The cause(s) of sarcoidosis is unknown.Mycobacteriumspp. are suspected in Europe andPropionibacteriumspp. are suspected in Japan. The present international collaboration evaluated the possible etiological links between sarcoidosis and the suspected bacterial species. Formalin-fixed and paraffin-embedded sections of biopsy samples of lymph nodes, one from each of 108 patients with sarcoidosis and 65 patients with tuberculosis, together with 86 control samples, were collected from two institutes in Japan and three institutes in Italy, Germany, and England. Genomes ofPropionibacterium acnes,Propionibacterium granulosum,Mycobacterium tuberculosis,Mycobacterium aviumsubsp.paratuberculosis, andEscherichia coli(as the control) were counted by quantitative real-time PCR. EitherP. acnesorP. granulosumwas found in all but two of the sarcoid samples.M. aviumsubsp.paratuberculosiswas found in no sarcoid sample.M. tuberculosiswas found in 0 to 9% of the sarcoid samples but in 65 to 100% of the tuberculosis samples. In sarcoid lymph nodes, the total numbers of genomes ofP. acnesorP. granulosumwere far more than those ofM. tuberculosis. P. acnesorP. granulosumwas found in 0 to 60% of the tuberculosis and control samples, but the total numbers of genomes ofP. acnesorP. granulosumin such samples were less than those in sarcoid samples.Propionibacteriumspp. are more likely thanMycobacteriaspp. to be involved in the etiology of sarcoidosis, not only in Japanese but also in European patients with sarcoidosis.

Sarcoidosis likely results from the exposure of a genetically susceptible subject to an environmental agent, possibly an infectious one. Mycobacterial and propionibacterial organisms are the most commonly implicated potential etiologic agents. Propionibacterium acnes is the only microorganism, however, found in sarcoid lesions by bacterial culture. To evaluate the pathogenic role of this indigenous bacterium, we screened for the bacterium in sarcoid and non-sarcoid tissues using immunohistochemical methods with novel P. acnes-specific monoclonal antibodies that react with cell-membrane-bound lipoteichoic acid (PAB antibody) and ribosome-bound trigger-factor protein (TIG antibody). We examined formalin-fixed and paraffin-embedded samples of lungs and lymph nodes from 196 patients with sarcoidosis, and corresponding control samples from 275 patients with non-sarcoidosis diseases. The samples were mostly from Japanese patients, with 64 lymph node samples from German patients. Immunohistochemistry with PAB antibody revealed small round bodies within sarcoid granulomas in 20/27 (74%) video-assisted thoracic surgery lung samples, 24/50 (48%) transbronchial lung biopsy samples, 71/81 (88%) Japanese lymph node samples, and 34/38 (89%) German lymph node samples. PAB antibody did not react with non-sarcoid granulomas in any of the 45 tuberculosis samples or the 34 samples with sarcoid reaction. In nongranulomatous areas, small round bodies detected by PAB antibody were found in alveolar macrophages of lungs and paracortical macrophages of lymph nodes from many sarcoid and some non-sarcoid patients. Large-spheroidal acid-fast bodies, Hamazaki–Wesenberg bodies, which were found in 50% of sarcoid and 15% of non-sarcoid lymph node samples, reacted with both PAB and TIG antibodies. Electron microscopy revealed that these Hamazaki–Wesenberg bodies had a single bacterial structure and lacked a cell wall with occasional protrusions from the body. The high frequency and specificity of P. acnes, detected by PAB antibody within sarcoid granulomas, indicates that this indigenous bacterium might be the cause of granuloma formation in many sarcoid patients.

Propionibacterium acnes is the only microorganism isolated from sarcoid lesions by bacterial culture. Numerous P. acnes genomes are found in lymph node samples from Japanese and European patients with sarcoidosis, whereas a few genomes are found in some non-sarcoid samples. The high frequency and specificity of detecting P. acnes within sarcoid granulomas suggests that this indigenous bacterium causes granuloma formation in many patients with sarcoidosis. P. acnes is the most common commensal bacterium in the lungs and lymph nodes. Occasional detection of P. acnes in non-granulomatous areas of these organs from non-sarcoid patients suggests that host factors are more critical than agent factors in the etiology of sarcoidosis. A particular protein, i.e., trigger factor, from P. acnes causes a cellular immune response only in sarcoid patients. The P. acnes trigger-factor protein induces pulmonary granulomas in mice sensitized with the protein and adjuvant, but only in those with latent P. acnes infection in their lungs. Eradication of P. acnes by antibiotics prevents the development of granulomas in this experimental model. P. acnes can cause latent infection in the lung and lymph nodes and persists in a cell wall-deficient form. The dormant form is endogenously activated under certain conditions and proliferates at the site of latent infection. In patients with P. acnes hypersensitivity, granulomatous inflammation is triggered by intracellular proliferation of the bacterium. Proliferating bacteria may escape granulomatous isolation, spreading to other organs. Latent P. acnes infection in systemic organs can be reactivated by another triggering event, leading to systemic sarcoidosis.

Sarcoidosis is a systemic granulomatous disease of unknown etiology.Propionibacterium acnesis the only microorganism that has been isolated from sarcoid lesions. ManyP. acneshave been detected in sarcoid lymph nodes using quantitative PCR and in sarcoid granulomas byin situhybridization.P. acnestrigger factor protein causes a cellular immune response only in sarcoid patients and induces pulmonary granulomas in mice sensitized with the protein and adjuvant, but only those with latentP. acnesinfection in their lungs. Eradication ofP. acnesby antibiotics prevents the development of granulomas in this experimental model. AlthoughP. acnesis the most common commensal bacterium in the lungs and lymph nodes,P. acnes-specific antibody detected the bacterium within sarcoid granulomas of these organs.P. acnescan cause latent infection in the lung and lymph node and persist in a cell-wall-deficient form. The dormant form is activated endogenously under certain conditions and proliferates at the site of latent infection. In patients withP. acneshypersensitivity, granulomatous inflammation is triggered by intracellular proliferation of the bacterium. Proliferating bacteria may escape granulomatous isolation, spreading to other organs. LatentP. acnesinfection in systemic organs can be reactivated by another triggering event, leading to systemic sarcoidosis.

Tryptases and chymases are the major proteins stored and secreted by mast cells, and they have various biological functions. However, the nature of proteases produced by basophils has been poorly characterized, particularly in mice. mMCP-11 is the most recently discovered mast cell tryptase in mice and was originally identified as Prss34, which is transcribed in some mast cell-like cell lines and at the early stage in the culture of BMMC with IL-3. Curiously, Prss34 is preferentially expressed in the BM and spleen among normal tissues in contrast to other mast cell tryptases. Therefore, it remains elusive what types of cells express mMCP-11 in vivo. Here, we show that mMCP-11 is highly expressed by primary basophils and to a much lesser extent, by some mast cells. Prss34 transcripts were detected abundantly in primary and cultured basophils and very weakly in peritoneal mast cells or cultured BMMC. Conversely, transcripts for mMCP-6 and mMCP-7 tryptases were preferentially expressed by cultured and peritoneal mast cells but not basophils. We established a mMCP-11-specific mAb and showed that mMCP-11 proteins are indeed expressed by primary basophils and those infiltrating the affected tissues during allergic inflammation and parasitic infections. Some primary mast cells also expressed mMCP-11 proteins, albeit at a much lower level. Thus, basophils rather than mast cells are the major source of mMCP-11. This is the first study to demonstrate that mouse basophils produce a trypsin-like protease.