Indigenous Pulmonary Propionibacterium acnes Primes the Host in the Development of Sarcoid-Like Pulmonary Granulomatosis in Mice

Abstract

Although many cases of sarcoidosis are self-limiting with spontaneous remission, uncontrolled pulmonary granulomatosis with fibrosis produces intolerable longterm respiratory symptoms in a minority of patients. Individuals with chronic pulmonary sarcoidosis require an alternative therapy to corticosteroidal treatment because of its insufficient effectiveness. Although many researchers have considered infection as the triggering factor for this disease, the mechanisms by which the candidate causative organisms induce this disorder remain unclear. We report here that extrapulmonary sensitization to Propionibacterium acnes, which is one of the candidates to date, induced pulmonary Th-1 granulomas mainly in the subpleural and peribronchovascular regions often observed in sarcoidosis. These granulomas appear to be caused by indigenous P. acnes pre-existing in the lower respiratory tract of the normal lung, which is believed to be germ-free, and by an influx of P. acnes-sensitized CD4 ؉ T cells from the circulation. Importantly, the eradication of indigenous P. acnes with antibiotics alleviated the granulomatous lung disease. This is the first report to present clear evidence of the contribution of an indigenous pulmonary bacterium to the formation of granulomatous lesions in the lung. We propose that treatment targeting indigenous P. acnes in the lung may be a possible remedy for pulmonary sarcoidosis. Sarcoidosis is one of the best-known systemic granulomatous diseases; however, despite a number of intensive investigations, its etiology has remained unresolved for more than 100 years. 1 The lung is the organ that is most commonly affected by this disorder. Although uncontrolled pulmonary granulomatosis only occurs in a minority of patients, these individuals are at risk of irreversible lung fibrosis and have a poor prognosis owing to interference with gaseous exchange. As the lung is constantly confronted with airborne substances, including pathogens, many researchers have considered infection as the trigger, and have tried to identify possible causative transmissible agents and their contribution to the mechanism of formation of pulmonary sarcoid granuloma. 2,3 Because of their clinical and immunopathological similarities, it has been suggested that the most common mycobacterial infection, tuberculosis, might be related to sarcoidosis. However, despite the use of bacterial culture systems, and histochemical and polymerase chain reaction (PCR)-based methods, an association between Mycobacterium tuberculosis and sarcoidosis remains controversial. 4 -6 Propionibacterium acnes, which is an anaerobic nonspore-forming gram-positive rod bacterium that exists indigenously on the skin or mucosal surfaces, 7 has been reported as one of the suggested causative antigens of sarcoidosis. 8 Some studies using quantitative PCR have revealed markedly higher levels of P. acnes genomes in the mediastinal or superficial lymph nodes (LNs) of sarcoid patients than in those of controls, suggesting that there is an intrinsic infection be...

Blockade of Th1 chemokine receptors ameliorates pulmonary granulomatosis in mice

“…injection of heat-killed P. acnes. As reported previously [26], many granulomatous lesions were developed in the liver, but not in the lungs, after immunisation with heatinactivated P. acnes and IFA ( fig. 1a and b).…”

“…E3), without heat-inactivated P. acnes also could induce many large granulomas in the lungs, indicating that the pulmonary granulomatosis seen in this model was mediated by immune reactions against P. acnes. NISHIWAKI et al [26] also reported that repeated immunisation with heat-killed P. acnes using complete Freund's adjuvant (CFA) induced pulmonary granulomatosis [26], although we could not reproducibly generate granulomas using similar methods with IFA. The reason for this discrepancy is not clear, but it is likely to be due to the difference in the route and dose of immunisation with heatkilled P. acnes or adjuvant.…”

“…In previous reports, levels of Th1 cytokines including IFN-c, TNF-a and IL-12 were elevated in models of pulmonary granulomatosis induced by P. acnes [26,29], whereas there is no published report analysing chemokines. Here, we showed significant upregulation of CXCL9 and CXCL10 expression during pulmonary granulomatosis induced by heat-killed P. acnes.…”

“…are aetiologically linked to sarcoidosis [16][17][18]. Using heat-inactivated P. acnes, several models of pulmonary granulomatosis have been established [26,28]. MCCASKILL et al [28] showed that the intratracheal administration of heat-killed P. acnes induced granulomatosis in the lungs of mice.…”

Diagnostic and Therapeutic Management of Cardiac Sarcoidosis -Application of High Resolution Electrocardiography

“…Sarcoidosis is thought to be caused by an abnormal, exaggerated response of the immune system. Infectious agents such as Propionibacterium acnes, Mycobacteria suspected of causing sarcoidosis (Nishiwaki et al, 2004;Hance, 1998) , but The American Thoracic Society's wide-ranging Statement on Sarcoidosis suggested that there is no clear evidence of an infectious agent causing sarcoidosis. Genetic factors such as the human leucocyte antigens (specifically HLA-DRB1) may be a predisposition for sarcoidosis (Maliark et al, 1998), but not the only cause.…”