about the antibodies generated upon Mycobacterium tuberculosis (MTB) exposure in humans. Here, we performed a molecular and functional characterization of the human B‐cell response to MTB by generating recombinant monoclonal antibodies from single isolated B cells of untreated adult patients with acute pulmonary TB and from MTB‐exposed healthcare workers. The data suggest that the acute plasmablast response to MTB originates from reactivated memory B cells and indicates a mucosal origin. Through functional analyses, we identified MTB inhibitory antibodies against mycobacterial antigens including virulence factors that play important roles in host cell infection. The inhibitory activity of anti‐MTB antibodies was directly linked to their isotype. Monoclonal as well as purified serum IgA antibodies showed MTB blocking activity independently of Fc alpha receptor expression, whereas IgG antibodies promoted the host cell infection. Together, the data provide molecular insights into the human antibody response to MTB and may thereby facilitate the design of protective vaccination strategies.

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Section: Embo Molecular Medicinementioning

confidence: 98%

Human isotype‐dependent inhibitory antibody responses against Mycobacterium tuberculosis

et al. 2016

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“…In addition, depletion of B cells in a non-human primate model of M. tuberculosis infection resulted in increased lesional bacterial burden 157 . Furthermore, in patients with active TB, B cell function is initially abnormal but returns to normal after successful treatment 158,159 . These observations highlight the immunoregulatory role of B cells in controlling M. tuberculosis infections, which extends beyond their direct antibody-mediated effector functions (FIG.…”

Section: B Cell-mediated Resistancementioning

confidence: 99%

Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection

et al. 2018

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Mycobacterium tuberculosis is a leading cause of mortality worldwide and establishes a long-lived latent infection in a substantial proportion of the human population. Multiple lines of evidence suggest that some individuals are resistant to latent M. tuberculosis infection despite long-term and intense exposure, and we term these individuals 'resisters'. In this Review, we discuss the epidemiological and genetic data that support the existence of resisters and propose criteria to optimally define and characterize the resister phenotype. We review recent insights into the immune mechanisms of M. tuberculosis clearance, including responses mediated by macrophages, T cells and B cells. Understanding the cellular mechanisms that underlie resistance to M. tuberculosis infection may reveal immune correlates of protection that could be utilized for improved diagnostics, vaccine development and novel host-directed therapeutic strategies.

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“…In addition, compared to healthy donors, LTBI individuals have been reported to have decreased B-cell frequencies [ 10 ], whereas those successfully treated for TB had increased B-cell frequencies [ 8 ]. In addition, patients with multi-drug resistant (MDR) TB were reported to have decreased frequencies of unswitched, IgD + CD27 + B-cells and decreased plasma cell frequencies, which are frequently observed during chronic inflammation [ 12 ]. The results described so far are rather conflicting and highly descriptive, without any analyses of the functional capacities of the B-cells.…”

Section: Introductionmentioning

confidence: 99%

Patients with Tuberculosis Have a Dysfunctional Circulating B-Cell Compartment, Which Normalizes following Successful Treatment

Joosten

Meijgaarden

Nonno³

et al. 2016

PLoS Pathog

140

118

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B-cells not only produce immunoglobulins and present antigens to T-cells, but also additional key roles in the immune system. Current knowledge on the role of B-cells in infections caused by intracellular bacteria is fragmentary and contradictory. We therefore analysed the phenotypical and functional properties of B-cells during infection and disease caused by Mycobacterium tuberculosis (Mtb), the bacillus causing tuberculosis (TB), and included individuals with latent TB infection (LTBI), active TB, individuals treated successfully for TB, and healthy controls. Patients with active or treated TB disease had an increased proportion of antibodies reactive with mycobacteria. Patients with active TB had reduced circulating B-cell frequencies, whereas only minor increases in B-cells were detected in the lungs of individuals deceased from TB. Both active TB patients and individuals with LTBI had increased relative fractions of B-cells with an atypical phenotype. Importantly, these B-cells displayed impaired proliferation, immunoglobulin- and cytokine- production. These defects disappeared upon successful treatment. Moreover, T-cell activity was strongest in individuals successfully treated for TB, compared to active TB patients and LTBI subjects, and was dependent on the presence of functionally competent B-cells as shown by cellular depletion experiments. Thus, our results reveal that general B-cell function is impaired during active TB and LTBI, and that this B-cell dysfunction compromises cellular host immunity during Mtb infection. These new insights may provide novel strategies for correcting Mtb infection-induced immune dysfunction towards restored protective immunity.

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Alterations in the peripheral blood B cell subpopulations of multidrug-resistant tuberculosis patients

Cited by 16 publications

References 32 publications

Human isotype‐dependent inhibitory antibody responses against Mycobacterium tuberculosis

Human isotype‐dependent inhibitory antibody responses against Mycobacterium tuberculosis

Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection

Patients with Tuberculosis Have a Dysfunctional Circulating B-Cell Compartment, Which Normalizes following Successful Treatment

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