دورية أكاديمية
Distinctive antibody responses to Mycobacterium tuberculosis in pulmonary and brain infection.
| العنوان: | Distinctive antibody responses to Mycobacterium tuberculosis in pulmonary and brain infection. |
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| المؤلفون: | Spatola M; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA., Nziza N; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA., Irvine EB; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA., Cizmeci D; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA0 2139, USA., Jung W; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA0 2139, USA., Van LH; Oxford University Clinical Research Unit, Centre for Tropical Medicine, 700000 Ho Chi Minh City, Vietnam., Nhat LTH; Oxford University Clinical Research Unit, Centre for Tropical Medicine, 700000 Ho Chi Minh City, Vietnam., Ha VTN; Oxford University Clinical Research Unit, Centre for Tropical Medicine, 700000 Ho Chi Minh City, Vietnam., Phu NH; Oxford University Clinical Research Unit, Centre for Tropical Medicine, 700000 Ho Chi Minh City, Vietnam.; Vietnam National University School of Medicine, 700000 Ho Chi Minh City, Vietnam., Nghia HDT; Hospital for Tropical Diseases, 700000 Ho Chi Minh City, Vietnam.; Pham Ngoc Thach University of Medicine, 700000 Ho Chi Minh City, Vietnam., Thwaites G; Oxford University Clinical Research Unit, Centre for Tropical Medicine, 700000 Ho Chi Minh City, Vietnam.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7LG, UK., Lauffenburger DA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA0 2139, USA., Fortune S; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA., Thuong NTT; Oxford University Clinical Research Unit, Centre for Tropical Medicine, 700000 Ho Chi Minh City, Vietnam.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7LG, UK., Alter G; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA. |
| المصدر: | Brain : a journal of neurology [Brain] 2024 Mar 05. Date of Electronic Publication: 2024 Mar 05. |
| Publication Model: | Ahead of Print |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: England NLM ID: 0372537 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2156 (Electronic) Linking ISSN: 00068950 NLM ISO Abbreviation: Brain Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Oxford : Oxford University Press Original Publication: London. |
| مستخلص: | Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains a global health burden. While Mtb is primarily a respiratory pathogen, it can spread to other organs, including the brain and meninges, causing TB meningitis (TBM). However, little is known about the immunological mechanisms that leads to differential disease across organs. Attention has focused on differences in T cell responses in the control of Mtb in the lungs, but emerging data point to a role for antibodies, as both biomarkers of disease control and as antimicrobial molecules. Given an increasing appreciation for compartmentalized antibody responses across the blood brain barrier, here we characterized the antibody profiles across the blood and brain compartments during TBM, and determined whether Mtb-specific humoral immune responses differed between Mtb infection of the lung (pulmonary TB) and TBM. Using a high throughput systems serology approach, we deeply profiled the antibody responses against 10 different Mtb antigens, including lipoarabinomannan (LAM) and purified protein derivative (PPD), in HIV-negative adults with pulmonary TB (n=10) vs TBM (n=60). Antibody studies included analysis of immunoglobulin isotypes (IgG, IgM, IgA) and subclass levels (IgG1-4), the capacity of Mtb-specific antibodies to bind to Fc receptors or C1q, and to activate innate immune effectors functions (complement and NK cells activation, monocyte or neutrophil phagocytosis). Machine learning methods were applied to characterize serum and CSF responses in TBM, identify prognostic factors associated with disease severity, and define the key antibody features that distinguish TBM from pulmonary TB. In individuals with TBM, we identified CSF-specific antibody profiles that marked a unique and compartmentalized humoral response against Mtb, characterized by an enrichment of Mtb-specific antibodies able to robustly activate complement and drive phagocytosis by monocytes and neutrophils, all of which were associated with milder TBM severity at presentation. Moreover, individuals with TBM exhibited Mtb-specific antibodies in the serum with an increased capacity to activate phagocytosis by monocytes, compared to individuals with pulmonary TB, despite having lower IgG titers and Fcγ receptors (FcγR)-binding capacity. Collectively, these data point to functionally divergent humoral responses depending on the site of infection (i.e. lungs vs brain), and demonstrate a highly compartmentalized Mtb-specific antibody response within the CSF during TBM. Moreover, our results suggest that phagocytosis- and complement-mediating antibodies may promote attenuated neuropathology and milder TBM disease. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) |
| فهرسة مساهمة: | Keywords: Fc receptors; TB meningitis; antibody-mediated complement deposition; antibody-mediated phagocytosis; neuroinflammation |
| تواريخ الأحداث: | Date Created: 20240305 Latest Revision: 20240305 |
| رمز التحديث: | 20240306 |
| DOI: | 10.1093/brain/awae066 |
| PMID: | 38442687 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1460-2156 |
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| DOI: | 10.1093/brain/awae066 |