BCG-specific IgG-secreting peripheral plasmablasts as a potential biomarker of active tuberculosis in HIV negative and HIV positive patients
- Senait Ashenafi1,2,
- Getachew Aderaye3,
- Martha Zewdie4,
- Rubhana Raqib5,
- Amsalu Bekele3,
- Isabelle Magalhaes6,
- Beede Lema7,
- Meseret Habtamu4,
- Rokeya Sultana Rekha5,
- Getachew Aseffa8,
- Markus Maeurer6,
- Abraham Aseffa4,
- Mattias Svensson1,
- Jan Andersson1,9,
- Susanna Brighenti1
- 1Department of Medicine, Center for Infectious Medicine (CIM), Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
- 2Department of Pathology, Faculty of Medicine, Black Lion University Hospital and Addis Ababa University, Addis Ababa, Ethiopia
- 3Department of Internal Medicine, Faculty of Medicine, Black Lion University Hospital and Addis Ababa University, Addis Ababa, Ethiopia
- 4Armauer Hansen Research Institute (AHRI), Addis Ababa, Ethiopia
- 5Laboratory Science Division, International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), Dhaka, Bangladesh
- 6Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
- 7Department of Surgery, Faculty of Medicine, Black Lion University Hospital and Addis Ababa University, Addis Ababa, Ethiopia
- 8Department of Radiology, Faculty of Medicine, Black Lion University Hospital and Addis Ababa University, Addis Ababa, Ethiopia
- 9Division of Infectious Diseases, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden
- Correspondence to Dr Susanna Brighenti, Department of Medicine, Center for Infectious Medicine (CIM), Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden;
Contributors All authors contributed substantially to this study. Conception and design: SA, GAd, RR, JA, SB; patient recruitment, clinical diagnosis and clinical care including acquisition of clinical data, analysis and interpretation of clinical data: GAd, AB, BL, GAs; laboratory work including acquisition of data, analysis and interpretation of data: SA, MZ, RR, IM, MH, RSR, MM, AA, MS, JA, SB; preparation and review of manuscript: SA, RR, MS, JA, SB.
- Received 24 February 2012
- Accepted 27 July 2012
- Published Online First 24 August 2012
Background Diagnosis of active tuberculosis (TB) among sputum-negative cases, patients with HIV infection and extra-pulmonary TB is difficult. In this study, assessment of BCG-specific IgG-secreting peripheral plasmablasts, was used to identify active TB in these high-risk groups.
Methods Peripheral blood mononuclear cells were isolated from patients with TB and controls and cultured in vitro using an assay called Antibodies in Lymphocyte Supernatant, which measures spontaneous IgG antibody release from migratory plasmablasts. A BCG-specific ELISA and flow cytometry were used to quantify in vivo activated plasmablasts in blood samples from Ethiopian subjects who were HIV negative or HIV positive. Patients diagnosed with different clinical forms of sputum-negative active TB or other diseases (n=96) were compared with asymptomatic individuals including latent TB and non-TB controls (n=85). Immunodiagnosis of TB also included the tuberculin skin test and the interferon (IFN)-γ release assay, QuantiFERON.
Results This study demonstrated that circulating IgG+ plasmablasts and spontaneous secretion of BCG-specific IgG antibodies were significantly higher in patients with active TB compared with latent TB cases and non-TB controls. BCG-specific IgG titres were particularly high among patients coinfected with TB and HIV with CD4 T-cell counts <200 cells/ml who produced low levels of Mycobacterium tuberculosis-specific IFNγ in vitro.
Conclusions These results suggest that BCG-specific IgG-secreting peripheral plasmablasts could be successfully used as a host-specific biomarker to improve diagnosis of active TB, particularly in people who are HIV positive, and facilitate administration of effective treatment to patients. Elevated IgG responses were associated with impaired peripheral T-cell responses, including reduced T-cell numbers and low M tuberculosis-specific IFNγ production.
- Mycobacterium tuberculosis
- atypical mycobacterial infection
- macrophage biology
- infection control
- innate immunity
- oxidative stress
- respiratory infection
- viral infection
- bacterial infection
- lymphocyte biology
Funding This work was supported by funding from the Swedish research council (VR), the Heart and Lung Foundation (HLF), the Swedish Society for Medical Research (SSMF), the Swedish International Development Cooperation Agency (Sida), the Swedish Civil Contingencies Agency (MSB) and the Swedish Foundation for Strategic Research (SSF).
Competing interests None.
Ethics approval Ethics approval was provided by the Regional Ethical Review Board in Stockholm, Sweden (EPN) and the National Health Research Ethics Committee (NERC) in Ethiopia.
Provenance and peer review Not commissioned; externally peer reviewed.
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/3.0/ and http://creativecommons.org/licenses/by-nc/3.0/legalcode