Susceptibility to pulmonary disease due to Mycobacterium avium–intracellulare complex may reflect low IL-17 and high IL-10 responses rather than Th1 deficiency
Introduction
Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that rarely cause disease in immunocompetent hosts. However, some individuals are susceptible and develop lung disease, most commonly due to organisms from the Mycobacterium avium–intracellulare complex (MAC). The incidence of non-tuberculous mycobacterial lung disease (NTMLD) is increasing worldwide, particularly in Western countries where isolates of NTM now outnumber those of M. tuberculosis in patients with mycobacterial lung disease [1], [2], [3], [4].
The most common form of NTMLD occurs as nodular bronchiectasis predominantly in white, non-smoking, post-menopausal women with a slender body habitus. These patients typically present with cough and weight loss but are otherwise healthy and do not have any apparent underlying immune defect. Physical chest abnormalities and changes in levels of sex hormones may be predisposing factors [5], [6], [7], but there is little evidence for causative roles. It is unclear why this demographic exhibits greater susceptibility to infection with NTM.
There is a paucity of research addressing immunological susceptibility to NTMLD. These few studies suggest that patients with NTMLD have suboptimal mitogen- and antigen-specific inflammatory responses compared with healthy controls. Specifically, peripheral blood mononuclear cells (PBMC) and monocytes from NTM patients cultured with anti-CD3, phytohaemagglutinin (PHA) or heat-killed MAC produced less Th1 cytokines (IFNγ, IL-12, and TNFα) compared with those from healthy controls [8], [9], [10], [11], prompting the hypothesis that NTMLD may reflect defects in the IL-12/IFNγ pathway. PHA-induced production of IL-10 was higher in NTM patients than healthy controls in one study [11]. Another report found no differences in the levels of proinflammatory cytokines or IL-10 after stimulation of PBMC with PHA [7].
PBMC from patients with nodular bronchiectatic presentation of NTMLD were stimulated with tuberculin protein purified derivative (PPD) and sensitin PPD to assess and compare mycobacteria-specific Th1, Th2 and Th17 immune responses with those of adult offspring (household contacts with past or current exposure to NTM) and healthy population controls. PBMC were also stimulated with the mitogen staphylococcal enterotoxin B (SEB) to assess overall capacity for cytokine production. The frequencies of cytokine-producing CD4+ T cells and levels of cytokines released into cell culture supernatant were measured.
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Study groups and sample collection
The study investigated 17 patients with NTMLD attending outpatient clinics at Royal Perth Hospital (Western Australia) enrolled between March 2007 and August 2008 (4 males and 13 females; median age, range = 66, 52–92), 15 adult offspring of 12 patients (6 males and 9 females; median age, range = 39, 30–67) and 13 healthy population controls (6 males and 7 females; median age, range = 58, 44–79). All subjects were Caucasian. Offspring and healthy population controls had no histories of mycobacterial
NTM patients and their offspring display similar or higher mitogen- and mycobacteria-specific IFNγ responses compared with population controls
PBMC were assessed for their capacity to produce IFNγ and IL-5 as markers of Th1 and Th2 responses, respectively. All groups had similar frequencies of IFNγ+CD4+ T cells responding to SEB after 6 h (Fig. 2A). Frequencies of IFNγ+CD4+ T cells and IFNγ levels in supernatants after 24 h were higher in patients and/or offspring compared with population controls (Figs. 2B and C). In 24-hour cultures with SEB, frequencies of IFNγ-producing CD4+ T cells correlated with total IFNγ release in culture
Discussion
NTM are becoming more prevalent as a cause of pulmonary disease in older adults but immunological susceptibility to NTMLD remains poorly understood. Previous studies that have characterised cellular immune responses in NTM patients implicate poor Th1 responses against mitogens, heat-killed NTM or antigens of NTM. Here, responses of PBMC from patients with the nodular bronchiectatic form of MAC lung disease were assessed to identify any cellular defect in or bias towards Th1, Th2 or Th17
Conclusions
It is unclear why some individuals and not others are susceptible to lung infection by NTM. To shed light on an immunological basis for susceptibility to NTMLD, the present study measured pro- and anti-inflammatory cytokine responses by cultured CD4+ T cells and PBMC in response to mitogen and mycobacterial antigens. The patient group consisted of individuals with the nodular bronchiectatic form of NTMLD, who generally have no known risk factors or underlying immune defects. In contrast to
Acknowledgments
The authors thank Shona Hendry for her assistance in collation of patient medical records, and all the patients, their families and controls who donated the samples. This work was supported by a Research Development Award to A.L. from the University of Western Australia.
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