Cigarette smoking impairs human pulmonary immunity to Mycobacterium tuberculosis.
BACKGROUND
Cigarette smoking is linked to important aspects of tuberculosis, such as susceptibility to infection, disease reactivation, mortality, transmission, and persistent infectiousness. The mechanistic basis for this remains poorly understood.


OBJECTIVE
To compare the functional impairment seen in human alveolar macrophages (AM) from nonsmokers, smokers, and ex-smokers after infection with Mycobacterium tuberculosis (Mtb).


METHODS
AM were acquired at bronchoscopy, and number and viability from smoking donors were compared with nonsmoking donors. AM were challenged in vitro with Mtb and intracellular bacterial viability was measured. Cytokine secretion was measured 24 hours postinfection by ELISA. Previously we determined the frequency of CD4(+)FoxP3(+) T cells in the presence or absence of allogeneic AM, and data were reanalyzed to separate the patient subjects according to smoking status.


RESULTS
There were significantly more AM from smokers compared with nonsmokers or ex-smokers (P < 0.01). AM from smokers could not control intracellular Mtb growth. Nonsmokers' AM generated significantly more tumor necrosis factor (TNF)-α, IFN-γ, and IL-1β after Mtb infection compared with uninfected AM (P < 0.05). However, Mtb-infected AM from smokers did not secrete significantly more TNF-α, IFN-γ, and IL-1β compared with uninfected smokers' AM. AM taken from ex-smokers also failed to secrete significantly increased TNF-α, IFN-γ, and IL-1β after Mtb infection. Both smokers' and nonsmokers' AM induced FoxP3(+) T regulatory cell phenotype responses in allogeneic admixed T cells (>4.8 fold; P < 0.05). Even after Mtb infection, AM continued to drive this regulatory phenotype.


CONCLUSIONS
In smokers, the pulmonary compartment has a number of macrophage-specific immune impairments that provide some mechanistic explanations whereby cigarette smoking renders a patient susceptible to tuberculosis infection and disease.
1 Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland; and.
Seónadh M
SM
O'Leary
Michelle M
MM
Coleman
Wui Mei
WM
Chew
Colette
C
Morrow
Anne Marie
AM
McLaughlin
Laura E
LE
Gleeson
Mary P
MP
O'Sullivan
Joseph
J
Keane
D000368:Aged; D001999:Bronchoscopy; D016022:Case-Control Studies; D016207:Cytokines / Q000502:physiology; D004198:Disease Susceptibility / Q000209:etiology / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007111:Immunity, Cellular; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000502:physiology; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology; D012907:Smoking / Q000009:adverse effects*; D014397:Tuberculosis, Pulmonary / Q000209:etiology* / Q000276:immunology
D016207:Cytokines
Mycobacterium tuberculosis; innate immune response; tobacco products