Friend or Foe: The Protective and Pathological Roles of Inducible Bronchus-Associated Lymphoid Tissue in Pulmonary Diseases

Marín, Nancy D.; Dunlap, Micah; Kaushal, Deepak; Khader, Shabaana A.

doi:10.4049/jimmunol.1801135

Cited by 53 publications

(58 citation statements)

References 79 publications

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“…However, CD69 + CD4 + T cell levels, a marker of early activation in response to M. tuberculosis antigen (21, 30), were higher in BAL samples from the ART-treated group compared with levels detected in the ART-naive and LTBI groups. (iBALT) is known to contribute to protection against M. tuberculosis and prevent reactivation of latent TB (34). These iBALT structures that formed in the lungs of M. tuberculosis-infected macaques provide an environment for B cell maturation and antigen-specific memory effector T cells within the tissue (35).…”

Section: Resultsmentioning

confidence: 99%

Antiretroviral therapy does not reduce tuberculosis reactivation in a tuberculosis-HIV coinfection model

Ganatra¹,

Bucşan²,

Álvarez³

et al. 2020

Journal of Clinical Investigation

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While the advent of combination antiretroviral therapy (ART) has significantly improved survival, tuberculosis (TB) remains the leading cause of death in the HIV-infected population. We used Mycobacterium tuberculosis/simian immunodeficiency virus-coinfected (M. tuberculosis/SIV-coinfected) macaques to model M. tuberculosis/HIV coinfection and study the impact of ART on TB reactivation due to HIV infection. Although ART significantly reduced viral loads and increased CD4 + T cell counts in blood and bronchoalveolar lavage (BAL) samples, it did not reduce the relative risk of SIV-induced TB reactivation in ART-treated macaques in the early phase of treatment. CD4 + T cells were poorly restored specifically in the lung interstitium, despite their significant restoration in the alveolar compartment of the lung as well as in the periphery. IDO1 induction in myeloid cells in the inducible bronchus-associated lymphoid tissue (iBALT) likely contributed to dysregulated T cell homing and impaired lung immunity. Thus, although ART was indispensable for controlling viral replication, restoring CD4 + T cells, and preventing opportunistic infection, it appeared inadequate in reversing the clinical signs of TB reactivation during the relatively short duration of ART administered in this study. This finding warrants the modeling of concurrent treatment of TB and HIV to potentially reduce the risk of reactivation of TB due to HIV to inform treatment strategies in patients with M. tuberculosis/HIV coinfection.

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Section: Resultsmentioning

confidence: 99%

Antiretroviral therapy does not reduce tuberculosis reactivation in a tuberculosis-HIV coinfection model

Ganatra¹,

Bucşan²,

Álvarez³

et al. 2020

Journal of Clinical Investigation

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“…Together with the data presented here our observations in H37Rv-infected C57BL/6 mice point to an impaired formation of ELS in the male lung. These structures likely contribute significantly to the host response to Mtb as they orchestrate the local host defense and enable highly efficient interaction among the various immune cells such as DCs, macrophages and T cells present in the granulomatous tissues 13,[16][17][18]25 . The B cell chemoattractant CXCL13 is strongly associated with lymphoid neogenesis and orchestrates the homing of CXCR5 expressing lymphocytes to the follicular areas 17,18,26,27 .…”

Section: Discussionmentioning

confidence: 99%

Increased male susceptibility to Mycobacterium tuberculosis infection is associated with smaller B cell follicles in the lungs

Hertz

Dibbern

Eggers

et al. 2020

Sci Rep

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Tuberculosis prevalence is significantly higher among men than women. We have previously revealed an increased susceptibility of male C57BL/6 mice towards Mycobacterium tuberculosis (Mtb) H37Rv. In the current study, we confirm the male bias for infection with the Beijing strain HN878. Males succumbed to HN878 infection significantly earlier than females. In both models, premature death of males was associated with smaller B cell follicles in the lungs. Analysis of homeostatic chemokines and their receptors revealed differences between H37Rv and HN878 infected animals, indicating different immune requirements for follicle formation in both models. However, expression of IL-23, which is involved in long-term containment of Mtb and lymphoid follicle formation, was reduced in male compared to female lungs in both models. Our study reveals sex differences in the formation of B cell follicles in the Mtb infected lung and we propose that impaired follicle formation is responsible for accelerated disease progression in males.Tuberculosis (TB) is the most prevalent bacterial infectious disease in humans. The causative agent, Mycobacterium tuberculosis (Mtb), is carried by an estimated 2-3 billion people globally and claims approximately 1.5 million lives each year 1 . The global TB pandemic is characterized by significant differences in prevalence between men and women, reflected by a male-to-female ratio for worldwide case notifications of 1.8 1 . Both gender-and sex-related factors likely contribute to higher TB rates in men, but the role of the latter has been largely ignored 2-5 .We have previously shown an increased susceptibility for male C57BL/6 mice to infection with the laboratory-adapted strain Mtb H37Rv 6 . Accelerated disease progression in males after low-dose aerosol infection resulted in increased morbidity and mortality compared to females. Likewise, a study in BALB/c mice revealed that males are more susceptible to H37Rv infection than females 7 . The fact that two of the most widely used TB mouse models do reflect the global male bias in humans emphasizes the need to include both sexes in basic research and pre-clinical studies.Our observations in H37Rv infected C57BL/6 mice pointed to an impaired formation of lymphoid aggregates in the male lung 6 . In the current study, we substantiate our previous observation and show that B cell follicles that form in the Mtb infected lung were much smaller in males compared to females. Moreover, expression of chemokines associated with the homing of lymphocytes to the infected lung such as CXCL13 and CCL19 was significantly lower in males compared to females, further indicating that B cell follicle formation in response to H37Rv infection is impaired in males.Mtb is a member of the Mtb complex (Mtbc), and Mtbc strains are more genetically diverse than was previously recognized 8 . Importantly, genetic diversity might contribute to clinical, pathogenic, and immunologic heterogeneity in disease progression and outcome. H37Rv was isolated in 1905 and is not a relevant...

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“…Leukocytes that infiltrate the lung have been shown to assemble into inducible bronchus-associated lymphoid tissue (iBALT) after inflammation or infection (45). Like conventional lymphoid organs, iBALT contains segregated B and T cell areas, specialized stromal cells, high endothelial venules, and lymphatic vessels (46).…”

Section: Discussionmentioning

confidence: 99%

Mycobacteria-Specific T Cells Are Generated in the Lung During Mucosal BCG Immunization or Infection With Mycobacterium tuberculosis

et al. 2020

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Specific T cell responses are central for protection against infection with M. tuberculosis. Here we show that mycobacteria-specific CD4 and CD8 T cells accumulated in the lung but not in the mediastinal lymph node (MLN) at different time points after M. tuberculosis infection or BCG immunization. Proliferating specific T cells were found in the lung after infection and immunization. Pulmonary, but not MLN-derived CD4 and CD8 T cells, from M. tuberculosis-infected mice secreted IFN-γ after stimulation with different mycobacterial peptides. Mycobacteria-specific resident memory CD4 and CD8 T cells (TRM) expressing PD-1 accumulated in the lung after aerosol infection and intratracheal (i.t.)-but not subcutaneous (s.c.)-BCG immunization. Chemical inhibition of recirculation indicated that TRM were generated in the lung after BCG i.t. immunization. In summary, mycobacteria specific-TRM accumulate in the lung during i.t. but not s.c. immunization or M. tuberculosis infection. Collectively our data suggests that priming, accumulation and/or expansion of specific T cells during BCG immunization and M. tuberculosis infection occurs in the lung.

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Friend or Foe: The Protective and Pathological Roles of Inducible Bronchus-Associated Lymphoid Tissue in Pulmonary Diseases

Cited by 53 publications

References 79 publications

Antiretroviral therapy does not reduce tuberculosis reactivation in a tuberculosis-HIV coinfection model

Antiretroviral therapy does not reduce tuberculosis reactivation in a tuberculosis-HIV coinfection model

Increased male susceptibility to Mycobacterium tuberculosis infection is associated with smaller B cell follicles in the lungs

Mycobacteria-Specific T Cells Are Generated in the Lung During Mucosal BCG Immunization or Infection With Mycobacterium tuberculosis

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