Significance of antigen and epitope specificity in tuberculosis

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Background

Tuberculosis (TB) remains a major global health problem, despite the routine treatment of most patients with effective combined chemotherapy for the past 60 years. Of the research approaches toward improving infection and disease control, immunology and thereby the knowledge of immunodominant epitopes of Mycobacterium tuberculosis (Mtb) play a prominent role.

The research aims are to develop: (1) a new prophylactic vaccine (the currently used BCG being mostly ineffective); (2) immunodiagnosis of subjects, harbouring active TB, before they could transmit the infection; (3) biomarker tests for i) host protection ii) for predicting active disease and iii) Mtb & HIV coinfection; (4) novel immuno-therapies to shorten chemotherapy; (5) explaining how excessive host immune reactions can lead to lung pathology.

Dissection of the specificity of host immune responses to individual antigens and their constituent immunodominant epitopes has been a mandatory analytical research strategy. It flourished in the past 30 years with the aid of new technologies, such as monoclonal antibodies, recombinant gene expression, T cell cloning, peptide screening (pepscan), understanding of antigen processing and epitope binding to MHC molecules and characterization of cytokine production by different subsets of T cells, amongst others, using multi-parameter flow cytometry technology. .

However, the emphasis on the latter aspect and on the transriptomic signature of T cells expanded possibly at some expense of a corollary analysis of the specificity toward the epitopes of individual antigens. There is a compelling need to restore the balance of knowledge between the functional phenotype and recognition specificities of T cells.

The apparent abundance of MHC-permissively recognised epitopes and their possible role for the evolution of pathogenic mycobacteria is in need of re-evaluation. HLA-permissive epitopes may have evolved by the tubercle bacilli due to the advantage for transmission by infectious aerosol from immune reactions, which lead to lung pathology and protracted survival.

The extensive knowledge of the mapping of antigenic epitopes has been catalogued, and made accessible by the NIH IEDB Database http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2228276/ ; http://www.iedb.org/;
http://help.iedb.org/entries/19150-user-documentation-iedb-version-2). However, the significance of epitope specificity of immune responses of Mtb infected hosts for the host-parasite relationship for better understanding of disease immunopathogenesis and the potentials for improving the management and control of active TB has so far not been collated comprehensively.

The purpose of the proposed ‘Topic Review’ is to fill this gap by inviting researchers accomplished in the study of both experimental models using genetically defined strains of mice and clinical studies, which have characterised the human T and B cell immune repertoire extensively. Emphasis will be given toward the integration of data on the possible associations between epitope specificity and the different effector and regulatory T cell populations. Finally, epitopes will be reviewed for potentials towards the development of vaccines and diagnostics.

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