Detection of a combination of serum IgG and IgA antibodies against selected mycobacterial targets provides promising diagnostic signatures for active TB

Abstract

Immunoglobulin G (IgG) based tests for the diagnosis of active tuberculosis (TB) disease often show a lack of specificity in TB endemic regions, which is mainly due to a high background prevalence of LTBI. Here, we investigated the combined performance of the responses of different Ig classes to selected mycobacterial antigens in primary healthcare clinic attendees with signs and symptoms suggestive of TB. The sensitivity and specificity of IgA, IgG and/or IgM to LAM and 7 mycobacterial protein antigens (ESAT-6, Tpx, PstS1, AlaDH, MPT64, 16kDa and 19kDa) and 2 antigen combinations (TUB, TB-LTBI) in the plasma of 63 individuals who underwent diagnostic work-up for TB after presenting with symptoms and signs compatible with possible active TB were evaluated. Active TB was excluded in 42 individuals of whom 21 has LTBI whereas active TB was confirmed in 21 patients of whom 19 had a follow-up blood draw at the end of 6-month anti-TB treatment. The leading single serodiagnostic markers to differentiate between the presence or absence of active TB were anti-16 kDa IgA, anti-MPT64 IgA with sensitivity and specificity of 90%/90% and 95%/90%, respectively. The combined use of 3 or 4 antibodies further improved this performance to accuracies above 95%. After successful completion of anti-TB treatment at month 6, the levels of 16 kDa IgA and 16 kDa IgM dropped significantly whereas LAM IgG and TB-LTBI IgG increased. These results show the potential of extending investigation of anti-tuberculous IgG responses to include IgM and IgA responses against selected protein and non-protein antigens in differentiating active TB from other respiratory diseases in TB endemic settings.

An Inflammatory Story: Antibodies in Tuberculosis Comorbidities

“…This interest in humoral immunity in Mtb is evidenced by a mounting number of studies that have identified specific antibody targets, and structural or functional differences that are observed during different TB disease states (26)(27)(28)(29)(30). For example, while Mtb-specific IgG titers alone have been insufficient in distinguishing between latent and active TB, refinement of these correlates using additional isotypes, subclasses, and other Fc modifications are underway (see Figure 1) (31)(32)(33)(34)(35). Moreover, incorporating data including multiple instead of single Mtb antigens as well as Fab affinity and avidity to Mtb targets may improve sensitivity and specificity (36)(37)(38)(39)(40).…”

Biomarcadores da tuberculose: uma revisão da literatura.

“…Um trabalho sul-africano analisou a Imunoglobulina A (IgA) e IgM contra 10 Ag distintos do Mtb. Sendo estes: Lipoarabinomanana (LAM), 7 Ag micobacterianos proteicos (ESAT-6, Tiol peroxidase (Tpx), Proteína de ligação a fosfato 1 (PstS1), Alanina Desidrogenase (AlaDH), MPT64, proteínas de 16 kDa (também referido na literatura como Hsp16.3) e 19 kDa (p19)) e 2 combinações de Ag (TUB (PstS1, 16 kDa, APA), TB-LTBI (Tpx, L16)) (AWONIYI et al, 2017).…”

“…Não obstante, em perfis sorológicos utilizando múltiplos biomarcadores a acurácia para distinção tanto no contexto TB vs. ORD como TB vs. LTBI foi significativamente melhorada, alcançando valores próximos a 100%. Todavia, volta-se ao ponto das limitações inerentes ao delineamento do trabalho, carecendo estudos de maior proporção para fundamentar (ou não) seus dados (AWONIYI et al, 2017).…”

“…Apesar das numerosas discordâncias, o relato deste trabalho brasileiro não desvalida de forma alguma as evidências expostas por Awoniyi et al (2017). Pelo contrário, acaba por expor a inquestionável forma heterogênea com que indivíduos e populações reagem ao patógeno, o qual também possui mecanismos complexos e variados para a administração da sua replicação e transmissão.…”

“…Não obstante, nenhum dos outros grupos submetidos a análise possui sequer 50 indivíduos e não foram observados pacientes quais a quimioterapia falhou (MATTOS et al, 2016). Awoniyi et al (2017), também já mencionado, do mesmo modo acompanhou o curso da doença por meio de títulos dos Ac. Os autores reportaram uma queda significativa nos biomarcadores anti-16 kDa IgM e anti-16 kDa IgA após o que foi considerado uma terapia de sucesso.…”