Sarcoidosis is one of the best-known systemic granulomatous diseases. Despite intensive investigation, however, the etiology of sarcoidosis has remained unresolved for more than 100 years . Sarcoidosis seems to result from the exposure of a genetically susceptible subject to an environmental agent, and microbial etiologies of sarcoidosis have long been considered based on the clinical similarities to infectious granulomatous diseases . Several epidemiologic mechanisms may underlie the association of an infective agent or agents with the etiology of sarcoidosis, including spatial, seasonal, and occupational clustering . The results of the ACCESS (A Case Control Etiologic Study of Sarcoidosis) study support an association between selected microbially-rich environments and sarcoidosis .
Mycobacterial and propionibacterial organisms are the most commonly implicated etiologic agents based on studies indicating the detection by polymerase chain reaction (PCR) of microbial DNA from these organisms in tissues from sarcoid patients around the world [5-7]. Different studies have produced considerably varying results, however, with microbial DNA detected in 0% to 80% of sarcoidosis tissues and in 0% to more than 30% of control tissues [8, 9]. The failure to detect microbial DNA from these organisms in samples from some sarcoid patients suggests other causes of sarcoidosis in those patients, whereas detection of the microbial DNA in some control samples suggests latent infection of the bacterium.
Immune responses against microbial antigens from these organisms, such as ESAT-6 and KatG peptides from
Granuloma formation results from the persistence of a nondegradable product or a hypersensitivity response . The two mechanisms overlap in most infectious diseases because microorganisms act as both foreign bodies and antigens to induce immunologic responses. Granulomas serve as protective mechanism to sequester and degrade the invading agent. The pathologic hallmark of sarcoidosis is an epithelioid cell granuloma, thus some etiologic agent of sarcoidosis must be present or have been present within the sarcoid granuloma. Histopathologic studies are therefore essential to demonstrate mycobacterial or propionibacterial organisms or antigens within sarcoid granulomas to demonstrate an etiologic link between sarcoidosis and these organisms.
2. Bacterial culture
The lung and its draining lymph nodes are the organs most commonly affected by sarcoidosis. As the lung constantly encounters airborne substances, including pathogens, many researchers have considered infection to trigger sarcoidosis and have thus tried to identify possible causative transmissible agents and their contribution to the mechanism of sarcoid granuloma formation [15, 16].
2.1. Bacterial culture from tissue samples affected by sarcoidosis
In the late 1970s, a large Japanese research project conducted by many clinicians and microbiologists with support by a grant from Japanese Ministry of Health was organized to seek the pathogens responsible for sarcoidosis. Extensive trials were performed to isolate microorganisms, including bacteria, viruses, and fungi, from tissue samples (especially biopsied lymph nodes) affected by sarcoidosis. Only
2.2. Bacterial culture from tissue samples without sarcoidosis
2.3. Cell invasiveness of
Studies of cell-invading
3. Polymerase chain reaction
Some investigators in Europe using PCR assays detected mycobacterial DNA in samples of affected tissue from patients with sarcoidosis [20-22], but others did not [23-25]. Quantification of the bacterial genomes detected in sarcoid lesions is essential for clarifying the etiologic correlation between lesions and bacteria detected therein because a tiny volume of bacteria or bacterial DNA can be detected even in conditions of latent infection or contamination with no etiologic correlation.
3.1. Quantitative PCR for propionibacterial and mycobacterial DNA
3.2. International collaborative study with quantitative real-time PCR
The international collaborative study evaluated the possible etiologic link between sarcoidosis and the suspected bacterial species . Formalin-fixed and paraffin-embedded sections of biopsy samples of lymph nodes, 1 from each of 108 patients with sarcoidosis and 65 patients with tuberculosis, together with 86 control samples, were collected from 2 institutes in Japan and 3 institutes in Italy, Germany, and England (Figure 3). Genomes of
In situ hybridization
Granulomatous reactions are basically a defense mechanism that the body uses to fight off poorly degradable antigens. Granulomas begin as a small collection of lymphocytes and macrophages surrounding poorly degradable antigens. The aggregating macrophages, called an early focus of granuloma, then change to epithelioid cells and become organized into a cluster of cells, called an immature granuloma. Further progression results in ball-like clusters of cells and fusion of macrophages into giant cells, called a mature granuloma. The questions that must be asked in searching for the cause of sarcoidosis, therefore, are: “What is the antigen that the granulomas are fighting?” and “How is the antigen localized within the sarcoid lesion?” To evaluate the pathogenic role of
P. acnes detected within sarcoid granuloma
Immunohistochemistry with the 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. The PAB antibody did not react with non-sarcoid granulomas in any of the 45 tuberculosis samples or the 34 samples with sarcoid reaction. The appearance of the small round bodies detected by the PAB antibody within sarcoid granulomas did not differ between lungs and lymph nodes. In sarcoid granulomas with many small round bodies, the cytoplasm of some granuloma cells was filled with small round bodies, consistent with the intracellular proliferation of the bacterium (Figure 5). In many sarcoid granulomas, a few small round bodies with occasional degraded or large-sized features were scattered among the granuloma cells. The amount of these small round bodies varied from each granuloma in identical sarcoid samples as well as from each sarcoid tissue sample (Figure 6). The appearance of the small round bodies detected by the PAB antibody within sarcoid granulomas did not differ between lungs and lymph nodes (Figure 7, 8).
P. acnes in non-granulomatous areas
In non-granulomatous areas, small round bodies detected by the PAB antibody were found in alveolar macrophages of lungs and paracortical macrophages of lymph nodes from many sarcoid and some non-sarcoid patients. In the lymph nodes, paracortical macrophages with many small round bodies detected by the PAB antibody (Figure 9) were observed in 26 (22%) of 119 sarcoid samples and 18 (11%) of 165 non-sarcoid samples. The frequency was significantly higher in the sarcoid samples. Such small round bodies were observed in lymphatic endothelial cells in a few samples of sarcoid lymph nodes (Figure 10). In the lungs, alveolar macrophages with many small round bodies detected by the PAB antibody were found in 28 (36%) of 77 sarcoid samples and 18 (16%) of 110 non-sarcoid samples. The frequency was significantly higher in sarcoid samples. Such alveolar macrophages occasionally contained one or a few large spheroidal bodies detected by the PAB antibody that were acid-fast with Fite staining and also reacted with the TIG antibody.
5.3. Hamazaki-Wesenberg bodies
Hamazaki-Wesenberg (HW) bodies frequently appear in sarcoid lymph nodes although these bodies are not specific to sarcoidosis [29-31]. The large-spheroidal acid-fast bodies, HW 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 HW bodies had a single bacterial structure and lacked a cell wall with occasional protrusions from the body (Figure 11). Immunoelectron microscopy revealed that the immunoreactive products of the PAB antibody and TIG antibody were differentially distributed in the outer and inner areas of the HW bodies, respectively (Figure 12). The localization of cell-membrane-bound lipoteichoic acid detected by the PAB antibody and ribosome-bound trigger factor detected by the TIG antibody suggests that HW might not be phagolysosomally-degraded products of
5.4. Intracellular proliferation of
Histopathologic analysis with the PAB antibody led us to formulate a hypothesis for the mechanism of granuloma formation in sarcoidosis (Figure 13).
5.5. Histopathological diagnosis of sarcoidosis by the PAB antibody
The PAB antibody seems to be appropriate for detecting cell-wall-deficient
6. Host factor
Host factors may be more critical than agent factors in the etiology of sarcoidosis, as suggested by the Kveim test phenomenon , in which an intracutaneously injected suspension of sarcoid tissue causes sarcoid granulomas in patients with sarcoidosis but not in healthy people or patients with other diseases. The inflammatory response in sarcoidosis involves many activated T cells and macrophages , with a pattern of cytokine production in the lungs consistent with a helper T-cell type 1 (Th1) immune response triggered by undefined antigen(s) . If a propionibacterium caused a particular case of sarcoidosis, it is likely that an antigen arising from the bacterium gave rise to a Th1 immune response in the subject.
6.1. Hypersensitivity to
P. acnes antigens
Ebe and colleagues searched for propionibacterial antigens that evoked cellular immune responses only in patients with sarcoidosis . For this purpose, a λgt11 genomic DNA library of
Additional evidence of the hypersensitivity of sarcoid patients to
6.2. NOD1 gene polymorphism
Mutations in the related NOD2 gene predispose patients to granulomatous diseases, including Crohn’s disease , Blau syndrome , and early-onset sarcoidosis . Although Blau syndrome and early-onset sarcoidosis are reported to share identical NOD2 mutations, no association has been reported between NOD2 and sarcoidosis . NOD1 shares many structural and functional similarities with NOD2. Tanabe
7. Experimental models
In experimental animals, granulomatous lesions can be induced by
7.1. Pulmonary granulomatosis caused by sensitization with
P. acnes antigens
This experimental protocol may provide a satisfactory model of sarcoidosis. First, hypersensitivity to
Experimental models of allergic diseases, such as encephalomyelitis , thyroiditis , and orchitis  have been produced by immunizing animals with self-antigens (myelin basic protein, thyroglobulin, and testicular homogenate, respectively) emulsified in CFA, which is essential for the experiment. Autoimmune inflammatory lesions are induced in this way only in the organs from which the self-antigens used for the sensitization originated. In the animal model of sarcoidosis, sensitization of mice with
Similar to the results obtained by bacterial culture of human samples from lung and lymph nodes,
Using the same experimental protocol with rabbits bred in a conventional environment, rabbits sensitized with the
7.2. Mechanism of granuloma formation in the experimental models
The adoptive transfer of
That study also examined whether changes in the number of pre-existing
8. Etiology of sarcoidosis
In the past, once the germ theory of disease was accepted, microbes were considered to be pathogens if they met the stipulations of Koch’s postulates. Although there are many microbes, however, most human infections are caused by only a few. Some microbes have been classified as pathogens although they do not cause disease in every host. In addition, some microbes have been classified as nonpathogenic although they cause disease in certain hosts. For these reasons, in a redefinition of the concepts of virulence and pathogenicity of microbes, Casadevall and Pirofski suggested a classification system for pathogens based on their ability to cause damage as a function of the host’s immune response . Koch’s postulates for exogenous infection cannot be applied to diseases caused by endogenous bacteria. Endogenous infection is a disease caused by indigenous microorganisms. According to the classification system suggested by Casadevall and Pirofski, endogenous infection, which does not cause any lesions under normal immune conditions, can be classified into three major categories (Figure 22). Opportunistic infections, such as pneumocystis carinii pneumonia, are well known to be associated with immunodeficiency in AIDS patients. Combination type infections, such as Candida and Aspergillus, not only cause opportunistic infections, but may also cause hypersensitivity pneumonitis. The hypersensitivity type of endogenous infection does not cause any tissue damage until the hypersensitive immune response is triggered.
8.1. Commensalism of
P. acnes in the lungs and lymph nodes
8.2. Mechanism of granuloma formation in sarcoidosis
Intracellular proliferation of
Sarcoidosis is most likely the result of a complex interaction between infection, immunity, and allergic reaction (Figure 24). There are three conditions essential to the development of sarcoidosis caused by
8.3. Pathogenesis shared by sarcoidosis and tuberculosis
Tuberculosis shares many common features with sarcoidosis, not only their histopathologic features, but also aspects of their pathogenesis. Many tuberculosis cases arise from the endogenous activation of latent tuberculosis infection. Primary
Endogenous reactivation of latent bacteria is well known to occur in tuberculosis, which shares many common features with sarcoidosis, not only the histopathologic features, but also the pathogenic features. Many cases of adult tuberculosis are caused by endogenous activation of latent tuberculosis infection [59, 60]. Tuberculosis and sarcoidosis are side effects of the anti-tumor necrosis factor-α drugs administered to patients with rheumatoid arthritis [61, 62]. Anti-tumor necrosis factor-α treatment is thought to reactivate latent tuberculosis infection . In the same manner, latent
9. Treatment of sarcoidosis
Immunosuppressive, mainly corticosteroidal, therapy has been used for sarcoidosis for more than 50 years, but the long-term effects of steroidal treatment in chronic sarcoidosis are still disputed , Further, the high relapse rate after treatment and the side effects of long-term use are often a clinical challenge . Steroids suppress the allergic reaction, thereby providing therapeutic effects. Interference of the inflammatory process by these immunosuppressive drugs, however, may impede the formation of granulomas, which function to curtail the spread of
9.1. Strategy for treating sarcoidosis caused by P. acnes
Antibiotics not only kill the bacteria proliferating in cells, but also prevent the endogenous activation of latent bacteria. Long-term administration of antibiotics may therefore be effective for patients with progressive sarcoidosis by preventing inflammatory relapses caused by reactivation of the latent bacteria (Figure 25). If latent bacterial infection persisting in organs can be eradicated by treatment with antibiotics, complete remission of sarcoidosis may be achieved. Complete eradication of latent bacteria might be difficult to achieve through the conventional use of antibiotics, however, as in the case of pulmonary tuberculosis.
Another approach for treating sarcoidosis is specific suppression of the hypersensitivity to
9.2. Tetracyclines for treating sarcoidosis
Minocycline is the first-choice antibiotic for patients with acne vulgaris caused by
The results of a nationwide questionnaire survey, performed by a Japanese research group in 2005 (reported in Japanese), indicated that antibiotic therapy was effective in 43% of 87 patients with sarcoidosis treated with many kinds of antibiotics, including minocycline, doxycycline, and clarithromycin. Baba and colleagues  used minocycline and clarithromycin for therapy against worsening of multiple endobronchial mass lesions, given the possible roles of
Based on the studies described in this section, the antimicrobial properties of tetracyclines are effective for treating sarcoidosis. Many researchers, have questioned the antimicrobial role of tetracyclines because tetracyclines also have anti-inflammatory properties, which were demonstrated by in vitro studies and corroborated by clinical trials. Tetracycline suppresses neutrophil migration and chemotaxis , and minocycline inhibits T-lymphocyte activation and proliferation . Both minocycline and doxycycline obviate granuloma formation in vitro . Although it remains controversial whether these antibiotics kill microbes or have only an anti-inflammatory effect, the mechanisms of sarcoid granuloma formation caused by
9.3. Marshall protocol
The Marshall protocol  is an eradication therapy for intracellular bacteria established by Dr. Trevor Marshall. This therapeutic protocol is a combination of minocycline plus azithromycin or clindamycin, supported by the use of an angiotensin receptor blocker to prevent Herxheimer reactions. According to the results published by the Autoimmunity Research Foundation in 2006, this therapy is effective in 62% of patients with sarcoidosis. Information about the treatment can be found at the study site, marshallprotocol.com and also at autoimmunityresearch.org.
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