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


METHODS
To 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.


RESULTS
At 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.


CONCLUSIONS
This 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.
Mycobacterial Research Laboratories, Anandaban Hospital, Kathmandu, Nepal. saraswotikhadge@gmail.com.
Saraswoti
S
Khadge
International Center for Diarrhoeal Disease Research Bangladesh, Dhaka, Bangladesh. sbanu@icddrb.org.
Sayera
S
Banu
Dept. of Infectious Diseases, Leiden University Medical Center (LUMC), PO Box 9600, 2300 RC, Leiden, The Netherlands. kbobosha@gmail.com.|Armauer Hansen Research Institute, Addis Ababa, Ethiopia. kbobosha@gmail.com.
Kidist
K
Bobosha
Dept. of Infectious Diseases, Leiden University Medical Center (LUMC), PO Box 9600, 2300 RC, Leiden, The Netherlands. jjvanschip@hotmail.com.
Jolien J
JJ
van der Ploeg-van Schip
National Reference Center for Sanitary Dermatology and Leprosy, Faculty of Medicine, Federal University of Uberlandia, Minas Gerais, Brazil. isagoulart@centershop.com.br.
Isabela M
IM
Goulart
Mycobacterial Research Laboratories, Anandaban Hospital, Kathmandu, Nepal. pratibhathapakunwar@gmail.com.
Pratibha
P
Thapa
Mycobacterial Research Laboratories, Anandaban Hospital, Kathmandu, Nepal. kunwarcb@yahoo.co.uk.
Chhatra B
CB
Kunwar
Dept. of Infectious Diseases, Leiden University Medical Center (LUMC), PO Box 9600, 2300 RC, Leiden, The Netherlands. K.E.van_Meijgaarden@lumc.nl.
Krista E
KE
van Meijgaarden
Dept. of Infectious Diseases, Leiden University Medical Center (LUMC), PO Box 9600, 2300 RC, Leiden, The Netherlands. S.J.F.van_den_Eeden@lumc.nl.
Susan J F
SJ
van den Eeden
International Center for Diarrhoeal Disease Research Bangladesh, Dhaka, Bangladesh. G.L.Wilson@lumc.nl.
Louis
L
Wilson
International Center for Diarrhoeal Disease Research Bangladesh, Dhaka, Bangladesh. senjuti.kabir@icddrb.org.
Senjuti
S
Kabir
International Center for Diarrhoeal Disease Research Bangladesh, Dhaka, Bangladesh. hymonti7@gmail.com.
Hymonti
H
Dey
National Reference Center for Sanitary Dermatology and Leprosy, Faculty of Medicine, Federal University of Uberlandia, Minas Gerais, Brazil. goulartlr@gmail.com.
Luiz R
LR
Goulart
National Reference Center for Sanitary Dermatology and Leprosy, Faculty of Medicine, Federal University of Uberlandia, Minas Gerais, Brazil. janaina01@yahoo.com.
Janaina
J
Lobato
National Reference Center for Sanitary Dermatology and Leprosy, Faculty of Medicine, Federal University of Uberlandia, Minas Gerais, Brazil. washingtonjcarvalho@yahoo.com.br.
Washington
W
Carvalho
Armauer Hansen Research Institute, Addis Ababa, Ethiopia. yoni4m@gmail.com.
Yonas
Y
Bekele
Dept. of Infectious Diseases, Leiden University Medical Center (LUMC), PO Box 9600, 2300 RC, Leiden, The Netherlands. C.L.M.C.Franken@lumc.nl.
Kees L M C
KL
Franken
Armauer Hansen Research Institute, Addis Ababa, Ethiopia. aseffaa@gmail.com.
Abraham
A
Aseffa
Dept. of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, USA. John.Spencer@colostate.edu.
John S
JS
Spencer
National Reference Center for Sanitary Dermatology and Leprosy, Faculty of Medicine, Federal University of Uberlandia, Minas Gerais, Brazil. l.oskam@kit.nl.
Linda
L
Oskam
Dept. of Infectious Diseases, Leiden University Medical Center (LUMC), PO Box 9600, 2300 RC, Leiden, The Netherlands. t.h.m.ottenhoff@lumc.nl.
Tom H M
TH
Otttenhoff
Mycobacterial Research Laboratories, Anandaban Hospital, Kathmandu, Nepal. deannahagge@gmail.com.
Deanna A
DA
Hagge
Dept. of Infectious Diseases, Leiden University Medical Center (LUMC), PO Box 9600, 2300 RC, Leiden, The Netherlands. ageluk@lumc.nl.
Annemieke
A
Geluk
D001459:Bangladesh; D015415:Biomarkers / Q000032:analysis*; D001938:Brazil; D016207:Cytokines / Q000097:blood / Q000276:immunology*; D005002:Ethiopia; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology; D016753:Interleukin-10 / Q000097:blood; D020381:Interleukin-17 / Q000097:blood; D007918:Leprosy / Q000175:diagnosis / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000382:microbiology; D008297:Male; D008875:Middle Aged; D009166:Mycobacterium leprae / Q000276:immunology / Q000472:pathogenicity*; D009390:Nepal; D011446:Prospective Studies
D015415:Biomarkers; D016207:Cytokines; C508609:IL10 protein, human; C508717:IL17A protein, human; D020381:Interleukin-17; D016753:Interleukin-10