Ethnic Variation in Inflammatory Profile in Tuberculosis

et al. (2013) Ethnic Variation in Inflammatory Profile in Tuberculosis. PLoS Pathog 9(7): e1003468. doi:10.1371/journal.ppat.1003468 Ethnic Variation in Inflammatory Profile in Tuberculosis Anna K. Coussens 0 Robert J. Wilkinson 0 Vladyslav Nikolayevskyy 0 Paul T. Elkington 0 Yasmeen Hanifa 0 Kamrul Islam 0 Peter M. Timms 0 Graham H. Bothamley 0 Alleyna P. Claxton 0 Geoffrey E. Packe 0 Mathina Darmalingam 0 Robert N. Davidson 0 Heather J. Milburn 0 Lucy V. Baker 0 Richard D. Barker 0 Francis A. Drobniewski 0 Charles A. Mein 0 Leena Bhaw-Rosun 0 Rosamond A. Nuamah 0 Christopher J. Griffiths 0 Adrian R. Martineau 0 Thomas R. Hawn, University of Washington, United States of America 0 1 Division of Mycobacterial Research, MRC National Institute for Medical Research , London , United Kingdom , 2 Division of Medicine, Imperial College London , London , United Kingdom , 3 Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute , London , United Kingdom , 4 Department of Infectious Diseases and Immunity, Imperial College , London , United Kingdom , 5 Homerton University NHS Foundation Trust , London , United Kingdom , 6 Newham Chest Clinic, Forest Gate , London , United Kingdom , 7 Department of Respiratory Medicine, Whipps Cross University Hospital , London , United Kingdom , 8 Tuberculosis Clinic, Northwick Park Hospital, Harrow, United Kingdom, 9 Department of Respiratory Medicine, Guy's and St Thomas' NHS Foundation Trust , London , United Kingdom , 10 Department of Respiratory Medicine, Lewisham Hospital , London , United Kingdom , 11 Department of Respiratory Medicine, Kings College Hospital , London , United Kingdom , 12 Genome Centre, Queen Mary University of London, Barts and The London School of Medicine , London , United Kingdom Distinct phylogenetic lineages of Mycobacterium tuberculosis (MTB) cause disease in patients of particular genetic ancestry, and elicit different patterns of cytokine and chemokine secretion when cultured with human macrophages in vitro. Circulating and antigen-stimulated concentrations of these inflammatory mediators might therefore be expected to vary significantly between tuberculosis patients of different ethnic origin. Studies to characterise such variation, and to determine whether it relates to host or bacillary factors, have not been conducted. We therefore compared circulating and antigen-stimulated concentrations of 43 inflammatory mediators and 14 haematological parameters (inflammatory profile) in 45 pulmonary tuberculosis patients of African ancestry vs. 83 patients of Eurasian ancestry in London, UK, and investigated the influence of bacillary and host genotype on these profiles. Despite having similar demographic and clinical characteristics, patients of differing ancestry exhibited distinct inflammatory profiles at presentation: those of African ancestry had lower neutrophil counts, lower serum concentrations of CCL2, CCL11 and vitamin D binding protein (DBP) but higher serum CCL5 concentrations and higher antigen-stimulated IL-1 receptor antagonist and IL-12 secretion. These differences associated with ethnic variation in host DBP genotype, but not with ethnic variation in MTB strain. Ethnic differences in inflammatory profile became more marked following initiation of antimicrobial therapy, and immunological correlates of speed of elimination of MTB from the sputum differed between patients of African vs. Eurasian ancestry. Our study demonstrates a hitherto unappreciated degree of ethnic heterogeneity in inflammatory profile in tuberculosis patients that associates primarily with ethnic variation in host, rather than bacillary, genotype. Candidate immunodiagnostics and immunological biomarkers of response to antimicrobial therapy should be derived and validated in tuberculosis patients of different ethnic origin. - Funding: The study was funded by the British Lung Foundation (ref TB05/11, http://www.blf.org.uk) and the UK Medical Research Council (programme number U1175 22141, http://www.mrc.ac.uk). RJW also receives support from the Wellcome Trust (ref 088316, http://www.wellcome.ac.uk/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Introduction Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB), emerged as a pathogen in Africa and has co-evolved with humans following migration to Europe and Asia some 70,000 years ago [1]. Distinct phylogenetic lineages of MTB consistently associate with human populations of different genetic ancestry in a variety of settings [25] and elicit differing immune responses from antigen-presenting cells of healthy donors in vitro [611]. Antimycobacterial immune responses might therefore be expected to vary between TB patients of different ethnic origin; however, studies investigating this question have not been conducted. Demonstration of significant ethnic variation in inflammatory responses at presentation and after initiation of treatment would have implications for the development of immunodiagnostics and for the identification of surrogate endpoints for trials of antituberculous drugs. We therefore conducted a study to characterise ethnic variation in circulating and antigen-stimulated concentrations of a panel of 43 soluble inflammatory mediators and 14 haematological parameters (collectively termed inflammatory profile) before and after intensive-phase antituberculous therapy in a multiethnic cohort of patients with pulmonary tuberculosis (PTB) who participated in a clinical trial of adjunctive vitamin D supplementation conducted in London, UK [12]. The primary comparison was between patients of African vs. Eurasian ancestry, on the grounds of the distinct genetic structure of these populations [13], Mycobacterium tuberculosis (MTB) is the causative agent of tuberculosis. Genetically distinct strains of MTB cause disease in particular ethnic groups, and these strains vary in their ability to elicit inflammatory responses from antigen-presenting cells in vitro. Circulating and antigenstimulated concentrations of inflammatory mediators (inflammatory profile) might therefore be expected to differ between tuberculosis patients of different ethnic origin; however, this question has not previously been addressed. We therefore conducted a study to characterise ethnic variation in inflammatory profiles in a cohort of 128 newly-diagnosed tuberculosis patients in London, UK. Patients of African vs. Eurasian ancestry had distinct inflammatory profiles at presentation; differences did not relate to MTB strain variation between groups, but they did associate with ethnic variation in host genotype. Moreover, immunological correlates of the rate of MTB clearance from sputum differed between patients of African vs. Eurasian ancestry. Our findings provide insig (...truncated)