Elsevier

Tuberculosis

Volume 108, January 2018, Pages 70-76
Tuberculosis

Immunological Aspects
IgG subclasses' response to a set of mycobacterial antigens in different stages of Mycobacterium tuberculosis infection

https://doi.org/10.1016/j.tube.2017.10.010Get rights and content

Abstract

Despite the reported high heterogeneity of the human immune response to tuberculosis (TB), new studies may contribute to the understanding of Mycobacterium tuberculosis immunopathogenesis. To investigate the patterns of humoral response during latent (LTBI) and active TB, we evaluated specific IgG subclasses' response, by ELISA, to a set of mycobacterial antigens (Rv2029c, Rv2031c, Rv2034, Rv2628, Rv3353c ESAT6:CFP10, and the new chimeric PstS1(285-374):CFP10) in plasma samples from exposed uninfected controls (ExC, n = 24), LTBI (n = 61), and TB (n = 15) donors. In general, the TB group showed statistically higher levels of IgG1, and lower levels of IgG3. Keeping specificities ≥90%, the highest sensitivity for TB detection was observed for IgG1-ESAT6:CFP10 (93.3%), followed by IgG2-Rv3353 (86.7%), IgG1-Rv3353 (69.2%) and IgG1-PstS1(285-374):CFP10 (53.3%). The combinatory of high IgG1-ESAT6:CFP10, followed by low IgG2-Rv3353c titers increased the specificity for TB detection to 100%. Only IgG3-ESAT6:CFP10 showed statistical differences between ExC and LTBI, detecting 50% of the LTBI donors. For the first time, higher levels of IgG2-PstS1(285-374):CFP10 and IgG2-Rv3353 were observed in LTBI and ExC, as compared with a lower or absent immunoreactivity among TB. This study demonstrates differential modulation of subclasses' profiles for the stages of infection, which may contribute to the further development of new diagnostic tools.

Introduction

Tuberculosis (TB) is responsible for high human morbidity and mortality worldwide, especially in resource-poor scenarios [1]. As an intracellular microorganism, the immune response mediated by Th1 cell has a critical role in the containment and control of bacilli growth. Even so, from all infected subjects around 5% to 10% will progress to active TB and the others may remain latently infected (LTBI), but at risk of progression. The continued dependence on diagnostic test that are time-consuming, or show limited performance, and variable cost-effectiveness allows TB epidemic to persist [2], [3]. Therefore, a better understanding of the TB immunopathogenesis may contribute to elucidate the mechanisms involved in the maintenance of a LTBI, or disease progression; and the further development of improved diagnostic biomarkers to distinguish the different stages of Mycobacterium tuberculosis infection.

For this purpose, several approaches have been investigated during the past decades. The transcriptomic studies improved our knowledge about the host immune cells and pathogen interactions. A set of differentially expressed genes in TB and LTBI became available [4], but it is difficult to use a set of many genes in the routine of TB diagnostic [5]. The proteomics helped to identify new antigenic molecules, which facilitated a further selection, and evaluation, of potential candidates for new immunodiagnostic tools [6], [7].

However, most of the studies focused on the measurement of IFN-γ production, to decrypt Th1 response, to several of those novel mycobacterial antigens. Among these studies, it was usually shown high accuracy using cohorts from non-endemic areas, but insufficient accuracy in high TB-burden scenarios, even when priming the cells with the same antigenic stimulus [8]. But, led to the development of commercial IFN-γ release assay kits based on RD1 antigens (ESAT6:CFP10). These kits can be used to help in the TB/LTBI detection, but they do not distinguish one from the other [8].

Recent evidence suggests that B cells and their components can also modulate the host response to various intracellular pathogens as Plasmodium spp., Chlamydia, Cryptococcus neoformans and Mycobacterium spp. However, the importance of the humoral immunity in TB is commonly neglected [9]. Additionally, it has been shown that during TB pathogenesis, B cells can also modulate the level of granulomatous reaction, cytokine production, as well as, the T cell response [10]. As M. tuberculosis is able to change its physiological state according to different stages of infection in response to the host immunity and cellular/molecular stress, including the change in expression of immunodominant antigens; LTBI or active TB could be characterized by specific antibody profiles.

The adaptive immunity is composed of highly orchestrated and dynamic events, and the stress caused by infection and/or tissue damage could modulate different immunoglobulin (Ig) responses. The Ig subclasses have been described with unique properties with regard to antigen binding, immune complex formation, complement activation, triggering cell-mediated immunity, half-life, and abundance in plasma [11]. Thus, it is also important to evaluate the host antibody subclasses profile during the different stages of infection, as latency, reactivation and progression to active TB, to a variety of M. tuberculosis antigens [12], [13].

To date, a few studies had focused on the evaluation of IgG subclasses response during M. tuberculosis infection [14], [15], [16], [17], [18], [19]. Those studies reported statistically different immunoreactivity during TB, but some lacked in ROC curve analysis [14], [15], [16], [17]. Mattos et al. showed that the titration of IgG1 against a panel of 9 mycobacterial antigens (Rv0717, Rv0867, Rv1733, Rv1737, Rv2029, Rv2389, Rv3353, ESAT6, and CFP10) had diagnostic potential for TB detection, but with a very large accuracy range (sensitivity: 47.2–100%; specificities: 65.2%–95.7%), and did not investigate these antibodies immunoreactivity profile during the LTBI [18], [19].

Therefore, in the present study we used blood specimens from LTBI, and active TB cases, to assess the IgG subclasses immunoreactivity profile against a well selected panel of mycobacterial antigens. Among those: latency-associated antigens (LAA: Rv2029c, Rv2031c, Rv2034, and Rv2628); the new chimeric protein PstS1(285-374):CFP10, which is described to induce T-cell response among LTBI subjects [20]; as well as, the constitutively expressed M. tuberculosis antigens Rv3353 and ESAT6:CFP10.

Section snippets

Enrolled participants

From previous investigations [20], [21], a total of 85 plasma samples from rCt donors were available for use. Additionally, more 15 patients with microbiological evidences of pulmonary TB were recruited for this study. The criteria for TB/LTBI diagnoses is described elsewhere [20]. All enrolled subjects were clinically evaluated; TB was confirmed by clinical findings, followed by a positive sputum smear and/or culture. The majority of the TB participants were treatment-naïve, except for 3/15

Characteristics of the study participants

There was no statistical difference in the mean age of TB, LTBI, and ExC groups (P = 0.4) (Table 1). The majority of the rCt had a BCG scar (61/85, 71.8%), and were females (57/85, 67.1%). While around half of them lived in the same dwelling as the respective TB index case (42/85, n = 49.4%). The results of the chest X-ray examination was available for the majority of the ExC (95.8%, 23/24) and LTBI (90.2%, 55/61) groups, among them 4.3% (1/23) and 18.2% (10/55) presented radiographic

Discussion

Among our Brazilian cohort, we observed a diverse and specific tuning of the humoral immunity to each mycobacterial antigen, which would not be observed in studies that only evaluated the levels of primary antibody classes. Indeed, contrastingly to our findings (Fig. 1), a previous study showed statistically similar levels of IgG anti-Rv2628 and -Rv2029c among healthy, LTBI, and TB donors [25]. On the other hand, IgG anti -ESAT6, -CFP10, -PstS1 [26], [27], or -Rv2031c [28] were significantly

Acknowledgments

We are grateful to Dr Tom Ottenhoff for so kindly providing some of the antigens, to Renan Jeremias da Silva to recruit some participants, and to Azeem Ahmed Iqbal for kindly editing the manuscript. The study was supported by funds from the Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and the Oswaldo Cruz Institute (IOC/FIOCRUZ).

References (39)

  • C.V. Harding et al.

    Regulation of antigen presentation by Mycobacterium tuberculosis: a role for Toll-like receptors

    Nature

    (2010)
  • M.P. Berry et al.

    An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis

    Nature

    (2010)
  • S. Kunnath-Velayudhan et al.

    Immunodiagnosis of tuberculosis: a dynamic view of biomarker discovery

    Clin Microbiol Rev

    (2011)
  • S. Kunnath-Velayudhan et al.

    Dynamic antibody responses to the Mycobacterium tuberculosis proteome

    Proc Natl Acad Sci U. S. A

    (2010)
  • F. Abebe et al.

    The protective role of antibody responses during Mycobacterium tuberculosis infection

    Clin Exp Immunol

    (2009)
  • L.1 Kozakiewicz et al.

    The role of B cells and humoral immunity in Mycobacterium tuberculosis infection

    Adv Exp Med Biol

    (2013)
  • G. Vidarsson et al.

    IgG subclasses and allotypes: from structure to effector functions

    Front Immunol

    (2014)
  • A. Davidow et al.

    Antibody profiles characteristic of Mycobacterium tuberculosis infection state

    Infect Immun

    (2005)
  • U. Demkow et al.

    Heterogeneity of antibody response to mycobacterial antigens in different clinical manifestations of pulmonary tuberculosis

    J Physiol Pharmacol Off J Pol Physiol Soc

    (2007)
  • Cited by (17)

    • A recombinant selective drug-resistant M. bovis BCG enhances the bactericidal activity of a second-line anti-tuberculosis regimen

      2021, Biomedicine and Pharmacotherapy
      Citation Excerpt :

      Most importantly, vaccination of mice with a plasmid expressing Rv2628 induced expression of antigen specific antibody response which is suggestive of its potential role in TB vaccine development [30]. Additionally, the Rv2628 enhanced a sustained IgG antibody expression in vaccinated and M. tuberculosis challenged mice [31]. Despite so many advances in TB vaccine research and development, there’s no vaccine with proven preventive efficacy other than the traditional BCG against TB.

    • Role of IgG3 in Infectious Diseases

      2019, Trends in Immunology
      Citation Excerpt :

      For instance, a recent study suggested that excessive IgG3 might lead to negative regulation of TLM B cells, resulting in refractory BCR signaling, as seen in chronic HIV-1-infected individuals [68]. Similarly, overinduction of IgG3 effector functions, such as ADCC, have been reported to increase the severity of disease in the case of DENV infection [114] and might be associated with excessive inflammatory responses in active TB [115]. Future studies are warranted to better dissect the dynamics of IgG3 responses during a variety of infections.

    • Characteristic profile of antibody responses to PPD, ESAT-6, and CFP-10 of Mycobacterium tuberculosis in pulmonary tuberculosis suspected cases in Surabaya, Indonesia

      2019, Brazilian Journal of Infectious Diseases
      Citation Excerpt :

      M. tuberculosis can change its physiological state according to the different stages of infection in the host, including changes in immunodominant antigen expression. Thus, latent TB infection (LTBI) or active TB could be detected by a specific antibody profile.23 We observed that PPD had the highest AUC value among the tested antigens.

    View all citing articles on Scopus
    View full text