Abstract
BackgroundAcute inflammatory reactions are a frequently occurring, tissue destructing phenomenon in infectious- as well as autoimmune diseases, providing clinical challenges for early diagnosis. In leprosy, an infectious disease initiated by Mycobacterium leprae (M. leprae), these reactions represent the major cause of permanent neuropathy. However, laboratory tests for early diagnosis of reactional episodes which would significantly contribute to prevention of tissue damage are not yet available.Although classical diagnostics involve a variety of tests, current research utilizes limited approaches for biomarker identification. In this study, we therefore studied leprosy as a model to identify biomarkers specific for inflammatory reactional episodes.MethodsTo identify host biomarker profiles associated with early onset of type 1 leprosy reactions, prospective cohorts including leprosy patients with and without reactions were recruited in Bangladesh, Brazil, Ethiopia and Nepal. The presence of multiple cyto-/chemokines induced by M. leprae antigen stimulation of peripheral blood mononuclear cells as well as the levels of antibodies directed against M. leprae-specific antigens in sera, were measured longitudinally in patients.ResultsAt all sites, longitudinal analyses showed that IFN-γ-, IP-10-, IL-17- and VEGF-production by M. leprae (antigen)-stimulated PBMC peaked at diagnosis of type 1 reactions, compared to when reactions were absent. In contrast, IL-10 production decreased during type 1 reaction while increasing after treatment. Thus, ratios of these pro-inflammatory cytokines versus IL-10 provide useful tools for early diagnosing type 1 reactions and evaluating treatment. Of further importance for rapid diagnosis, circulating IP-10 in sera were significantly increased during type 1 reactions. On the other hand, humoral immunity, characterized by M. leprae-specific antibody detection, did not identify onset of type 1 reactions, but allowed treatment monitoring instead.ConclusionsThis study identifies immune-profiles as promising host biomarkers for detecting intra-individual changes during acute inflammation in leprosy, also providing an approach for other chronic (infectious) diseases to help early diagnose these episodes and contribute to timely treatment and prevention of tissue damage.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-015-1128-0) contains supplementary material, which is available to authorized users.
Highlights
Acute inflammatory reactions are a frequently occurring, tissue destructing phenomenon in infectious- as well as autoimmune diseases, providing clinical challenges for early diagnosis
Host resistance to M. leprae is associated with the emergence of a protective Thelper-1 (Th1)-based response characterized by the secretion of the innate and adaptive cytokines IL-12p70, IFN-γ, lymphotoxin-α/β, and other pro-inflammatory cytokines such as TNF-α
Since patients were frequently diagnosed with reaction before steroids (RR) at their first clinic-visit, it became clear that it was not always feasible to include these first samples
Summary
Acute inflammatory reactions are a frequently occurring, tissue destructing phenomenon in infectious- as well as autoimmune diseases, providing clinical challenges for early diagnosis. An infectious disease initiated by Mycobacterium leprae (M. leprae), these reactions represent the major cause of permanent neuropathy. The inter-individual variability in clinical manifestations of leprosy closely parallels the ability of the host to mount an effective immune response to M. leprae. This is depicted by an immunological and clinical spectrum in those who progress to disease, ranging between two completely different poles i.e. tuberculoid (TT) and lepromatous (LL) leprosy [8]. TT patients produce exacerbated levels of pro-inflammatory cytokines, including those produced by Th17 rather than Th1, and frequently driven by strong innate immune activation resulting in the release of IL-1β and/or IL-6, TGF-β and IL-23 [9, 10]
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