Cause of Sarcoidosis
The cause of sarcoidosis remains unknown, though current evidence suggests it results from an abnormal immune response to unidentified antigens in genetically predisposed individuals, possibly triggered by environmental exposures including microbial agents. 1, 2
Unknown Etiology with Multifactorial Hypothesis
The fundamental cause of sarcoidosis has not been definitively established despite over a century of investigation. 1, 3 The American Thoracic Society and American Heart Association both formally define sarcoidosis as a disease "of unknown cause" or "unknown origin." 1
Leading Pathogenic Theories
Genetic Predisposition
- Genetic factors clearly influence both disease susceptibility and clinical course, with different prevalence rates and disease manifestations observed across racial and ethnic groups. 3, 4
- The variable disease expression in different populations indicates the heterogeneous nature of sarcoidosis and suggests underlying genetic determinants. 4
Immune Dysregulation
- The disease involves accumulation of CD4+ T cells with release of IL-2 and formation of non-caseating granulomas, indicating a T helper-1 mediated immune response. 2, 5
- Oligoclonal expansion of CD4+ T cells suggests chronic antigenic stimulation by specific (but unidentified) antigens. 5
- Dysfunctional regulatory T-cell responses and dysregulated Toll-like receptor signaling contribute to the inflammatory cascade. 5
Environmental and Microbial Triggers
- Multiple environmental agents have been implicated, though no consensus exists on specific causative factors. 5, 6
- Some research groups have identified evidence suggesting mycobacterial or propionibacterial organisms based on tissue analyses and immunologic responses, though this remains controversial. 5
- Essentially identical clinical and pathologic features can be seen in berylliosis and aluminosis (disorders with known etiologies), suggesting that similar environmental exposures might trigger sarcoidosis. 1
Important Clinical Context
Autoimmune Hypothesis
- The typical T cell accumulation, local immune response, and granuloma formation indicate the inflammatory response may be induced by specific antigens, possibly including self-antigens, consistent with autoimmune involvement. 3, 7
Pathophysiologic Mechanism
- The disease is characterized by well-formed, concentrically arranged layers of immune cells with a central core of macrophage aggregates and multinucleated giant cells surrounded by lymphocytes. 2
- Pro-inflammatory cytokines released during granuloma formation drive the systemic inflammatory response. 2
Critical Diagnostic Implication
Because the etiology is unknown, diagnosis requires exclusion of alternative causes of granulomatous inflammation (including infections, berylliosis, and other granulomatous diseases) rather than identification of a specific causative agent. 1, 2 This makes sarcoidosis fundamentally a diagnosis of exclusion requiring compatible clinical presentation, histologic evidence of non-caseating granulomas, and systematic ruling out of other conditions. 2