Leprosy has intrigued immunologists for many decades. Despite minimal genetic variation between Mycobacterium leprae isolates worldwide, two completely different forms of the disease can develop in the susceptible human host: localized, tuberculoid, or
paucibacillary leprosy, which can heal spontaneously, and disseminating, lepromatous, or
multibacillary leprosy, which is progressive if untreated. The questions which host factors regulate these very different outcomes of
infection, by what mechanisms, and whether these can be used to combat disease remain unanswered.
Leprosy has been one of the very first human diseases in which
human leukocyte antigen (HLA) genes were demonstrated to codetermine disease outcome. Jon van Rood was among the earliest researchers to recognize the potential of this ancient disease as a human model to dissect the role of HLA in disease. Decades later, it is now clear that HLA molecules display highly allele-specific
peptide binding capacity. This restricts antigen presentation to M. leprae-reactive T cells and controls the magnitude of the ensuing immune response. Furthermore, specific
peptide/HLA class II complexes can also determine the quality of the immune response by selectively activating regulatory (suppressor) T cells. All these factors are believed to contribute to
leprosy disease susceptibility. Despite the global reduction in
leprosy disease prevalence, new case detection rates remain invariably high, demonstrating that treatment alone does not block transmission of
leprosy. Better tools for early detection of preclinical M. leprae
infection, likely the major source of unidentified transmission, therefore is a priority. Newly developed HLA-based bioinformatic tools now provide novel opportunities to help combat this disease. Here, we describe recent work using
HLA-DR peptide binding algorithms in combination with recently elucidated genome sequences of several different mycobacteria. Using this postgenomic HLA-based approach, we were able to identify 12 candidate genes that were unique to M. leprae and were predicted to contain
T cell epitopes restricted via several major
HLA-DR alleles. Five of these
antigens (ML0576, ML1989, ML1990, ML2283, ML2567) were indeed able to induce significant T cell responses in
paucibacillary leprosy patients and M. leprae-exposed healthy controls but not in most
multibacillary leprosy patients,
tuberculosis patients, or endemic controls. 71% of M. leprae-exposed healthy controls that did not have
antibodies to the M. leprae-specific phenolic
glycolipid-I responded to one or more M. leprae
antigen(s), highlighting the potential added value of these unique M. leprae
proteins in diagnosing early
infection. Thus current state-of-the-art HLA immunogenetics can provide new tools for specific diagnosis of M. leprae
infection, which can impact our understanding of
leprosy transmission and can lead to improved intervention.