Figures
- FIGURE 1
Potential mechanisms of action of antibodies in tuberculosis: a) antibodies enhance phagocytosis of Mycobacterium tuberculosis (MTB) by neutrophils and macrophage via FcR binding; b) antibodies also enhance the fusion of phagosome and lysosome; c) antibodies activate CD4+ T-cells; d) antibodies enhance killing of infected macrophages by activating natural killer (NK) cells; e) antibodies facilitate direct neutralisation of the bacilli; f) antibodies block the binding of MTB to epithelial cells and prevent extrapulmonary dissemination of the bacteria. ADCP: antibody-dependent cellular phagocytosis; CMI: cell-mediated immunity; ADCC: antibody-dependant cellular cytotoxicity; Ag: antigen; Ab: antibody; TCR: T-cell receptor; MHC: major histocompatibility complex.
Tables
- TABLE 1
List of antibodies for the diagnosis of active tuberculosis (TB), latent TB infection (LTBI) and treatment monitoring
Antibodies and MTB antigen Results and relevance References Sen and Sp TPP status Antibodies for diagnosis of active TB IgG against 11 antigens (Rv3881, Rv0934, Rv2031c, Rv1886c, Rv1860, Rv3874, Rv2875, Rv3841, Rv1926c, MEMH37Rv and Rv1984)# Sen: for dx of smear positive PTB, 95% Moderately comparable to the target (≥98%) [18] Sen: for dx of smear negative PTB, 88% Met the optimal value needed (≥68%) Sp: in COPD patients 96% and healthy controls 91% Moderately comparable to the target (>98%) IgG against 8 antigens (Ag85B, Ag85A, Ag85C, Rv0934-P38, Rv3881, BfrB, Rv3873 and Rv2878c)# Sen: for screening active TB: 90.6% Met the minimal value for TB screening (>90%) [19] Sp: 88.6% Met the optimal target for TB screening test (>70%) IgG against 6 antigens and fusion proteins from these antigens (Rv0934, Rv3874, Rv2875, Rv2031, Rv2032 and Rv0831)¶ Sen: for dx of smear positive PTB, 93% Moderately comparable to the target (≥98%) [23] Sp: 96% Moderately met the optimal value needed (>98%) IgG against 7 antigens (PstS1, Rv0831c, FbpA, EspB, bfrB, HspX and ssb)+ Sen: for dx of PTB, 74–90% Slightly comparable to target (>98%) [24] Sp: 96–100% Met the optimal value (>98%) IgG against Rv0220, Rv2958c, Rv2994 and Rv3347c§ Sen: 80.4–91.3% Slightly comparable to the optimal value (≥98%) [25] Sp: 91.7–98.3% Moderately comparable Anti-TB-LTBI IgG, anti-Tpx IgG and anti-MPT64 IgA. TB-LTBI: (antigen cocktail composed of Tpx and L16)ƒ Sen: for dx of active TB, 95.2% Moderately comparable to the optimal value (≥98%) [5] Sp: 97.6% Comparable to the target (≥98%) Anti-LAM IgA, anti-LAM IgG, anti-Tpx IgA, anti-HSP16.3 IgG and anti-HSP20 IgA## Sen: 81% Slightly comparable to the optimal value (≥98%) [21] Sp: for dx of non-TB cases, 94% Moderately comparable to the target (≥98%) IgG against A60 (commercial test)¶¶ Sen: 91.2% Moderately comparable [26] Sp: 92% Moderately comparable IgG against 38-kDa, 16-kDa, and 6-kDa (commercial test)# Sen: 78.1% Slightly comparable to the optimal value (≥98%) [29] Specificity: 100% Met the optimal value (>98%) Antibodies for diagnosis of LTBI IgG against ESAT6 and MDP1 IgG against ESAT6 and MDP1 were significantly higher in recent LTBI compared to remote LTBI (Sen and Sp data not available) [17] IgG against PPE17 Sen for dx of LTBI 87%, for dx of active TB (95%) (Sp data not available) [4] IgG against PPD Sera from LTBI has less fucose and more galactose and sialic acid compared to active TB patient [13] Antibodies for treatment monitoring IgG against 14 kDa Increased following treatment, and decreased after 3 years [33] IgG against 38 kDa and LAM Increased at month 2 and month 8 following treatment [34] IgG against Rv2626c and ESAT6 Decreased following treatment Anti-16 kDa IgA and IgM Decreased following treatment [5] IgG against LAM and TB – LTBI Increased at month 6 of anti-TB treatment completion Anti-Tpx IgG and anti-ESAT-6 IgA Predicated slow responders with an accuracy of 90.5% [32] Anti-16 kDa IgG Increased following TB treatment [6] Anti-ESAT-6 and CFP-10 IgG Higher before treatment, and increased following treatment Recent LTBI: <2 years since infection; remote LTBI: >2 years since infection. MTB: Mycobacterium tuberculosis; Sen: sensitivity; Sp: specificity; TTP: targeted product profiles; PTB: pulmonary TB; LAM: Lipoarabinomannan; dx: diagnosis. #: IgG against multiple antigens (measured individually, analysed in combination); ¶: IgG against multiple antigens and fusion protein (measured individually, analysed in combination); +: IgG against multiple antigens and antigen cocktails (measured individually, analysed in combination); §: IgG against novel single or multiple antigens; ƒ: multiple antibodies (IgG, IgM, IgA) against multiple antigens and antigen cocktail (measured individually, analysed in combination); ##: multiple antibodies against multiple antigens (measured individually, analysed in combination); ¶¶: IgG against single protein (multiantigen complex).
- TABLE 2
Descriptions of the Mycobacterium tuberculosis (MTB) antigens included in this review
Antigens Synonyms Descriptions and biological activities References esxA Rv3875, ESAT-6 6 kDa early secretory antigenic target of unknown function. Elicits high level of INF-γ from memory effector cells during the first phase of a protective immune response. Component of QuantiFERON test, and absent in BCG strain. [17, 77] esxB Rv3874, CFP10 10 kDa culture filtrate antigen of unknown function. [77] esxW Rv3620 Putative ESAT-6 like protein 10 of unknown function. [77] esxV Rv3619 Putative ESAT-6 like protein 1 of unknown function. [77] Rv1813c Rv1813c A conserved hypothetical protein of unknown function. [78] LAM Components of MTB-cell wall. Inhibit IFN-γ mediated macrophage activation; T-cell proliferation, IL-12 production, neutrophil recruitment, DC activation. [79] fbpA Rv3804c, Ag85a Fibronectin binding protein A and components of Ag85 complex (Ag85a), possesses a mycolyltransferase activity (85A) required for the biogenesis of trehalose dimycolate (cord factor), main component for maintaining cell wall integrity. [77] fbpB Rv1886c, Ag85b Fibronectin binding protein B and components of Ag85 complex (Ag85b). Secreted antigen acts as mycolyltransferase (85B), which is involved in cell wall mycoloylation. [77, 80] fbpC Rv0129c, Ag85c Fibronectin binding protein C and components of Ag85 complex (Ag85c). Secreted antigen acts as mycolyltransferase (85C), which is involved in cell wall mycoloylation. [77] espB Rv3881c Secreted ESX-1 substrate protein B, EspB. A conserved alanine and glycine-rich protein of unknown function. [77] mpt70 Rv2875 Major secreted immunogenic protein of unknown function. [77] Acg Rv2032 Acg (acr-coregulated gene). Conserved protein of unknown function. [77] Rv0831 Rv0831 A conserved protein of unknown function. [77] bfrB Rv3841 Bacterioferritin. Intracellular molecule involved in iron storage. [77] Rv0831c Rv0831c A conserved protein of unknown role. [77] HspX Rv2031c, 16/14 kDa Heat shock protein (alpha-crystallin homolog). Stress protein induced by anoxia. Proposed role in long-term survival of the bacilli during latent infections. [77, 79] PstS1 Rv0934, 38kDa Periplasmic phosphate-binding lipoprotein (PBP-1). Immunodominant antigen involved in active transport of inorganic phosphate across the membrane. [34, 77] Ssb Rv0054 Helix-destabilising protein involved in DNA replication, recombination and repair. [77] lipC Rv0220 Probable esterase LipC with unknown function. A lipolytic enzyme probably active in cellular metabolism. [77] Rv2958c Rv2958c Possible glycosyl transferase with unknown function. Probably involved in cellular metabolism and has a role in resistance to killing by human macrophages. [77] Rv2994 Rv2994 Probable conserved integral membrane protein with unknown function; could be involved in efflux system. [77] Rv1813c Rv1813c A conserved hypothetical protein of unknown function. [81, 82] A60 Located in the cytosol, macromolecular antigen complex, conserved in typical and atypical mycobacteria, main component of commercial ELISA kit (Anda Biologicals, Strasbourg, France). [26] HbhA Rv0475 Protein regulated by iron that promotes extrapulmonary dissemination and facilitates adherence to epithelial cells. Induces mycobacterial aggregation. [79] Tpx Rv1932 Probable thiol peroxidase with antioxidant activity. Could remove peroxides or H2O2. [77] Apa Rv1860, MPT-32
45/47kDaAlanine- and proline-rich secreted protein (fibronectin attachment protein). Could mediate bacterial attachment to host cells. [77] AcrA1 Rv3391 Multifunctional enzyme with acyl-CoA-reductase activity. Possibly involved in cellular metabolism. [77] hrp1 Rv2626c Hypoxic response protein 1 of unknown function. [77] PPE17 Rv1168c PPE of unknown function. Induces strong B-cell responses. [4, 77] PPE42 Rv2608 PPE family protein of unknown function. [77] PPE55 Rv3347c PPE family protein of unknown function. [77] MDP1 A histone-like nucleoid associated protein expressed by many mycobacterial species. Could play a role in long-term survival of mycobacteria. [17] INF: interferon; BCG: bacille Calmette–Guérin; LAM: lipoarabinomannan; IL: interleukin; DC: dendritic cell; MDP1: mycobacterial DNA-binding protein 1; HbhA: heparin binding haemagglutinin (adhesin); Ssb: single-strand binding protein; H2O2: hydrogen peroxide; PPE: proline-proline-glutamic acid.
- TABLE 3
The protective antibodies in tuberculosis (TB) upon passive transfer of polyclonal and monoclonal antibodies
Antibody Description Protective effects References Polyclonal antibodies in TB Human IVIg Treatment in MTB-infected mice Significant reduction in bacterial load in spleen and lung [43] Human IVIg Intact versus deglycosylated IVIg in murine models of progressive TB Intact IVIg reduced bacillary load in the lung [42] Human IgG Intranasal inoculation 2 h before MTB infection in mice Significant reduction in pulmonary bacterial load lasting for 2 months [41] Hyperimmune sera (RUTI) Protection against post-chemotherapy relapse TB infection in SCID mice Significant reduction in bacillary load, less granuloma and less pneumonia compared to the control sera [44] Human sera Antibodies from LTBI and active TB in aerosol MTB challenge in mice Antibodies from LTBI showed moderate protection [40] Human IgG against PPD IgG from LTBI showed higher sialic acid and galactose Anti-inflammatory activity [13] Monoclonal antibodies in TB Human mAb (2E9IgA1) against Acr Intranasal inoculation in transgenic mice Reduced the bacterial burden
Dependant on CD98 (FcαRI)[39] mAbs IgA (TBA61) against Acr Intranasal inoculation in mice 10-fold reduction in CFU [45] Coating of BCG mAbs against HBHA Intranasal infection in mice Prevents extrapulmonary dissemination [47] mAbs (SMITB14) anti-LAM IgG1 Intranasal administration in mice Improved survival, reduced CFU, reduced weight loss [48] IVIg: intravenous immunoglobulin; MTB: Mycobacterium tuberculosis; SCID: severe combined immunodeficiency; LTBI: latent TB infection; mAb: monoclonal antibody; Acr: alpha crystalline; LAM: lipoarabinomannan; CFU: colony-forming unit; HBHA: heparin-binding haemagglutinin adhesin.
- TABLE 4
Antibody responses in current tuberculosis (TB) vaccine candidates
TB vaccine Current stage# Evidence of humoral immunity References Antibodies in BCG vaccines BCG IgG against AM enhanced phagolysosome fusion and intracellular growth inhibition [51] BCG IgG against LAM enhanced cell and innate immunity, enhanced phagocytosis [52] BCG IgG against mycobacterial cell lysate elevated post-BCG [53] Antibodies in subunit TB vaccines M72/AS01E IIb Anti-M72 IgG in humans correlated with protection and persisted for 3 years [56] H56:IC31 IIb Induced H56-specific IgG in phase I trial [61] (H4:IC31, H56:IC31 and BCG revaccination) I Induced anti-H4 and anti-H56 IgG1 and IgG3 [59] ID93/GLA-SE IIa ID93-specific IgG induced in phase I trials [62] AM-Ag85A Protective anti-AM and anti-Ag85A antibodies in preclinical study [63] Antibodies in viral vector-based TB vaccines MVA85A II Ag85A-specific CD4 T-cell failed to show protection while anti-Ag85A IgG was protective [12] MVA85A-IMX313 and MVA85A Induced IgG specific to Ag85A in phase I trials [66] ChAdOx185A/MVA85A I Prime vaccination induced anti-Ag85A IgG, and IgG levels increased by a booster vaccine [67] Antibodies in whole-cell TB vaccines VPM1002 (rBCG) Live/II Higher anti-PPD antibodies in human in phase II compared to BCG [68] DAR-901 Killed/IIb Induced humoral immunity in mouse model of infection [69] RUTI Killed/IIa Mixed Th1 and Th2 response with antigen-specific antibodies [70] BCG: bacille Calmette–Guérin; AM: arabinomannan; LAM: lipoarabinomannan; Th: T-helper cell. #: the stages of the current TB vaccines included in the table refer to clinical development stages and are based on the TuBerculosis Vaccine Initiative [54].
Supplementary Material
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Supplementary material ERR-0218-2021.SUPPLEMENT
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- Abstract
- Abstract
- Introduction
- The role of antibodies in TB diagnosis and treatment monitoring
- The role of antibodies in TB prophylaxis and therapy
- Antibody response in TB vaccines
- Mechanism of antibody-mediated protection
- Studies not showing the protective functions of antibodies
- Conclusion and perspectives
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