Abstract
Leprosy reversal reactions type 1 (T1R) are acute immune episodes that affect a subset of leprosy patients and remain a major cause of nerve damage. Little is known about the relative importance of innate versus environmental factors in the pathogenesis of T1R. In a retrospective design, we evaluated innate differences in response to Mycobacterium leprae between healthy individuals and former leprosy patients affected or free of T1R by analyzing the transcriptome response of whole blood to M. leprae sonicate. Validation of results was conducted in a subsequent prospective study. We observed the differential expression of 581 genes upon exposure of whole blood to M. leprae sonicate in the retrospective study. We defined a 44 T1R gene set signature of differentially regulated genes. The majority of the T1R set genes were represented by three functional groups: i) pro-inflammatory regulators; ii) arachidonic acid metabolism mediators; and iii) regulators of anti-inflammation. The validity of the T1R gene set signature was replicated in the prospective arm of the study. The T1R genetic signature encompasses genes encoding pro- and anti-inflammatory mediators of innate immunity. This suggests an innate defect in the regulation of the inflammatory response to M. leprae antigens. The identified T1R gene set represents a critical first step towards a genetic profile of leprosy patients who are at increased risk of T1R and concomitant nerve damage.
Highlights
Leprosy is a chronic human infectious disease caused by Mycobacterium leprae
Leprosy type 1 reversal reactions (T1R) are an important cause of nerve damage in leprosy patients and accurate prediction of patients at increased risk of T1R is a major challenge of current leprosy control
As the discovery sample we enrolled cured leprosy patients who had been diagnosed with T1R at the time of leprosy diagnosis and leprosy patients who had never undergone T1R
Summary
Leprosy is a chronic human infectious disease caused by Mycobacterium leprae. If left untreated the disease results in pronounced skin deformities and nerve disabilities due to preferential invasion of macrophages and Schwann cells by M. leprae. Efforts by the World Health Organisation (WHO) to eliminate leprosy resulted in a substantial reduction of global disease prevalence from 5.35 million in 1985 to 211,903 by 2010. Leprosy displays a wide spectrum of clinical manifestations. Tuberculoid (TT) and lepromatous leprosy (LL), characterized by the presence and absence of specific cellular immune responses, respectively, represent the opposite ends of the clinical spectrum [2,3]. Immunological, bacteriological, and clinical criteria, Ridley and Jopling classified three additional intermediate, or ‘‘borderline,’’ types as borderline tuberculoid (BT), mid borderline (BB), and borderline lepromatous (BL) leprosy [4]
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