Summary Differences in the activity of monocytes/macrophages, important target cells of Mycobacterium tuberculosis, might influence tuberculosis progression. With the purpose of identifying candidate genes for tuberculosis susceptibility we infected monocytes from both healthy elderly individuals (a tuberculosis susceptibility group) and elderly tuberculosis patients with M. tuberculosis, and performed a microarray experiment. We detected 78 differentially expressed transcripts and confirmed these results by quantitative PCR of selected genes. We found that monocytes from tuberculosis patients showed similar expression patterns for these genes, regardless of whether they were obtained from younger or older patients. Only one of the detected genes corresponded to a cytokine: IL26, a member of the interleukin‐10 (IL‐10) cytokine family which we found to be down‐regulated in infected monocytes from tuberculosis patients. Non‐infected monocytes secreted IL‐26 constitutively but they reacted strongly to M. tuberculosis infection by decreasing IL‐26 production. Furthermore, IL‐26 serum concentrations appeared to be lower in the tuberculosis patients. When whole blood was infected, IL‐26 inhibited the observed pathogen‐killing capability. Although lymphocytes expressed IL26R, the receptor mRNA was not detected in either monocytes or neutrophils, suggesting that the inhibition of anti‐mycobacterial activity may be mediated by lymphocytes. Additionally, IL‐2 concentrations in infected blood were lower in the presence of IL‐26. The negative influence of IL‐26 on the anti‐mycobacterial activity and its constitutive presence in both serum and monocyte supernatants prompt us to propose IL26 as a candidate gene for tuberculosis susceptibility.

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Part of the susceptibility to tuberculosis has a genetic basis, which is clear in primary immunodeficiencies, but is less evident in apparently immunocompetent subjects. Immune responses were analysed in blood samples from tuberculosis patients and their healthy first-degree relatives who were infected in vitro with mycobacteria (either Mycobacterium tuberculosis or M. bovis BCG). The antimicrobial activity against M. tuberculosis in blood from relatives was significantly lower than that observed in healthy controls. Tuberculosis patients exhibited a higher number of neutrophils, and monocyte phagocytosis was inhibited in both relatives and tuberculosis patients. A remarkable finding was that the production of reactive oxygen species by infected neutrophils was higher in relatives than in healthy controls. A higher production of TNFα in infected blood from relatives was also observed. These results may indicate that relatives display a stronger inflammatory response and that their immune response to M. tuberculosis is different from those of unrelated controls. First-degree relatives may represent a highly informative group for the analysis of tuberculosis susceptibility.