The exact cause of sarcoidosis is not known. Many researchers have hypothesized the role of genetic susceptibility, environmental factors, putative antigens, and autoimmunity in the development of this disease, but no single cause has been identified to date.

Genetic Factors

Various studies suggest that genetic factors could play a crucial role in establishing the risk and clinical development of sarcoidosis [1]. Eleven sarcoidosis risk loci (BTNL2, HLA-B, HLA-DPB1, ANXA11, IL23R, SH2B3/ATXN2, IL12B, NFKB1/MANBA, FAM177B, chromosome 11q13.1, and RAB23) have been identified to date [2]. A previous study reported that familial sarcoidosis occurred in 17% of African-Americans [3], while only 1.4% of Spanish people exhibited this same risk [4]. According to A Case-Control Etiologic Sarcoidosis Study (ACCESS) the chance of developing sarcoidosis is five-fold among sib­lings [5]. Monozygotic siblings with sarcoidosis had an 80-fold higher risk of developing the condition, although the estimated risk of developing sarcoidosis in dizygotic twins was only seven-fold [6].

Genome wide association studies have demonstrated that several HLA and non-HLA alleles are associated with the development of this disease [7]. HLA-DRB1*0301/ DQB1*0201 [8], transforming growth factor β (TGF-β) [9], tumor necrosis factor α (TNF-α) [10], and Toll-like receptor 4 (TLR-4) [11] are all considered significant indicators for susceptibility to sarcoidosis [12,13].

Environmental Risk Factors

Various environmental factors, including exposure to wood stoves, soil, tree pollen, inorganic particulates, insecticides, and nanoparticles, have been associated with an increased risk for developing sarcoidosis. In addition to these factors, some workers, such as those involved in hardware, gardening materials, building supplies, and metal work as well as ship servicemen in the navy, fire workers, and educators, are prone to sarcoidosis [14–16]. It has been suggested that silica exposure also triggers the risk of sarcoidosis [17]. The underlying hypothesis for this association is that the environment is an important risk factor for the development of sarcoidosis, which has been further strengthened by reports that US World Trade Center workers exposed to the crash debris, in particular firefighters; all experienced an increased risk for developing sarcoidosis or “sarcoid-like” disease [18].

Infection

In addition to all of the factors mentioned above, infectious agents such as mycobacteria, have been suggested to be associated with the development of sarcoidosis, because the production of granulomas is a key factor in the immune defense response against these agents. Studies have identified numerous microbial agents as a potential eliciting agents of the immune response in sarcoidosis including Leptospira species, Mycoplasma species, herpes virus, retrovirus, Chlamydia pneumoniae, Borrelia burgdorferi, [19] Pneumocystis jirovecii [20], Mycobacterium (M.tb) [21], and Propionibacterium species [22]. Isolation of M.tb. DNA, from tissue specimens collected from sarcoidosis patients, with sequences specific to mycobacterial proteins, such as ESAT-6, Kat G, and SoD A, illustrate that Mycobacterium is the strongest candidate for infection-mediated sarcoidosis [23–25]. It has been reported that patients treated with interferon α therapy for hepatitis C infection developed sarcoidosis [26,27]. A few studies have suggested that hepatitis C infection on its own could increase the risk of developing sarcoidosis. However, it seems more likely that therapy with interferon α increases interferon-γ and interleukin-2 expression, stimulating granuloma formation and thus sarcoidosis [28,29].

Autoimmunity

Autoimmunity has not been studied as extensively but given the underlying pathological mechanism of sarcoidosis there is certainly potential for these conditions to play a contributing role in disease development. Although no disease-specific auto-antibodies have been observed, it has been shown that the major histocompatibility complex (MHC) class II molecules on antigen-presenting cells possess an autoantigen that is recognized by the T-cell receptor (TCR) of the responding T-cells in sarcoidosis patients [30,31]. Vimentin-derived peptides are the most plausible candidate for the activation of both T-cells and B-cells in the lung [32]. Autoimmunity presents a as a novel spectrum for sarcoidosis immunopathogenesis and may help elucidate sarcoid etiology [33–35].

Another important aspect of autoimmunity is the imbalanced gut microbiome. Gianchecchi et al. reported the associations between the presence of microbiome dysbiosis and the development of autoimmune conditions [36]. Sarcoidosis overlaps with other autoimmune diseases, including rheumatoid arthritis, autoimmune thyroid disease, Sjogren’s syndrome, and ankylosing spondylitis [37]. The role of the microbiota in these autoimmune diseases has been evaluated in previous studies and been shown to lay a significant role in their pathogenesis [38]; thus, study of the microbiome of sarcoidosis patients and its correlation with other diseases could open new avenues for investigating the underlying causes of this disease [39,40].

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