Etiology of Sarcoidosis

Despite the tools of modern medicine, the cause of sarcoidosis remains unknown. Since sarcoidosis was first recognized as a distinct clinical entity in the early 1900s, investigators have speculated that a transmissible agent may be its cause. By the 1950s, the clinical and laboratory features of sarcoidosis were sufficiently specific that the epidemiology of the disease could be investigated critically. Epidemiologic studies throughout the world in the 1950s and 1960s led to a variety of hypothesized infectious and environmental causes but none survived tests of reproducibility and universality. During the same period, attempts at culturing infectious organisms from sarcoid tissue led to unconfirmed reports that transmissible organisms were present. More recently, investigators have used molecular biologic techniques in an attempt to detect microbial DNA or RNA from sarcoid tissue. The results of those studies also have been inconclusive. At the same time progress toward identifying the initiating cause(s) of sarcoidosis has been uncertain, significant advances have been made toward understanding the immunopathogenesis of the disease. The central defining characteristic of sarcoidosis is the formation of granulomas. In addition, sarcoidosis is now recognized to be characterized by enhanced immune activity with activated T cells and macrophages producing a variety of proinflammatory mediators at sites of granulomatous inflammation. Recent studies support the concept that sarcoidosis is a disease of immune dysregulation, likely the result of persistent antigenic stimulation at sites of inflammation. Uncertainty remains as to whether sarcoidosis is caused by a single agent, a relatively few closely related agents, or multiple factors.85, 87 Hypothetical causative agents might derive from infectious organisms, environmental compounds, or autoantigens: Infectious organisms Mycobacterium tuberculosis Nontuberculous mycobacteria Cell-wall deficient (L-form) mycobacteria Fungi Spirochetes Tropheryma whippelii (agent of Whipple's disease) Corynebacteria Viral agents Environmental (noninfectious) agents Metals (e.g., beryllium, zirconium, aluminum) Organic dusts (e.g., pine, pollen) Inorganic dusts (e.g., clay, soil, talc) Autoantigens Heat-shock proteins Investigators who believe a single agent is responsible for most cases of sarcoidosis must account for its the worldwide distribution and variety of clinical presentations. Those who suggest sarcoidosis has multiple causes often invoke host susceptibility factors as a necessary precondition to develop the disease; those investigators must account for the worldwide uniformity of the Kveim response. Whatever the cause, it may be possible to gain insights into the nature of the underlying stimulus by exploring the mechanisms operative in the enhanced immune activity that is a part of sarcoidosis.