Mycobacterium tuberculosis infection is associated with increased B cell responses to unrelated pathogens

Abstract

Antigens from Mycobacterium tuberculosis (M.tb), have been shown to stimulate human B cell responses to unrelated recall antigens in vitro. However, it is not known whether natural M.tb infection or whether vaccination with, Mycobacterium bovis BCG, has a similar effect. This study investigated the effects of M.tb infection and BCG vaccination on B cell responses to heterologous pathogen recall antigens. Antibodies against several bacterial and viral pathogens were quantified by ELISA in 68 uninfected controls, 62 individuals with latent TB infection (LTBI) and 107 active pulmonary TB (APTB) cases, and 24 recently BCG-vaccinated adolescents and naive controls. Antibody avidity was investigated using surface plasmon resonance and B cell ELISPOTs were used to measure plasmablast and memory B cell responses (MBC) in APTB cases and healthy donor controls. APTB was associated with higher levels of antibodies to respiratory syncytial virus and measles virus, compared to uninfected controls. BCG vaccination did not alter levels of antibodies against heterologous pathogens. Tetanus toxoid (TT)-specific antibody avidity was increased in APTB cases in comparison to uninfected individuals and the ratio of TT-specific plasmablasts to MBCs in the APTB cases was 7:1. M.tb infection is associated with increased antibody responses to heterologous pathogens in human subjects.

Figure 1

Variations in antibody responses to heterologous pathogens across M.tb infection state. The horizontal bars shown are median IgG antibody optical densities in each group. Antibody responses were compared across uninfected controls (n = 68), individuals with LTBI (n = 62) and APTB cases (n = 107). The p values shown correspond to results from Kruskal–Wallis test (*p < 0.05; **p < 0.01). PPD purified protein derivative, TT tetanus toxoid, DT diphtheria toxoid, RSV respiratory syncytial virus, MV measles virus, KSHV Kaposi’s sarcoma herpesvirus, CMV cytomegalovirus.

Figure 2

Antibody responses to heterologous pathogens in BCG vaccinated individuals and their age-matched BCG naïve controls. (a) antibody responses before BCG vaccination. (b) antibody responses 3 weeks after BCG vaccination. The horizontal bars shown are median IgG antibody optical density in each group. The p values shown correspond to results from Wilcoxon rank sum test (*p < 0.05; **p < 0.01) from comparing antibody responses in BCG vaccinated (n = 12) and BCG naïve controls (n = 13). PPD purified protein derivative, TT tetanus toxoid, DT diphtheria toxoid, RSV respiratory syncytial virus, MV measles virus, CMV cytomegalovirus, EBV Epstein–Barr virus.

Figure 3

TT-specific plasmablasts are higher than TT-specific MBCs in APTB. MBC responses were evaluated in 18 APTB cases while PB responses were evaluated in 30 APTB cases. The p values are from Wilcoxon-rank sum tests. MBC memory B cells, PB plasmablasts, TT tetanus toxoid.

Figure 4

Lower TT-specific MBC frequencies in APTB cases compared to healthy donor controls. MBC responses were evaluated in 115 healthy donors and 18 APTB cases. The p values are from Wilcoxon-rank sum tests. MBC memory B cells, TT tetanus toxoid.