The role of antibodies in tuberculosis

Simple item page
dc.contributor.advisorWilkinson, Robert
dc.contributor.authorJacobs, Ashley
dc.date.accessioned2025-02-13T08:37:06Z
dc.date.available2025-02-13T08:37:06Z
dc.date.issued2024
dc.date.updated2025-02-13T08:15:28Z
dc.description.abstractThe role of antibodies in tuberculosis (TB) has been debated for over a century. Antibodies against Mycobacterium tuberculosis (M.tb) are detectable in persons who appear to resist M.tb infection, and yet humoral immune activation is a consistent biomarker of TB disease progression. Antibody responses to TB could therefore be a dual-edged sword, whereby antibodies promote TB pathogenesis, but some people produce antibodies that contribute to immunity against M.tb. In this thesis, I have therefore investigated the role of antibodies in TB in multiple clinical cohorts. Firstly, I generated fully human monoclonal antibodies (mAbs) against M.tb from patients with ATB. I identify the antigen of one mAb as the secreted antigen GlnA1, and then show that this mAb promotes in vitro production of TNF-α, IL-6, and IL-1β in the absence of mycobacterial killing. Secondly, I investigated antibody responses against M.tb in persons who live with HIV (PLWH). PLWH fail to mount a significant increase in IgG levels against M.tb in ATB. M.tb-specific IgG responses are also detectable in different cohorts of PLWH with negative interferon gamma release assay (IGRA) tests. However, greater levels of M.tb-specific IgG associates with IGRA conversion. Thirdly, I showed the development of flow cytometric assays to study opsonization and antibody dependant cellular phagocytosis (ADCP) of live mycobacteria in BCG vaccinated adults. These methods show that BCG vaccination induces ADCP 28 days post-vaccination. Fourthly, I tested whether unswitched memory B cells, and specifically the marginal zone B cells (MZB) subset, are impacted by ATB. MZB respond to capsular pathogens and could thus recognize the M.tb cell wall. MZB are found to be depleted in ATB but are not enriched at the site of disease in PLWH with pericardial TB. The depletion of unswitched memory B cells in TB observed in this study resembles that reported in autoimmune disease. Taken together, I provide support to the notion that at least some antibodies against M.tb could contribute to immunopathology in TB. The fact that PLWH are at greater risk of disseminated TB, and mount less of an antibody response, however, supports a role for antibodies in preventing disseminated disease that remains to be studied.
dc.identifier.apacitationJacobs, A. (2024). <i>The role of antibodies in tuberculosis</i>. (). University of Cape Town ,Faculty of Health Sciences ,Department of Medicine. Retrieved from http://hdl.handle.net/11427/40943en_ZA
dc.identifier.chicagocitationJacobs, Ashley. <i>"The role of antibodies in tuberculosis."</i> ., University of Cape Town ,Faculty of Health Sciences ,Department of Medicine, 2024. http://hdl.handle.net/11427/40943en_ZA
dc.identifier.citationJacobs, A. 2024. The role of antibodies in tuberculosis. . University of Cape Town ,Faculty of Health Sciences ,Department of Medicine. http://hdl.handle.net/11427/40943en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Jacobs, Ashley AB - The role of antibodies in tuberculosis (TB) has been debated for over a century. Antibodies against Mycobacterium tuberculosis (M.tb) are detectable in persons who appear to resist M.tb infection, and yet humoral immune activation is a consistent biomarker of TB disease progression. Antibody responses to TB could therefore be a dual-edged sword, whereby antibodies promote TB pathogenesis, but some people produce antibodies that contribute to immunity against M.tb. In this thesis, I have therefore investigated the role of antibodies in TB in multiple clinical cohorts. Firstly, I generated fully human monoclonal antibodies (mAbs) against M.tb from patients with ATB. I identify the antigen of one mAb as the secreted antigen GlnA1, and then show that this mAb promotes in vitro production of TNF-α, IL-6, and IL-1β in the absence of mycobacterial killing. Secondly, I investigated antibody responses against M.tb in persons who live with HIV (PLWH). PLWH fail to mount a significant increase in IgG levels against M.tb in ATB. M.tb-specific IgG responses are also detectable in different cohorts of PLWH with negative interferon gamma release assay (IGRA) tests. However, greater levels of M.tb-specific IgG associates with IGRA conversion. Thirdly, I showed the development of flow cytometric assays to study opsonization and antibody dependant cellular phagocytosis (ADCP) of live mycobacteria in BCG vaccinated adults. These methods show that BCG vaccination induces ADCP 28 days post-vaccination. Fourthly, I tested whether unswitched memory B cells, and specifically the marginal zone B cells (MZB) subset, are impacted by ATB. MZB respond to capsular pathogens and could thus recognize the M.tb cell wall. MZB are found to be depleted in ATB but are not enriched at the site of disease in PLWH with pericardial TB. The depletion of unswitched memory B cells in TB observed in this study resembles that reported in autoimmune disease. Taken together, I provide support to the notion that at least some antibodies against M.tb could contribute to immunopathology in TB. The fact that PLWH are at greater risk of disseminated TB, and mount less of an antibody response, however, supports a role for antibodies in preventing disseminated disease that remains to be studied. DA - 2024 DB - OpenUCT DP - University of Cape Town KW - tuberculosis KW - TB KW - Mycobacterium tuberculosis KW - M.tb LK - https://open.uct.ac.za PB - University of Cape Town PY - 2024 T1 - The role of antibodies in tuberculosis TI - The role of antibodies in tuberculosis UR - http://hdl.handle.net/11427/40943 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/40943
dc.identifier.vancouvercitationJacobs A. The role of antibodies in tuberculosis. []. University of Cape Town ,Faculty of Health Sciences ,Department of Medicine, 2024 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/40943en_ZA
dc.language.isoen
dc.language.rfc3066eng
dc.publisher.departmentDepartment of Medicine
dc.publisher.facultyFaculty of Health Sciences
dc.publisher.institutionUniversity of Cape Town
dc.subjecttuberculosis
dc.subjectTB
dc.subjectMycobacterium tuberculosis
dc.subjectM.tb
dc.titleThe role of antibodies in tuberculosis
dc.typeThesis / Dissertation
dc.type.qualificationlevelDoctoral
dc.type.qualificationlevelPhD
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
thesis_hsf_2024_jacobs ashley.pdf
Size:
9.7 MB
Format:
Adobe Portable Document Format
Description:
Download
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
1.72 KB
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
PhD / Doctoral