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].

Immunopathogenesis of sarcoidosis

Many etiological agents, including infectious microbes, as well as organic and inorganic compounds, contribute to the development of sarcoidosis. These antigens are first cleared by the immune system, but this is not infallible and some undegraded antigens may remain in the cells, which can initiate an immune feedback loop. In response to this feedback loop, the antigen-presenting cells (APCs), such as dendritic cells (DCs), alveolar macrophages (AMs), and alveolar epithelial cells, produce high levels of TNF-α, and secrete interleukins-12, -15, and -18, macrophage inflammatory protein-1 (MIP-1), monocyte chemoattractant protein-1 (MCP-1), and granulocyte macrophage colony-stimulating factor (GM-CSF) [41]. These APCs also present antigens to CD4+ T-cells initiating granuloma construction, a critical feature of sarcoidosis. The growth of these granulomas establishes the primary abnormality in most cases of sarcoidosis. Sarcoid granulomas are ordered, structured masses comprised of macrophages and their derivatives, epithelioid cells, giant cells, and T-cells.

Activated CD4+ T-cells can differentiate into two distinct subsets, namely, T helper 1 (Th1) and T helper 2 (Th2) cells, based on their cytokines profile. Th1 cells predominantly secrete interleukin-2 (IL-2) and interferon-gamma (IFN-γ), while IL-4 and IL-13 are the major secretions of Th2 cells. Resolution or maintenance oferenc granuloma is determined by the proportion of Th1 and Th2 cells, respectively. Alveolar macrophages are activated in the Th2 milieu and stimulate fibroblast and collagen proliferation culminating in progressive fibrosis [42].

Incapacitation of Tregs is also a key feature of granuloma maintenance. It is presumed that infiltrating Tregs fail to reduce the exaggerated inflammatory response, thereby contributing to granuloma persistence and integrity. Tregs also release transforming growth factor β (TGF-β) that may contribute to fibrosis and granuloma organization [43].

Th17 and Th17. 1 cells have only recently been linked to the pathogenesis of sarcoidosis [44]. These cells are recruited to the disease site and are involved in the construction of the granuloma. The balance between Th17 and Treg cells is thought to be disrupted in sarcoidosis [45] and is an important factor in its prognosis [46]. The regulation of antigen processing, antigen presentation to the APCs, and cytokine release are all controlled through genetic elements and may link the various causal factors of sarcoidosis together [47–49].

References

1. Grunewald, J.; Spagnolo, P.; Wahlstrom, J.; Eklund, A. Immunogenetics of disease-causing inflammation in sarcoidosis. Clin. Rev. Allergy Immunol. 2015, 49, 19–35. [CrossRef]

2. Fischer, A.; Ellinghaus, D.; Nutsua, M.; Hofmann, S.; Montgomery, C.G.; Iannuzzi, M.C.; Rybicki, B.A.;

Petrek, M.; Mrazek, F.; Pabst, S.; et al. Identification of immune-relevant factors conferring sarcoidosis

genetic risk. Am. J. Respir. Crit. Care Med. 2015, 192, 727–736. [CrossRef]

3. Rybicki, B.A.; Iannuzzi, M.C. Epidemiology of sarcoidosis: Recent advances and future prospects. Semin.

Respir. Crit. Care Med. 2007, 28, 22–35. [CrossRef]

4. Fabrellas, E.F. Epidemiología de la sarcoidosis. Arch. Bronconeumol. 2007, 43, 92–100. [CrossRef]

5. Rybicki, B.A.; Iannuzzi, M.C.; Frederick, M.M.; Thompson, B.W.; Rossman, M.D.; Bresnitz, E.A.; Terrin, M.L.; Moller, D.R.; Barnard, J.; Baughman, R.P.; et al. Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (access). Am. J. Respir. Crit. Care Med. 2001, 164, 2085–2091. [CrossRef]

6. Sverrild, A.; Backer, V.; Kyvik, K.O.; Kaprio, J.; Milman, N.; Svendsen, C.B.; Thomsen, S.F. Heredity in

sarcoidosis: A registry-based twin study. Thorax 2008, 63, 894–896. [CrossRef]

7. Schurmann, M.; REICHEL, P.; Muller-Myhsok, B.; Schlaak, M.; Muller-Quernheim, J.; Schwinger, E. Results

from a genome-wide search for predisposing genes in sarcoidosis. Am. J. Respir. Crit. Care Med. 2001, 164,

840–846. [CrossRef] [PubMed]

8. Ishihara, M.; Ohno, S.; Ishida, T.; Ando, H.; Naruse, T.; Nose, Y.; Inoko, H. Molecular genetic studies of hla class ii alleles in sarcoidosis. Tissue Antigens 1994, 43, 238–241. [CrossRef]

9. Pabst, S.; Fränken, T.; Schönau, J.; Stier, S.; Nickenig, G.; Meyer, R.; Skowasch, D.; Grohé, C. Transforming growth factor- gene polymorphisms in dierent phenotypes of sarcoidosis. Eur. Respir. J. 2011, 38, 169–175.[CrossRef] [PubMed]

10. Sharma, S.; Ghosh, B.; Sharma, S. Association of tnf polymorphisms with sarcoidosis, its prognosis and

tumour necrosis factor (tnf)- levels in Asian Indians. Clin. Exp. Immunol. 2008, 151, 251–259. [CrossRef]

[PubMed]

11. Pabst, S.; Baumgarten, G.; Stremmel, A.; Lennarz, M.; Knüfermann, P.; Gillissen, A.; Vetter, H.; Grohe, C. Toll-like receptor (tlr) 4 polymorphisms are associated with a chronic course of sarcoidosis. Clin. Exp.

Immunol. 2006, 143, 420–426. [CrossRef] [PubMed]

12. Grunewald, J. Role of genetics in susceptibility and outcome of sarcoidosis. Semin. Respir. Crit. Care Med. 2010, 31, 380–389. [CrossRef]

13. Iannuzzi, M.C. Genetics of sarcoidosis. Semin. Respir. Crit. Care Med. 2007, 28, 15–21. [CrossRef]

14. Kucera, G.P.; Rybicki, B.A.; Kirkey, K.L.; Coon, S.W.; Major, M.L.; Maliarik, M.J.; Iannuzzi, M.C. Occupational risk factors for sarcoidosis in african-american siblings. Chest 2003, 123, 1527–1535. [CrossRef]

15. Newman, L.S.; Rose, C.S.; Bresnitz, E.A.; Rossman, M.D.; Barnard, J.; Frederick, M.; Terrin, M.L.;

Weinberger, S.E.; Moller, D.R.; McLennan, G.; et al. A case control etiologic study of sarcoidosis:

Environmental and occupational risk factors. Am. J. Respir. Crit. Care Med. 2004, 170, 1324–1330.

[CrossRef] [PubMed]

16. Newman, K.L.; Newman, L.S. Occupational causes of sarcoidosis. Curr. Opin. Allergy Clin. Immunol. 2012, 12, 145–150. [CrossRef] [PubMed]

17. Vihlborg, P.; Bryngelsson, L.; Andersson, L.; Gra, P. Risk of sarcoidosis and seropositive rheumatoid arthritis from occupational silica exposure in swedish iron foundries: A retrospective cohort study. BMJ Open 2017, 7, e016839. [CrossRef]

18. Izbicki, G.; Chavko, R.; Banauch, G.I.;Weiden, M.D.; Berger, K.I.; Aldrich, T.K.; Hall, C.; Kelly, K.J.; Prezant, D.J. World trade center “sarcoid-like” granulomatous pulmonary disease in new york city fire department rescue workers. Chest 2007, 131, 1414–1423. [CrossRef] [PubMed]

19. Newman, L. Aetiologies of sarcoidosis. Eur. Respir. Monogr. 2005, 32, 23–48.

20. Vidal, S.; De la Horra, C.; Martin, J.; Montes-Cano, M.; Rodríguez, E.; Respaldiza, N.; Rodriguez, F.; Varela, J.;Medrano, F.; Calderón, E. Pneumocystis jirovecii colonisation in patients with interstitial lung disease. Clin.Microbiol. Infect. 2006, 12, 231–235. [CrossRef]

21. Drake, W.P.; Newman, L.S. Mycobacterial antigens may be important in sarcoidosis pathogenesis. Curr.

Opin. Pulm. Med. 2006, 12, 359–363. [CrossRef]

22. Ishige, I.; Eishi, Y.; Takemura, T.; Kobayashi, I.; Nakata, K.; Tanaka, I.; Nagaoka, S.; Iwai, K.;Watanabe, K.;Takizawa, T. Propionibacterium acnes is the most common bacterium commensal in peripheral lung tissue and mediastinal lymph nodes from subjects without sarcoidosis. Sarcoidosis Vasc. Diuse Lung Dis. 2005, 22,33–42.

23. Allen, S.S.; Evans, W.; Carlisle, J.; Hajizadeh, R.; Nadaf, M.; Shepherd, B.E.; Pride, D.T.; Johnson, J.E.;

Drake,W.P. Superoxide dismutase a antigens derived from molecular analysis of sarcoidosis granulomas

elicit systemic th-1 immune responses. Respir. Res. 2008, 9, 36. [CrossRef]

24. Song, Z.; Marzilli, L.; Greenlee, B.M.; Chen, E.S.; Silver, R.F.; Askin, F.B.; Teirstein, A.S.; Zhang, Y.; Cotter, R.J.; Moller, D.R. Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis. J. Exp. Med. 2005, 201, 755–767. [CrossRef]

25. Drake,W.P.; Dhason, M.S.; Nadaf, M.; Shepherd, B.E.; Vadivelu, S.; Hajizadeh, R.; Newman, L.S.; Kalams, S.A. Cellular recognition of mycobacterium tuberculosis esat-6 and katg peptides in systemic sarcoidosis. Infect. Immun. 2007, 75, 527–530. [CrossRef] [PubMed]

26. Hirano, A.; Kataoka, M.; Nakata, Y.; Takeda, K.; Kamao, T.; Hiramatsu, J.; Kimura, G.; Tanimoto, Y.;

Kanehiro, A.; Tanimoto, M. Sarcoidosis occurring after interferon-alpha therapy for chronic hepatitis c:

Report of two cases. Respirology 2005, 10, 529–534. [CrossRef] [PubMed]

27. Trien, R.; Cooper, C.J.; Paez, D.; Colon, E.; Ajmal, S.; Salameh, H. Interferon-alpha-induced sarcoidosis in a patient being treated for hepatitis c. Am. J. Case Rep. 2014, 15, 235–238.

28. Brjalin, V.; Salupere, R.; Tefanova, V.; Prikk, K.; Lapidus, N.; Jõeste, E. Sarcoidosis and chronic hepatitis c: A case report. World J. Gastroenterol. 2012, 18, 5816–5820. [CrossRef] [PubMed]

29. Ramos-Casals, M.; Mana, J.; Nardi, N.; Brito-Zeron, P.; Xaubet, A.; Sanchez-Tapias, J.M.; Cervera, R.; Font, J. Sarcoidosis in patients with chronic hepatitis c virus infection: Analysis of 68 cases. Medicine 2005, 84, 69–80.[CrossRef] [PubMed]

30. Grunewald, J.; Kaiser, Y.; Ostadkarampour, M.; Rivera, N.V.; Vezzi, F.; Lötstedt, B.; Olsen, R.-A.; Sylwan, L.;Lundin, S.; Käller, M. T-cell receptor—Hla-drb1 associations suggest specific antigens in pulmonary

sarcoidosis. Eur. Respir. J. 2016, 47, 898–909. [CrossRef] [PubMed]

31. Wahlström, J.; Dengjel, J.; Winqvist, O.; Targo, I.; Persson, B.; Duyar, H.; Rammensee, H.-G.; Eklund, A.;Weissert, R.; Grunewald, J. Autoimmune t cell responses to antigenic peptides presented by bronchoalveolar lavage cell hla-dr molecules in sarcoidosis. Clin. Immunol. 2009, 133, 353–363. [CrossRef]

32. Zissel, G.; Müller-Quernheim, J. Specific antigen(s) in sarcoidosis: A link to autoimmunity? Eur. Respir. Soc. 2016, 47, 707–709. [CrossRef]

33. Kaiser, Y.; Eklund, A.; Grunewald, J. Moving target: Shifting the focus to pulmonary sarcoidosis as an

autoimmune spectrum disorder. Eur. Respir. J. 2019, 54, 1802153. [CrossRef]

34. Starshinova, A.A.; Malkova, A.M.; Basantsova, N.Y.; Zinchenko, Y.S.; Kudryavtsev, I.V.; Ershov, G.A.;

Soprun, L.A.; Mayevskaya, V.A.; Churilov, L.P.; Yablonskiy, P.K. Sarcoidosis as an autoimmune disease. Front. Immunol. 2019, 10, 2933. [CrossRef]

35. Haggmark, A.; Hamsten, C.; Wiklundh, E.; Lindskog, C.; Mattsson, C.; Andersson, E.; Lundberg, I.E.;

Gronlund, H.; Schwenk, J.M.; Eklund, A.; et al. Proteomic profiling reveals autoimmune targets in sarcoidosis. Am. J. Respir. Crit. Care Med. 2015, 191, 574–583. [CrossRef] [PubMed]

36. Gianchecchi, E.; Fierabracci, A. Recent advances on microbiota involvement in the pathogenesis of

autoimmunity. Int. J. Mol. Sci. 2019, 20, 283. [CrossRef] [PubMed]

37. Korsten, P.; Tampe, B.; Konig, M.F.; Nikiphorou, E. Sarcoidosis and autoimmune diseases: Dierences,

similarities and overlaps. Curr. Opin. Pulm. Med. 2018, 24, 504–512. [CrossRef] [PubMed]

38. Chu, F.; Shi, M.; Lang, Y.; Shen, D.; Jin, T.; Zhu, J.; Cui, L. Gut microbiota in multiple sclerosis and experimental autoimmune encephalomyelitis: Current applications and future perspectives. Mediat. Inflamm. 2018.[CrossRef] [PubMed]

39. Becker, A.; Vella, G.; Galata, V.; Rentz, K.; Beisswenger, C.; Herr, C.; Walter, J.; Tierling, S.; Slevogt, H.;

Keller, A.; et al. The composition of the pulmonary microbiota in sarcoidosis—An observational study. Respir.

Res. 2019, 20, 46. [CrossRef] [PubMed]

40. Inaoka, P.T.; Shono, M.; Kamada, M.; Espinoza, J.L. Host-microbe interactions in the pathogenesis and clinical course of sarcoidosis. J. Biomed. Sci. 2019, 26, 45. [CrossRef]

41. Agostini, C.; Adami, F.; Semenzato, G. New pathogenetic insights into the sarcoid granuloma. Opin. Rheumatol. 2000, 12, 71–76.

42. Wynn, T.A.; Barron, L. Macrophages: Master regulators of inflammation and fibrosis. Liver Dis. 2010, 30, 245–257.

43. Branton, M.H.; Kopp, J.B. Tgf-beta and fibrosis. Infect. 1999, 1, 1349–1365.

44. Miedema, J.R.; Kaiser, Y.; Broos, C.E.; Wijsenbeek, M.S.; Grunewald, J.; Kool, M. Th17-lineage cells in pulmonary sarcoidosis and löfgren’s syndrome: Friend or foe? Autoimmun. 2018, 87, 82–96.

45.Huang, H.; Lu, Z.; Jiang, C.; Liu, J.; Wang, Y.; Xu, Z. Imbalance between th17 and regulatory t-cells in sarcoidosis. J. Mol. Sci. 2013, 14, 21463–21473.

46. Liu, Y.; Qiu, L.; Wang, Y.; Aimurola, H.; Zhao, Y.; Li, S.; Xu, Z. The circulating treg/th17 cell ratio is correlated with relapse and treatment response in pulmonary sarcoidosis patients after corticosteroid withdrawal. PLoS ONE 2016, 11, e0148207.

47. Kelly, A.; Trowsdale, J. Genetics of antigen processing and presentation. Immunogenetics 2019, 71, 161–170.

48. Lee, J.A.; Sinkovits, R.S.; Mock, D.; Rab, E.L.; Cai, J.; Yang, P.; Saunders, B.; Hsueh, R.C.; Choi, S.; Subramaniam, S.; et al. Components of the antigen processing and presentation pathway revealed by gene expression microarray analysis following b cell antigen receptor (bcr) stimulation. BMC Bioinformatics 2006, 7, 237.

49. Bennett, D.; Bargagli, E.; Refini, R.M.; Rottoli, P. New concepts in the pathogenesis of sarcoidosis. Expert Rev. Respir. Med. 2019, 13, 981–991.