Etiologic Role of Infectious Agents

Abstract

A consensus statement found in most peer-reviewed literature on sarcoidosis is that the etiology of sarcoidosis is unknown. It is timely to review whether this statement should be revised. Many infectious agents meet the basic requirements of inducing granulomatous inflammation and immunologic responses consistent with sarcoidosis including oligoclonal expansion of CD4+ T cells, polarized Th1 and possibly Th17 responses, and dysregulated regulatory T-cell function. Studies over the past decade provide increasing and complementary data to implicate a role for infectious agents in sarcoidosis etiology. These studies used different methodologies such as polymerase chain reaction and mass spectrometry to document microbial nucleic acids and proteins in sarcoidosis tissues. Multiple studies report antigen-specific immune responses to specific microbial proteins in sarcoidosis. In aggregate, these studies provide compelling evidence that mycobacteria play a major etiologic role in sarcoidosis in the United States and Europe. Studies from Japan support a role for Propionibacteria as a major etiologic agent in the country. There is controversy over how these (or other) infectious agents cause sarcoidosis. The hypothesis that chronic sarcoidosis is caused by a viable, replicating mycobacterial or other infection has no direct pathologic, microbiologic, or clinical evidence. A novel hypothesis links microbial triggers to a sarcoidosis outcome from the accumulation of aggregated proinflammatory serum amyloid A within granulomas, providing a mechanism for chronic disease in the absence of any viable tissue infection. Further studies are needed to provide more definitive evidence for these competing hypotheses before the statement that the etiology of sarcoidosis is unknown becomes obsolete.

Increased T-helper 17.1 cells in sarcoidosis mediastinal lymph nodes

“…Although IL-23p19 expression in sarcoid lungs remains uncertain, high expression of IL-12p40 compared with IL-12p70 may very well indicate elevated levels of IL-23 [25], as IL-12p40 is also a subunit of IL-23 [17]. Notably, IL-23 transcription was enhanced in sarcoid skin lesions compared with controls [26] and serum amyloid A, an antigen that was speculated to contribute to the development of chronic ( pulmonary) sarcoidosis [27], has been described to increase IL-23 production by dendritic cells [28]. Strikingly, BALF IL-12p40 protein levels are highest in patients developing chronic disease [29].…”

AtopobiumandFusobacteriumas novel candidates for sarcoidosis-associated microbiota

“…Organic and inorganic factors such as occupational exposure to respirable dust have been investigated [2,4]. Owing to the similarities with mycobacterial disease, an inhaled infectious agent has been hypothesised, and mycobacterial antigens as well as some other bacterial candidates such as Chamydophilia pnemoniae and Propionibacterium acnes have been examined as potential triggers [5][6][7][8][9][10]. However, results regarding probable microbial involvement in disease manifestation are inconsistent.…”

Identifying Novel Biomarkers in Sarcoidosis Using Genome-Based Approaches

“…While the etiology of sarcoidosis remains unclear, there has long been an implicated linkage to mycobacterial and propionibacter organisms [48-53], although a consensus on the nature of a microbial pathogenesis in sarcoidosis and environmental factors (e.g., mold/mildew exposure) [15] has not yet been reached. Koth et al pointed out the significant overlap in gene expression profiles between sarcoidosis and tuberculosis due to the histologic similarities (e.g., interferon signaling-related genes) [44].…”