Sarcoidosis is a multisystem granulomatous disease with nonspecific clinical manifestations
that commonly aects the pulmonary system and other organs including the eyes, skin, liver,
spleen, and lymph nodes. Sarcoidosis usually presents with persistent dry cough, eye and skin
manifestations, weight loss, fatigue, night sweats, and erythema nodosum. Sarcoidosis is not
influenced by sex or age, although it is more common in adults (< 50 years) of African-American
or Scandinavians decent. Diagnosis can be dicult because of nonspecific symptoms and can only
be verified following histopathological examination. Various factors, including infection, genetic
predisposition, and environmental factors, are involved in the pathology of sarcoidosis. Exposures
to insecticides, herbicides, bioaerosols, and agricultural employment are also associated with an
increased risk for sarcoidosis. Due to its unknown etiology, early diagnosis and detection are dicult;
however, the advent of advanced technologies, such as endobronchial ultrasound-guided biopsy,
high-resolution computed tomography, magnetic resonance imaging, and 18F-fluorodeoxyglucose
positron emission tomography has improved our ability to reliably diagnose this condition and
accurately forecast its prognosis. In a recent review published in the Journal of Clinical Medicine (https://doi.org/10.3390/jcm9041081) discusses the causes and clinical features of sarcoidosis,
and the improvements made in its prognosis, therapeutic management, and the recent discovery of
potential biomarkers associated with the diagnostic assay used for sarcoidosis confirmation.
Sarcoidosis is not influenced by sex or age, although it is more common in adults (< 50 years) of African-American or Scandinavians decent. Diagnosis can be dicult because of nonspecific symptoms and can only be verified following histopathological examination. Various factors, including infection, genetic predisposition, and environmental factors, are involved in the pathology of sarcoidosis. Exposures to insecticides, herbicides, bioaerosols, and agricultural employment are also associated with an increased risk for sarcoidosis. Due to its unknown etiology, early diagnosis and detection are dicult; however, the advent of advanced technologies, such as endobronchial ultrasound-guided biopsy, high-resolution computed tomography, magnetic resonance imaging, and 18F-fluorodeoxyglucose positron emission tomography has improved our ability to reliably diagnose this condition and accurately forecast its prognosis. In a recent review published in the Journal of Clinical Medicine (https://doi.org/10.3390/jcm9041081) discusses the causes and clinical features of sarcoidosis, and the improvements made in its prognosis, therapeutic management, and the recent discovery of potential biomarkers associated with the diagnostic assay used for sarcoidosis confirmation.
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.
Various studies suggest that genetic factors could play a crucial role in establishing the risk and clinical development of sarcoidosis . 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 . A previous study reported that familial sarcoidosis occurred in 17% of African-Americans , while only 1.4% of Spanish people exhibited this same risk . According to A Case-Control Etiologic Sarcoidosis Study (ACCESS) the chance of developing sarcoidosis is five-fold among siblings . 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 .
Genome wide association studies have demonstrated that several HLA and non-HLA alleles are associated with the development of this disease . HLA-DRB1*0301/ DQB1*0201 , transforming growth factor β (TGF-β) , tumor necrosis factor α (TNF-α) , and Toll-like receptor 4 (TLR-4)  are all considered significant indicators for susceptibility to sarcoidosis [12,13].
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 . 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 .
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,  Pneumocystis jirovecii , Mycobacterium (M.tb) , and Propionibacterium species . 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 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 . 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 . Sarcoidosis overlaps with other autoimmune diseases, including rheumatoid arthritis, autoimmune thyroid disease, Sjogren’s syndrome, and ankylosing spondylitis . 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 ; 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].
M1. Grunewald, J.; Spany etiological agents, includgnolo, P.; Wahlstrom, J.; Eklund, A. Immunogenetics of disease-causing infelammation in
sarctoious microbedosis. Clin. Rev. Allergy Immunol. 2015, 49, 19–35. [CrossRef]
2. Fischer, as well as organic A.; Ellinghaus, D.; Nutsua, M.; Hofmann, S.; Montgomery, C.G.; Iannuzzi, M.C.; Rybicki, B.A.;
Petrek, M.; Mrazek, F.; Pabst, S.; et al. Idend inorganic compounds, cotification of immune-relevant factors conferring sarcoidosis
genetribute to the devic risk. Am. J. Respir. Crit. Care Med. 2015, 192, 727–736. [CrossRef]
3. Rybicki, B.A.; Iannuzzi, M.C. Epidemiolopmentgy of sarcoidosis. These antigens are first cl: Recent advances and future prospects. Semin.
Respir. Crit. Cared Med. 2007, 28, 22–35. [CrossRef]
4. Fabyrellas, the immune system, E.F. Epidemiología de la sarcoidosis. Arch. Bronconeumol. 2007, 43, 92–100. [CrossRef]
5. Rybicki, B.A.; Iannut this is not izzi, M.C.; Frederick, M.M.; Thompson, B.W.; Rossman, M.D.; Bresnitz, E.A.; Terrin, M.L.;
Moller, D.R.; Barnfard, J.; Baughman, R.P.; et allible an. Familial aggregation of sarcoidosis. A case-control etiologic
study some undegof sarcoidosis (access). Am. J. Respir. Crit. Care Med. 2001, 164, 2085–2091. [CrossRef]
6. Sverrild, A.; Baded antigens mcker, V.; Kyvik, K.O.; Kaprio, J.; Milman, N.; Svendsen, C.B.; Thomsen, S.F. Heredity in
sayrcoidosis: A remain in thegistry-based twin study. Thorax 2008, 63, 894–896. [CrossRef]
7. Scells, which churmann, M.; REICHEL, P.; Muller-Myhsok, B.; Schlaak, M.; Muller-Quernheim, J.; Schwinger, E. Results
from a gen initiate an immune feedome-wide search for predisposing genes in sarcoidosis. Am. J. Respir. Crit. Care Med. 2001, 164,
840–846. [CrossRef] [PubMed]
8. Ishiharack, M.; loop. In response to thOhno, S.; Ishida, T.; Ando, H.; Naruse, T.; Nose, Y.; Inoko, H. Molecular genetic studies of hla
class isi feedback loop, the aalleles in sarcoidosis. Tissue Antigen-pres 1994, 43, 238–241. [CrossRef]
9. Pabst, S.; Fränkenting cells (APCs), sucn, T.; Schönau, J.; Stier, S.; Nickenig, G.; Meyer, R.; Skowasch, D.; Grohé, C. Transforming
growth fas dendritic cells (Dctor- gene polymorphisms in dierent phenotypes of sarcoidosis. Eur. Respir. J. 2011, 38, 169–175.
10. Sharma, alveS.; Gholar macrophagsh, B.; Sharma, S. Association of tnf polymorphisms with sarcoidosis, its prognosis and
tumour necros (Ais factor (tnf)- levels in Asian Indians. Clin. Exp. Immunol. 2008, 151, 251–259. [CrossRef]
11. Pabs)t, and alveolar epitheS.; Baumgarten, G.; Stremmel, A.; Lennarz, M.; Knüfermann, P.; Gillissen, A.; Vetter, H.; Grohe, C.
Toll-lial cells, produce high ke receptor (tlr) 4 polymorphisms are associated with a chronic course of sarcoidosis. Clin. Exp.
Immunol. 2006, 143, 420–426. [CrossRevf] [PubMed]
12. Grunewals of TNF-α, and secrete interleukins-d, J. Role of genetics in susceptibility and outcome of sarcoidosis. Semin. Respir. Crit. Care Med.
2010, 312, -380–389. [CrossRef]
153. Iannuzzi, and -18, m M.C. Genetics of sarcoidosis. Semin. Respir. Crit. Care Med. 2007, 28, 15–21. [CrossRef]
14. Kucera, G.P.; Rybicrophage inflammatory protein-1 (MIP-1), monoki, B.A.; Kirkey, K.L.; Coon, S.W.; Major, M.L.; Maliarik, M.J.; Iannuzzi, M.C. Occupational
risk facyte chemoattractant protors for sarcoidosis in african-american siblings. Chest 2003, 123, 1527–1535. [CrossRef]
15. Newman, L.S.; Rose, C.S.; Bresnin-1 (MCP-1), and tz, E.A.; Rossman, M.D.; Barnard, J.; Frederick, M.; Terrin, M.L.;
Weinbergeranulocyte macrophage colo, S.E.; Moller, D.R.; McLennan, G.; et al. A case control etiologic study of sarcoidosis:
Eny-stvimulatingronmental and occupational risk factor (GM-CSF)s. Am. J. Respir. Crit. ThCarese AP Med. 2004, 170, 1324–1330.
[Cros also pressRef] [PubMed]
16. Newmant antigens to CD4+ T-cell, K.L.; Newman, L.S. Occupational causes of sarcoidosis. Curr. Opin. Allergy Clin. Immunol. 2012,
12, 145–150. [CrossRef] [PubMed]
17. Vinitiatinhlborg granuloma constru, P.; Bryngelsson, L.; Andersson, L.; Gra, P. Risk of sarcoidosis and seropositive rheumatoid arthritis
from occupation, a critical feature of sarcoidal silica exposure in swedish iron foundries: A retrospective cohort study. BMJ Open 2017, 7,
18. Izbiscki, G.; Chavko, R. The growth ; Banauch, G.I.;Weiden, M.D.; Berger, K.I.; Aldrich, T.K.; Hall, C.; Kelly, K.J.; Prezant, D.J.
Wofrld trade thesecenter “sarcoid-like” granulomas establishes the primary abnormality in mtous pulmonary disease in new york city fire department rescue
workerst c. Chest 2007, 131, 1414–1423. [CrossRef] [PubMed]
19. Newmasn, L. Aetiologies of sarcoidosis. Sarcoid grEur. Respir. Monogr. 2005, 32, 23–48.
20. Vidanul, S.; De lomas are orderea Horra, C.; Martin, J.; Montes-Cano, M.; Rodríguez, E.; Respaldiza, N.; Rodriguez, F.; Varela, J.;
Medrano, structured masses F.; Calderón, E. Pneumocystis jirovecii colonisation in patients with interstitial lung disease. Clin.
Micromprised ofbiol. Infect. 2006, 12, 231–235. [CrossRef]
21. Drake, W.P.; Newmacrophages and theirn, L.S. Mycobacterial antigens may be important in sarcoidosis pathogenesis. Curr.
Opin. Pulm. Mede. 2006, 12, 359–363. [CrossRef]
22. Ishige, I.; Eishi, Y.; Takemura, T.; Kobayashivatives, I.; Nakata, K.; Tanaka, I.; Nagaoka, S.; Iwai, K.;Watanabe, K.;
Takizawa, T. Propionibacterium acnepithelioid cells, gis is the most common bacterium commensal in peripheral lung tissue
antd cells, and T-cellmediastinal lymph nodes from subjects without sarcoidosis.
A Sarctoidosivated CDs Vasc. Diuse Lung Dis. 2005, 22,
23. T-cAllells can differenn, S.S.; Evans, W.; Carlisle, J.; Hajizadeh, R.; Nadaf, M.; Shepherd, B.E.; Pride, D.T.; Johnson, J.E.;
Drake,W.P. Superoxide dismutiase a ate into two disntigens derived from molecular analysis of sarcoidosis granulomas
elicit systeminct subsets, c th-1 immune responses. Respir. Res. 2008, 9, 36. [CrossRef]
24. Song, Z.; Mamely, T helper 1 (Th1) and T herzilli, L.; Greenlee, B.M.; Chen, E.S.; Silver, R.F.; Askin, F.B.; Teirstein, A.S.; Zhang, Y.; Cotter, R.J.;
Molpler 2 (Th2) cells, based on their, D.R. Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response
in csytokinesstemic sarcoidosis. J. Exp. Med. 2005, 201, 755–767. [CrossRef]
25. pDrofile. Th1 cake,W.P.; Dhason, M.S.; Nadaf, M.; Shepherd, B.E.; Vadivelu, S.; Hajizadeh, R.; Newman, L.S.; Kalams, S.A.
Cellsular predominantly secrete interlerecognition of mycobacterium tuberculosis esat-6 and katg peptides in systemic sarcoidosis. Infect.
Immukin-2 (IL-2) and. 2007, 75, 527–530. [CrossRef] [PubMed]
26. Hinterferon-gamma (IFN-γ)rano, A.; Kataoka, M.; Nakata, Y.; Takeda, K.; Kamao, T.; Hiramatsu, J.; Kimura, G.; Tanimoto, wY.;
Kanehilero, IL-4 and IL-13 are the major secretiA.; Tanimoto, M. Sarcoidosis occurring after interferon-alpha therapy for chronic hepatitis c:
Reponsrt of Th2 celltwo cases. Resolutpirology 2005, 10, 529–534. [CrossRef] [PubMed]
27. Trioen or maintenance o, R.; Cooper, C.J.; Paez, D.; Colon, E.; Ajmal, S.; Salameh, H. Interferon-alpha-induced sarcoidosis in a
patient being treated for ghepatitis c. Am. J. Case Rep. 2014, 15, 235–238.
28. Brjanuloma is determined by thlin, V.; Salupere, R.; Tefanova, V.; Prikk, K.; Lapidus, N.; Jõeste, E. Sarcoidosis and chronic hepatitis c:
A case proportion of Th1 and Th2 celeport. World J. Gastroenterol. 2012, 18, 5816–5820. [CrossRef] [PubMed]
29. Ramos-Casals, M.; Mana, respectively. AlveolJ.; Nardi, N.; Brito-Zeron, P.; Xaubet, A.; Sanchez-Tapias, J.M.; Cervera, R.; Font, J.
Sarcoidosis macrophages are activated in the Th2 miliin patients with chronic hepatitis c virus infection: Analysis of 68 cases. Medicine 2005, 84, 69–80.
30. Grunewand stimulate fibroblast anld, J.; Kaiser, Y.; Ostadkarampour, M.; Rivera, N.V.; Vezzi, F.; Lötstedt, B.; Olsen, R.-A.; Sylwan, L.;
Lundin, collagen proliferation culminating in prS.; Käller, M. T-cell receptor—Hla-drb1 associations suggest specific antigens in pulmonary
sarcoidogsis. Euressive fibrosi. Respir. J. 2016, 47, 898–909. [CrossRef] [PubMed]
Inc Wapacihlstation of Tregs is also a kröm, J.; Dengjel, J.; Winqvist, O.; Targo, I.; Persson, B.; Duyar, H.; Rammensee, H.-G.; Eklund, A.;
Weyissert, R.; feature of granuloma maintenance. It iGrunewald, J. Autoimmune t cell responses to antigenic peptides presumed that infiltented by bronchoalveolar
latinvag Tregs fail to rede cell hla-dr molecules in sarcoidosis. Clin. Immunol. 2009, 133, 353–363. [CrossRef]
32. Zissel, G.; Müller-Quce the exaggerated inflammatory responrnheim, J. Specific antigen(s) in sarcoidosis: A link to autoimmunity? Eur. Respir. Soc.
2016, 47, 707–709. [CrossRef]
33. Kaiser, thereby contribuY.; Eklund, A.; Grunewald, J. Moving target: Shifting to granuloma persishe focus to pulmonary sarcoidosis as an
autoimmunence and integrity. Treg spectrum disorder. Eur. Respir. J. 2019, 54, 1802153. [CrossRef]
34. Starshinova, also release transforming growth factA.A.; Malkova, A.M.; Basantsova, N.Y.; Zinchenko, Y.S.; Kudryavtsev, I.V.; Ershov, G.A.;
Sopr β (TGF-β) that may contribute tun, L.A.; Mayevskaya, V.A.; Churilov, L.P.; Yablonskiy, P.K. Sarcoidosis as an autoimmune disease. Front.
Immunol. fibrosis2019, 10, 2933. [CrossRef]
35. Hand granuloma organizatiggmark, A.; Hamsten, C.; Wiklundh, E.; Lindskog, C.; Mattsson, C.
Th17; aAnd Th17.1 cells have ersson, E.; Lundberg, I.E.;
Gronlyund, H.; recently been linked to the pathogenesis ofSchwenk, J.M.; Eklund, A.; et al. Proteomic profiling reveals autoimmune targets in sarcoidosis.
Am. J. ThRese cells are recruitedpir. Crit. Care Med. 2015, 191, 574–583. [CrossRef] [PubMed]
36. to tGianche disease site and arecchi, E.; Fierabracci, A. Recent advances on microbiota involvedment in the conspathogenesis of
autroimmuction of nity. Int. J. Mol. Sci. 2019, 20, 283. [CrossRef] [PubMed]
37. Korsthen, P.; Tampe granuloma. Th, B.; Konig, M.F.; Nikiphorou, E. Sarcoidosis and autoimmune diseases: Dierences,
similarities balance betweenand overlaps. Curr. Opin. Pulm. Med. 2018, 24, 504–512. [CrossRef] [PubMed]
38. Chu, F.; TSh17 and Treg cells is thought to be disrupted in sarcoidi, M.; Lang, Y.; Shen, D.; Jin, T.; Zhu, J.; Cui, L. Gut microbiota in multiple sclerosis and experis mental
autoimmun important factor in its prognosie encephalomyelitis: Current applications and future perspectives. ThMe diat. Inflamm. 2018.
39. Becker, A.; Vellation of antigen processing, antigen p, G.; Galata, V.; Rentz, K.; Beisswenger, C.; Herr, C.; Walter, J.; Tierling, S.; Slevogt, H.;
Keller, A.; esentation to the APCs, and cytokine releast al. The composition of the pulmonary microbiota in sarcoidosis—An observational study. Respir.
Res. 2019, are20, 46. [CrossRef] [PubMed]
40. Inaokall controlled through genetic element, P.T.; Shono, M.; Kamada, M.; Espinoza, J.L. Host-microbe interactions in the pathogenesis and may link the various causaclinical fa
ctorsurse of sarcoidosis together.. J. Biomed. Sci. 2019, 26, 45. [CrossRef]