Serum antibody profiles in individuals with latent Mycobacterium tuberculosis infection

Abstract

One-third of the world's humans has latent tuberculosis infection (LTBI), representing a large pool of potentially active TB. Recent LTBI carries a higher risk of disease progression than remote LTBI. Recent studies suggest important roles of antibodies in TB pathology, prompting us to investigate serum antibody profiles in a cohort with LTBI. In this single-center prospective observational study, we analyzed IgG-antibody concentrations against five major Mycobacterium tuberculosis (Mtb) antigens (including 6 kDa early secretory antigenic target (ESAT6), CFP10, and antigen 85A, which are expressed mainly in the growth phase; and mycobacterial DNA-binding protein 1 (MDP1) and alpha-crystallin like protein (Acr), which are expressed in the dormant phases) in individuals with recent (n=13) or remote (n=12) LTBI, no Mtb infection (n=19), or active TB (n=15). Antibody titers against ESAT6 and MDP1 were significantly higher in individuals with recent LTBI than in those with no Mtb infection or remote LTBI. All pairwise antibody titers against these five major antigens were significantly correlated throughout the stages of Mtb infection. Five individuals with recent LTBI had significantly higher antibody titers against ESAT6 (P = 0.03), Ag85A (P = 0.048), Acr (P = 0.057), and MDP1 (P = 0.0001) than in individuals with remote LTBI; they were also outside the normal range (+2 SDs). One of these individuals was diagnosed with active pulmonary TB at 18-month follow-up examination. These findings indicated that concentrations of antibodies against both multiplying and dormant Mtb are higher in recent LTBI and that individuals with markedly higher antibody titers may be appropriate candidates for prophylactic therapy.

Keywords: Biomarker; latent tuberculosis infection; mycobacterial DNA-binding protein 1; serum antibody.

Figure 1

Comparative analysis of IgG antibody titers against four Mtb antigens among the five study groups. Individuals with recent LTBI had significantly higher logarithm‐converted antibody titers against ESAT6 (P < 0.0001; P = 0.0004) and MDP1 (P < 0.0001; P = 0.0003) than those in the groups with no Mtb infection or remote LTBI. ESAT, early secretory antigenic target; LTBI, latent tuberculosis infection; MDP1, mycobacterial DNA‐binding protein 1; Mtb, Mycobacterium tuberculosis [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Relationships between logarithm‐converted antibody titers against the five selected antigens in all participants. There were significant correlations between all pairs of antibody titers against ESAT6, CFP10, Ag85A, Acr, and MDP1 (all P < 0.0001). Each symbol indicates an individual from one of the five groups [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Antibody titers against four antigens are shown for all healthcare workers, except for those whose antibody titers were below the detection level. The cutoff values (dotted lines) for positivity were defined as two SDs above the mean titer in the group without Mtb infection. Arrow indicates an individual with preclinical TB. Numbers 1, 2, 3, and 4 indicate cases 1, 2, 3, and 4 in the recent LTBI group, respectively. In these five individuals, the antibody titers against ESAT6 (P = 0.03), Ag85A (P = 0.048), Acr (P = 0.057), and MDP1 (P = 0.0001) were significantly higher than those in the remote LTBI group [Color figure can be viewed at wileyonlinelibrary.com]

Figure 4

Detection of preclinical TB. An individual with recent LTBI was found to have progressed to having active pulmonary TB with pleurisy 19 months after measurement of serum antibody titers. Log‐corrected antibody titers for ESAT‐6, CFP10, MDP1, Acr, and Ag85A were 0.2, −0.57, 0.14, −0.14, and 0.22, respectively