Comparative Evaluation of Profiles of Antibodies to Mycobacterial Capsular Polysaccharides in Tuberculosis Patients and Controls Stratified by HIV Status

Abstract

The results were compared with Ab responses to the mycobacterial glycolipid cell wall antigen lipoarabinomannan (LAM) and to the proteins malate synthase (MS) and MPT51. We found that the main immunoglobulin (Ig) isotype response to polysaccharides was IgG, predominantly of subclass IgG2. IgG responses to AM were significantly higher for HIV ؊ and HIV ؉ TB cases than for controls (P, <0.0001 and <0.01, respectively); significantly higher for HIV ؊ than for HIV ؉ TB cases (P, <0.01); and significantly higher in sputum smear-positive than smear-negative patients in both HIV ؊ and HIV ؉ cases (P, 0.01 and 0.02, respectively). In both TB groups, titers of Ab to glucan were significantly lower than titers of Ab to AM (P, <0.0001). IgG responses to AM and MS or to AM and MPT51 did not correlate with each other in HIV ؊ TB patients, while they correlated significantly in HIV ؉ TB patients (P, 0.01 and 0.05, respectively). We conclude that Ab responses to AM could contribute to the serodiagnosis of TB, especially for HIV ؊ TB patients. This study also provides new and important insights into the differences in the profiles of Abs to mycobacterial antigens between HIV ؊ and HIV ؉ TB patients. New biomarkers for the diagnosis of active tuberculosis (TB) are urgently needed. Despite a history of disappointing results, antibodies (Abs) to Mycobacterium tuberculosis antigens remain attractive biomarkers for TB. Detection of serum Abs to M. tuberculosis antigens (serology) does not require a specimen from the site of disease, and tests could easily be developed into a simple, rapid dipstick format. However, commercially available serodiagnostic tests to date have been limited by a lack of sensitivity and specificity (51; reviewed in references 45 and 46). Therefore, the World Health Organization (WHO) recently cautioned against the use of such tests, while strongly recommending further targeted research in the field of TB serology (26).Studies show that multiple antigen testing provides higher sensitivities for TB serodiagnostic assays than tests based on single antigens (reviewed in reference 45). Many mycobacterial proteins and a few lipids and glycolipids have been evaluated for their serodiagnostic potential in recent decades, and some promising antigens have been identified (reviewed in reference 44). However, polysaccharide antigens have been insufficiently studied. Recent studies have confirmed the existence of a mycobacterial capsule that consists mainly of the polysaccharides glucan (70 to 80%) and arabinomannan (AM) (10 to 20%) and, to a lesser extent, of proteins and glycolipids (8,23,36). Located at the interface between the bacterium and host cells, capsular antigens are involved in mycobacterial pathogenicity (8,13,36,47) and therefore likely elicit host immune responses. Navoa et al. demonstrated that titers of Ab to AM were significantly higher in Indian smearpositive cavitary TB patients (n ϭ 20) than in healthy, tuberculin skin test-negative (TST Ϫ ) controls (n ϭ 17) (27). Ab responses to glucan have been e...

Antibodies against Mycobacterial Proteins as Biomarkers for HIV-Associated Smear-Negative Tuberculosis

“…Our prior studies with subjects living in the United States demonstrated a more homogeneous Ab response against MPT51 and MS in HIV ϩ TB than in HIV Ϫ TB patients (17). In this study, Ab responses to the proteins MPT51 and echA1 did not correlate significantly in HIV ϩ TB patients, while in accordance with our prior studies, the ones against MPT51 and MS did, although to a lesser extent (17).…”

“…We have previously investigated Ab responses to a variety of mycobacterial antigens according to HIV status. We found that IgG responses against polysaccharide antigens were significantly lower in HIV ؉ than in HIV Ϫ TB patients (17). In contrast, IgG reactivity against certain mycobacterial proteins, specifically, MPT51 and malate synthase (MS), were significantly higher in HIV ؉ than in HIV Ϫ TB patients, and reactivity against MPT51 could distinguish between HIV ϩ TB and other respiratory diseases (18).…”

“…Our prior studies with subjects living in the United States demonstrated a more homogeneous Ab response against MPT51 and MS in HIV ϩ TB than in HIV Ϫ TB patients (17). In this study, Ab responses to the proteins MPT51 and echA1 did not correlate significantly in HIV ϩ TB patients, while in accordance with our prior studies, the ones against MPT51 and MS did, although to a lesser extent (17). These findings are consistent with the differences in gene and protein expression during various levels of M. tuberculosis infection activity, which may be reflected by the subjects' Ab responses (40).…”

Serological Diagnostic Assays for HIV-Associated Tuberculosis in Sub-Saharan Africa?

“…Among the range of purified immunodominant antigens that have previously been evaluated for serological detection of M. tuberculosis (31), selected proteins which demonstrate greater potential utility as biomarkers of TB among HIV-infected patients have been studied by Siev and colleagues (32,33). Antibody responses to two of these antigens, malate synthase (MS) and MPT51, have been detected among patients months before the development of overt clinical TB, suggesting that they may serve as biomarkers for detection of both active and subclinical TB (34,35).…”

Interplay of human macrophages and Mycobacterium tuberculosis phenotypes

“…In the serum of TB patients, antibodies against arabinomannan have been found [360], but it was not clear whether those antibodies were mounted against the arabinomannancontaining portion of lipoarabinomannan, which is a glycolipid antigen situated in the cell wall and not part of the capsule [361]. Furthermore, killing and degradation of Mtb and presentation of its antigen would explain inconclusive humoral responses in vivo.…”