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| Nature | Causative agent | Evidence for | Evidence against |
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Infective | Mycobacterium | (i) Immunohistochemical studies showed possible remnants of cell wall deficient mycobacteria [61].
(ii) A mycobacterial cell wall component, tuberculostearic acid, was found in sarcoid specimens [62].
(iii) Techniques such as enzyme-linked immunospot assay (ELISpot) and polymerase chain reactions (PCR) have shown increasing evidence for mycobacteria in the mediastinal lymph nodes and peripheral lung tissues of sarcoidosis patients [63].
(iv) Mycobacterium tuberculosis DNA: mycobacterium tuberculosis catalase-peroxidase protein (mKatG) and circulating IgG for mKatG have been identified in sarcoidosis patients [64]. Additionally, compared to healthy controls, sarcoidosis patients have amplified T-cell responses in the peripheral blood and lungs to mKatG and mycobacteria antigens [65, 66].
(v) Mycobacterial heat-shock proteins (Mtb-hsp)70, 65, and 16 were found in the lymph nodes and sera of sarcoidosis patients [67].
(vi) Dubaniewicz and colleagues (2013) suggested that, in genetically different individuals, Mtb-hsp 16 can induce an autoimmune response in sarcoidosis. | (i) Acid-fast stains and cultures of sarcoid specimens do not routinely demonstrate the presence of mycobacterium species.
(ii) The mere presence of the mycobacterial antigens in sarcoid specimens is not proof of a causal relationship.
(iii) Mycobacterial nucleic acid and antigens are not detected in many sarcoid specimens; therefore, mycobacteria may not be the sole cause of sarcoidosis [3]. |
| Propionibacterium | (i) It has been shown to be able to induce a granulomatous reaction [68].
(ii) P. acnes has been found in up to 78% of sarcoidosis sample cultures [69].
(iii) An antibody response to P. acnes proteins has been observed in 40% of BALF samples (compared to 5% in healthy controls) [70]. | (i) Cultures from healthy controls also yield this commensal organism [71]. |
| Viruses and other infectious pathogens | (i) Serum antibodies to herpes-like viruses (human herpes virus-8, herpes simplex virus, and Epstein-Barr virus) were elevated in patients with sarcoidosis [72]. | (i) Significant proportions of the general population have also been previously exposed to herpes-like viruses.
(ii) A nonspecific polyclonal hypergammaglobulinemia, common in sarcoidosis, may explain the increased antibody titre for these viruses [73].
(iii) Viruses do not cause the epithelioid granulomas of sarcoidosis [74].
(iv) The mechanism for granuloma formation by molecular mimicry after viral exposure remains undetermined [74].
(v) Granulomatous reactions resulting from spirochetes, fungi, Tropheryma whipplei, and Borrelia species infection can be difficult to discriminate from sarcoidosis [75]. |
| | | (vi) The notion that cell-wall deficient organisms like mycobacteria, rickettsia, and chlamydia species cause sarcoidosis is founded on limited data. There is a shortage of conformation from well-controlled epidemiological and laboratory studies [75]. |
| Transplants | (i) Immune dysregulation following allogeneic hematopoietic cell transplantation has been shown to promote sarcoidosis in patients with susceptible HLA subtypes [76].
(ii) Individuals have developed granulomatous inflammation post lung and heart transplant from patients with sarcoidosis [77–79].
(iii) An increased incidence of sarcoidosis in closed populations may suggest an infection-related disease. | |
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Noninfectious | Environmental | (i) Wood stoves and fireplaces have been associated with an increased risk of sarcoidosis [80].
(ii) Fire rescue workers, military personnel, and healthcare workers who were exposed to the dust from the destruction of the World Trade Centre in New York were found to have a higher risk of developing sarcoidosis [81, 82].
(iii) Findings from the ACCESS study showed the modest positive odds ratios (~1.5) that workplace exposure to organic solvents, dusts, pesticides, insecticides, and musty odours can increase one’s risk of sarcoidosis. Reduced risk was associated with exposures to animal dander and other allergic (TH2) responses [83].
(iv) Nanoparticles of common minerals and metals can elicit a dysregulated immune response [84]. | (i) The ACCESS study failed to identify risk factors that accrue a greater than two-fold risk (odds ratio). Moreover, it had inadequate power to ascertain the sarcoidosis risk among fire rescue workers, military personnel, and healthcare workers. Lastly, it failed to prove an association between previously hypothesised exposures (e.g., wood dust, metals, and silica) and sarcoidosis [1, 3]. |
| Autoantigens | (i) Sarcoidosis patients express low titre levels of autoantibodies.
(ii) The BALF of HLA-DRB1*0301-positive sarcoidosis patients with Löfgren’s syndrome had antigenic peptides that were bound to HLA-DR molecules of lung cells that have the TCR AV2S3+ gene segment. These antigenic peptides include vimentin, ATP synthase, and lysyl tRNA synthetase, thought to be autoantigens in various conditions [85].
(iii) IFNγ enzyme-linked immunospot assays revealed a strong T-cell response to the cytoskeletal peptides of vimentin from the peripheral blood of patients with HLA-DRB1*0301. The same was observed for ATP synthase and lysyl tRNA synthetase from BALF. Thus, this suggests a possible autoimmune response in patients with HLA-DRB1*0301, contributing to sarcoid granulomatous inflammation [86]. | (i) The pathological significance of autoantibodies in sarcoidosis remains unclear. The disease-specific autoantibody profile has not been described. Therefore, it has been postulated that these autoantibodies are most likely the product of general B-cell stimulation in the progression of T-cell stimulation by antigens [1]. |
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