Longitudinal immune profiles in type 1 leprosy reactions in Bangladesh, Brazil, Ethiopia and Nepal

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.

Longitudinal IP-10 Serum Levels Are Associated with the Course of Disease Activity and Remission in Patients with Rheumatoid Arthritis

“…The level of IP-10 at a single time point is therefore not informative whatsoever with respect to disease activity, as it may fluctuate significantly between different individuals, regardless of their clinical status. Similar results were obtained for sera derived from leprosy patients with or without leprosy reactions (8,26). Longitudinal monitoring is therefore vital for management of inflammatory diseases and can provide…”

“…The increase in IP-10 serum levels during acute inflammatory episodes of leprosy (7)(8)(9), the exaggerated inflammatory responses in Behçet's syndrome (32), and the association with augmented RA disease activity observed in this study suggest a longitudinal increase in IP-10 as a general marker for episodes of exacerbated inflammation. The association of IP-10 with DAS shows that rapid assessment of IP-10 levels by use of user-friendly UCP-LFAs can potentially be used as an easy and cheap alternative or additional tool to help monitor disease activity in RA.…”

“…In this respect, it is notable that RA shares genetic risk factors with completely different inflammatory diseases, such as leprosy (5,6). In leprosy, a chronic infectious disease caused by Mycobacterium leprae, an increase of gamma interferon-induced protein 10 (IP-10) can be used to monitor the onset of leprosy reactions, acute episodes of increased inflammation which are the major cause of leprosy-associated tissue damage (7)(8)(9). The chemokine IP-10 is secreted by various cell types, and through its receptor (CXCR3), it regulates immune responses by activation and recruitment of leukocytes (T cells, monocytes, and NK cells) (10).…”

Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy

“…Although the gene expression profiles of these subforms of leprosy overlapped, the RR samples showed a greater heterogeneity, as indicated by the size of the ellipsoid that represents the 95% confidence interval. The heterogeneity of the RR samples may relate to differences in the severity and/or duration of the reactional state or intrinsic host ability to respond, as was also observed for RR blood samples (17). It is noteworthy that the histologic differentiation of T-lep and RR forms is often difficult (18,19).…”

Field-Friendly Test for Monitoring Multiple Immune Response Markers during Onset and Treatment of Exacerbated Immunity in Leprosy

“…Moreover, increased IP-10 serum levels are part of the biomarker profile characterizing the early onset of RRs (12,13). Levels of IP-10 decline again during antireactional therapy (13), similar to what has been described during tuberculosis treatment (14).…”