Meeting Report: NIH Workshop on the Tuberculosis Immune Epitope Database
Introduction
The National Institutes of Health, National Institute of Allergy and Infectious Diseases, sponsored a workshop in Potomac, Maryland on June 26, 2007, to review the database and analysis tools created by the Immune Epitope Database (IEDB) and Analysis Resource pertaining to Mycobacterium tuberculosis and other mycobacteria. At the workshop, the authors and other experts on immune responses to mycobacteria reviewed the database and discussed the value of the format and the curated data on mycobacterial epitopes, and discussed the biological relevance, potential, and shortcomings of the current information.
As recently reviewed in depth,1, 2 adaptive immune responses to M. tuberculosis and other mycobacteria involve CD4+ and CD8+ T lymphocytes, whose peptide antigens are presented by MHC (HLA in human) class II and class I, respectively. In addition, recent work has revealed that T lymphocytes isolated from humans infected with Mycobacterium tuberculosis can recognize specific lipids, phospholipids, and glycolipids presented by nonpolymorphic CD1a, CD1b, or CD1c molecules on dendritic cells (reviewed in3). Moreover, while antibodies are widely thought to be of little, if any, protective value in tuberculosis, antibody responses to mycobacterial antigens are common, and may have diagnostic value.4
The identification and characterization of specific mycobacterial antigens and epitopes recognized by B and T lymphocytes has considerable value for research, as well as demonstrated practical value in the diagnosis of latent tuberculosis. For example, as a result of research studies on the immune response to M. tuberculosis, identification of commonly recognized antigens and their epitopes has led to development of a recombinant BCG vaccine that overexpresses antigen 85B5 and is currently being studied in clinical trials in humans. Investigation of the CD4+ T cell epitopes contained in Ag85B identified peptide-25 and the subsequent preparation of mice with a transgenic T cell antigen receptor (TCR) specific for peptide-25 and the murine class II allele I-Ab, has proven valuable in studies of the adaptive immune response to M. tuberculosis.6, 7, 8, 9 In addition, identification of specific M. tuberculosis epitopes recognized by CD4+ and CD8+ T lymphocytes during murine infection has permitted study of the frequency, trafficking, differentiation, and fate of antigen-specific T lymphocyte populations during infection.10, 11 Knowledge of mycobacterial epitopes recognized by CD4+ and CD8+ T lymphocytes from humans infected with M. tuberculosis is essential for preparation of peptide-loaded HLA (class I and II) tetramers for study of the frequency and phenotypes of antigen-specific T lymphocytes in humans with latent or active tuberculosis, and in vaccine trials. Moreover, characterization of antigens (and their epitopes) specific for M. tuberculosis, and not present in BCG, has already guided the development of improved interferon gamma-release assays that distinguish between immune responses due to BCG vaccination and those due to latent tuberculosis.12 It is widely hoped that these efforts will also provide the foundation for development of tuberculosis vaccines with improved efficacy against pulmonary tuberculosis in adults. With this background, the IEDB and Analysis Resource, with the support of the US National Institutes of Allergy and Infectious Diseases (NIAID), initiated a project to collect, curate, and provide ready access to the existing knowledge of epitopes derived from M. tuberculosis and other mycobacteria.
Section snippets
The Immune Epitope Database
The IEDB, a continuously updated online resource available at http://immuneepitope.org/, contains data on T cell and B cell epitopes obtained from published studies, as well as from direct data submissions, with a focus on NIAID Category A, B and C priority pathogens and emerging/re-emerging infectious diseases (http://www3.niaid.nih.gov/research/topics/emerging/list.htm), including M. tuberculosis. In order to provide data on epitopes and not all immunogenic molecules, only molecular
Biological significance and utility of reference epitope datasets
The discussion sessions in the workshop focused on the biological significance of the information in the epitope database. One topic of particular interest was the potential variation in structure, sequence, and expression of genes encoding epitope-bearing antigens.
Recent characterization of M. tuberculosis strains by analysis of large sequence polymorphisms (insertions and deletions) and single-nucleotide polymorphisms has revealed more diversity between strains than previously believed,
Knowledge gaps
The participants at the workshop discussed and identified a wide range of existing gaps in knowledge regarding epitopes and immune responses. Several of the topics that received the longest discussion are noted below.
The species and strain specificity of most of the epitopes in the IEDB for mycobacteria is unknown. Epitopes of greatest value for diagnostic tests should be specific for the species of interest, e.g., M. tuberculosis or M. leprae. In the case of vaccine epitopes, species
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Designing fusion molecules from antigens of Mycobacterium tuberculosis for detection of multiple antibodies in plasma of TB patients
2020, TuberculosisCitation Excerpt :RD2 region, which spans from Rv1978 to Rv1988, gained importance due to its high immune response and absence from the BCG genome. Of these, Immune Epitope Database (IEDB) [7] confirmed seven ORF's, including Rv1984c that possess capability of eliciting strong immune response [8]. Functional studies reveal that Rv1984c hydrolyzes cutin and hence exhibit esterase activity with profound role in lipid metabolism [2,9].
Genetic diversity of immune-related antigens in Region of Difference 2 of Mycobacterium tuberculosis strains
2017, TuberculosisCitation Excerpt :Region of Difference 2 was lost between the years 1927 and 1931, a time when vaccinologists reported the further attenuation of the BCG vaccine [8]. According to IEDB [5], there were seven antigens (Rv1979c, Rv1980c, Rv1983, Rv1984c, Rv1985c, Rv1986 and Rv1987) encoded by RD2 that harbored T- and/or B-cell epitopes. We excluded Rv1983 in the study, as it belongs to PE/PPE genes which reported to be independent of Human T cell recognition [9].
M. tuberculosis T cell epitope analysis reveals paucity of antigenic variation and identifies rare variable TB antigens
2015, Cell Host and MicrobeCitation Excerpt :Again consistent with our previous findings (Comas et al., 2010), we found that all epitope regions combined showed a significantly lower dN/dS compared to the corresponding nonepitope regions of the same proteins, or to essential genes (Wilcoxon signed-rank test p = p < 2.2−16 and p = 4.4−14, respectively) (Figure 1B). Since inclusion of epitopes in the IEDB does not require that peptides meet preset criteria (Ernst et al., 2008), we separately analyzed a subset of 163 peptides (included in the initial set of 1,226) identified in a recent T cell epitope screen as the most immunodominant among 20,610 peptides examined (Lindestam Arlehamn et al., 2013). After filtering out epitopes found in repetitive loci (58/163), we found that 9 of the 105 immunodominant epitopes (8.6%) contained sequence variants in more than one strain, while 11 additional epitopes contain variants in a single strain (singletons) (Table S1).