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Hindawi Publishing Corporation

International Journal of Chronic Diseases
Volume 2013, Article ID 928601, 13 pages
http://dx.doi.org/10.1155/2013/928601

Review Article
Sarcoidosis: Immunopathogenesis and Immunological Markers
Wei Sheng Joshua Loke,1,2 Cristan Herbert,1 and Paul S. Thomas1,2
1
2

Inflammation and Infection Research Centre, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia
Department of Respiratory Medicine, Prince of Wales Hospital, Randwick, NSW 2031, Australia

Correspondence should be addressed to Paul S. Thomas; paul.thomas@unsw.edu.au
Received 20 April 2013; Accepted 17 June 2013
Academic Editor: Maria Gazouli
Copyright © 2013 Wei Sheng Joshua Loke et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Sarcoidosis is a multisystem granulomatous disorder invariably affecting the lungs. It is a disease with noteworthy variations
in clinical manifestation and disease outcome and has been described as an “immune paradox” with peripheral anergy despite
exaggerated inflammation at disease sites. Despite extensive research, sarcoidosis remains a disease with undetermined aetiology.
Current evidence supports the notion that the immune response in sarcoidosis is driven by a putative antigen in a genetically
susceptible individual. Unfortunately, there currently exists no reliable biomarker to delineate the disease severity and prognosis.
As such, the diagnosis of sarcoidosis remains a vexing clinical challenge. In this review, we outline the immunological features
of sarcoidosis, discuss the evidence for and against various candidate etiological agents (infective and noninfective), describe the
exhaled breath condensate, a novel method of identifying immunological biomarkers, and suggest other possible immunological
biomarkers to better characterise the immunopathogenesis of sarcoidosis.

1. Introduction
Sarcoidosis is a multisystem, inflammatory disorder of obscure aetiology. Its defining histopathology is the existence
of noncaseating epithelioid granulomas with accompanying
mononuclear cell infiltration and microarchitecture destruction [1, 2].
Although sarcoidosis involves the lungs in >90% of cases,
it also affects the heart, skin, eye, and central nervous system
[3]. This accounts for its heterogeneous clinical manifestation
which ranges from having no symptoms to severe consequences, namely respiratory insufficiency, cardiac death,
neurological disease, and blindness [4].
Sarcoidosis has been reported in all ethnic and racial
groups with the majority of studies recording a peak incidence of 20–39 years of age for both males and females and
a bimodal distribution whereby women have another peak
incidence at 65–69 [4].
Disease remission occurs in as many as two-thirds
of patients, usually in the first 3 years after diagnosis.
Other patients have chronic unremitting sarcoidosis which
may subsequently lead to lung fibrosis [1]. The erratic
clinical course has impelled research into biomarkers that

could delineate disease severity and outcome [5]. To date,
there exist no reliable and practical biomarkers for sarcoidosis [6]. Moreover, despite earnest research efforts, the
immunopathogenesis and aetiology underpinning sarcoidosis remains elusive [3].
This review outlines the current understanding of sarcoidosis, with reference to ex vivo lymphocyte stimulation in
the peripheral blood and bronchoalveolar lavage fluid (BALF)
of sarcoidosis patients, describes the exhaled breath condensate, an innovative method of identifying immunological
markers, and proposes novel immunological markers to
better characterise the immunopathogenesis of sarcoidosis.

2. Immunopathogenesis of Sarcoidosis
2.1. Key Features of the Pathological Process
2.1.1. Immune Paradox. Sarcoidosis can be described as an
“immune paradox.” Peripheral anergy is observed despite
exaggerated inflammation at disease sites [7]. This is demonstrated by a reduced delayed-type hypersensitivity to tuberculin and common antigens [8]. It has been postulated that

This leads to an increase in the production of TNF𝛼. the Treg cells in the sarcoid granulomas (as opposed to peripheral Treg cells) have undergone extensive amplification and are therefore impaired in their ability to repress immune responses. MMPs cause lung damage and fibrosis and the chemokines attract more Tcells and myeloid cells into the inflammatory milieu. IL-15 is capable of promoting CD4+ T-cell survival by binding to IL-2R. a negative regulator of inflammation. This results in the amplification of TH 1 responses to local pathogenic antigens. T-bet enhances IFN𝛾 gene transcription competence and ultimately increases the production of IFN𝛾 (Figure 1). In sarcoidosis. regulatory T cells. CXCL-10. Antigen Presentation. The inflammatory response is potentiated as SAA proteins readily accumulate and release more soluble SAA peptides into the surrounding tissue [29. Finally. and growth factor of T cells.g. NKT cells have been known to moderate CD4-mediated immune responses. resulting in an anergic response [11]. 2. surrounded by macrophages that will differentiate to epithelioid cells which subsequently fuse to form multinucleated giant cells. Interleukin-12 (IL-12) secreted by DCs is a TH 1 polarising cytokine.2. a transcription factor that regulates TH 2 differentiation.2. 2. They journey to lymph nodes where they mature and prime the adaptive immune system by displaying the antigen peptide on the surface major histocompatibility complex (MHC) class II peptide groove. CXCR3. Persistent granulomatous inflammation can be attributed to the inability of the immune regulatory mechanisms to limit the duration of the inflammatory process [12]. 2. CD4+ T helper cells are interspersed in the granuloma while CD8+ T cells. through the ligation of a T-cell receptor.. With the aid of STAT4. induce T-cell chemotaxis. CD1d-Restricted Natural Killer T (NKT) Cells. IFN𝛾 binds to IFN receptors and stimulates STAT1 which promotes Tbx21 gene expression of T-bet. interacts with CD86 on DCs [15].1. PPAR𝛾 promotes macrophage IL-10 production which inhibits the release of TNF𝛼.2. Others argue that the intense immune response at disease sites results in activated T cells gathering at these disease sites and consequent peripheral blood lymphopenia [10]. T Regulatory (𝑇𝑟𝑒𝑔 ) Cells. T-Helper 1 (T𝐻1) Immune Response. NKT cell numbers have been noted to be markedly reduced in sarcoid blood and BALF except in patients . Its centre is hypothesized to contain a poorly degraded antigen.2. Serum Amyloid A Protein. 2. A specific T cell receptor (TCR) fixes its variable region to the antigen-MHC complex and is activated [18].3. 32]. 2. T-bet also up regulates IL-12 𝛽 receptor (IL-12𝛽R) expression and antagonises Gata3. They only weakly suppress TNF𝛼 production [9]. and B cells surround the periphery [4. Moreover. IFN𝛾 production inhibits the expression of the immunosuppressive cytokine. These IL-15 responses are upregulated in the presence of TNF𝛼 [27].2. a costimulatory signalling molecule on T cells.1. increased TNF𝛼 and decreased IL-10 expression liberate DCs from the inhibition by macrophages. 2. SAA triggers cytokine release by interacting with Toll-like receptor 2. The interplay of antigen-presenting dendritic cells (DCs) and na¨ıve CD4+ T-cells is necessary for granuloma formation [18]. IL-4) which encourages granuloma formation via mast cell activation and fibroblast amplification [31. 12]. These cells accumulate in the periphery of the granuloma and peripheral blood of patients with active disease and exert anti-proliferative effects on na¨ıve T cells. IL-12. Hamazaki-Wesenberg. 28]. International Journal of Chronic Diseases Therefore.3. 25] and indirectly by causing DC to mature into antigen presenting cells [26]. To optimise this activation. The DCs also produce a battery of mediators which facilitates the sarcoid immune reaction (Figure 1) [20].2 underpinning this paradoxical situation is a disequilibrium between effector and regulatory lymphocytes (Treg cells). Serum amyloid A (SAA) proteins are extensively deposited in sarcoid granulomas. 30]. CD28. 2. immunosuppressive CD8+ T cells become more abundant peripherally. therefore allowing granuloma formation.3. TNF𝛼 produced by the DCs also encourages CD4+ Tcell proliferation and survival. Autocrine IL-2 production results in the clonal proliferation of CD4+ T cells (Figure 1) [2. and asteroid bodies may also be present but are nonspecific [13]. Upon TCR activation.2. IL-12 facilitates IFN𝛾 expression. IL-18 upregulates IL-12𝛽R and IFN𝛾 expression while IL12 increases IL-18 receptor expression on CD4+ T cells.3. Moreover. CD4+ T-cell activation also increases IL-2 production.1. Persistent Granulomatous Inflammation. Under normal physiological conditions. Schaumann bodies. The noncaseating epithelioid granuloma is the histologic hallmark of sarcoidosis. The CD4+ T cells that trigger the granuloma formation are strongly TH 1 polarised. Still others have suggested that with disease chronicity. fibroblasts. Treg cells are vital for the suppression of cell-mediated immune responses. initiating a self-amplifying inflammatory loop [19]. differentiation. However. macrophages constitutively express PPAR𝛾. Granuloma Formation. IL-10 (Figure 1). and MMP and induces chemokines CXCL-9. the expression of IFN𝛾 and Tbx21 genes in CD4+ T cells becomes more pronounced. IFN𝛾 is highly expressed in the BALF of sarcoidosis patients. directly through the induction of T-cell IL-2R [24. IL-12 and matrix metalloproteinase (MMP) from DCs. notably CD4+ CD25bright FoxP3+ cells [7]. This amplifies the responsiveness of CD4+ T-cells to IL-12 and inhibits IL-4 and IL-13 (cytokines that facilitate the fibroproliferative response) production [16]. IFN𝛾 inhibits the expression of macrophage peroxisome proliferator-activated receptor 𝛾 (PPAR𝛾). DCs phagocytose the inciting sarcoid antigen. they secrete proinflammatory cytokines (e. and CXCL-11 production which.3. Birefringent crystals. IL-2 is a local survival. IL-12 and IL-18 act synergistically to promote the formation of sarcoid granulomas [20–23]. Immune Reactions in Sarcoidosis 2.

MIP1-𝛽. IL-16. upon TCR activation. TGF. IL-15. AV2S3+ (V𝛼2. IL-6. and CXCL-11 Monocyte CD4+ CD4+ V𝛼. 5. HLA-DRB1∗03. Furthermore. HLA-DRB1∗11. MIP3-𝛽. GM-CSF. or 𝛾𝛿+ genes. CD86. RANTES. TNF𝛼. Antigen clearance and increased IL-10 levels facilitate disease remission.International Journal of Chronic Diseases 3 Infective factors Macrophage Presumptive antigen (1) Mycobacterium (2) Propionibacterium (3) Virus and other infectious pathogens Noninfective factors (1) Environmental (2) Transplants (3) Autoantigens Serum amyloid A IL-2 Lymph node TLR2 PPAR𝛾 2 L BTN ↓ IL-10 ? CD28 CD86 Dendritic cell HLA-DRB1∗01. The presumptive sarcoid antigen is engulfed by circulating dendritic cells. and BTNL2 optimises the activation of T cells. Disease chronicity results in a predominance of TH 2 cytokines which leads to lung remodelling by fibrosis (adapted from: [2. V𝛽. IL-12. a myriad of inflammatory mediators is released. Serum amyloid A proteins can also interact with Toll-like receptor 2 and be presented to T cells via major histocompatibility complex Class II to specific T cell receptors (TCRs) along with processed antigen peptides. IL-18. HLA-DRB1∗12. Thereafter. T-bet upregulates and perpetuates the production of IFN𝛾 which facilitates granuloma formation. T-bet production increases. 14–19]). HLA-DRB1∗1501/DQB1∗0602 IL-2R MHC II IFN𝛾 T cell IL-1. Activated T cells are highly TH 1 polarised. IGF-1 IFN𝛾 CD4+ + Treg CD4 M Treg + CD4+ CD4 M CD4+ CD8+ M CD8+ CD4+ CD4+ M CD4+ CD8+ M Treg M M CD4+ Treg TH 1 CD4+ M CD8+ CD4+ Blood vessel Monocyte Chemokines CXCL-9. HLA-DRB1∗14. Ligation of costimulatory molecules CD28. 12. They release IL-2 which causes clonal proliferation of T cells. HLA-DRB1∗04. .3) TCR CD4+ CD4+ Treg + CD4 CD4+ CD8+ CD8+ + CD4 Treg CD8+ TH 2 Noncaseating granuloma T cell (TH 1 program) IL-12Rb2 Tbx21 TCR IL-12R IL-12 IFN𝛾 Remission (1) Antigen clearance (2) ↑ IL-10 Remission Tbet STAT4 IL-13 TGF-𝛽 CCL-18 IFN𝛾 Positive feedback loop 𝛾 IFN STAT1 Persistent granulomas: (1) Serum amyloid A protein (2) ↓ Immunosuppression by Treg cells (3) ↓ NKT cells Fibrosis Figure 1: The immunopathogenesis of sarcoidosis (a proposed model). CXCL-10. HLA-DRB1∗15. MIP1-𝛼.

5. Additionally.1.3. CCL2. 3. Variants of the TNF gene confer a 1.. Therefore. an analogous granulomatous lung disease. the close . augmenting the effects of TGF𝛽 [38]. based on chronic beryllium disease. the TH 2 chemokine. Remission and Progression to Fibrosis. HLA-DRB1∗ 03 is associated with L¨ofgren’s syndrome (∼80% of patients with L¨ofgren’s syndrome experience disease remission). reduction in the number of NKT cells can account for the persistence of sarcoidosis [34]. HLA-DRB1∗ 12. Genetic Polymorphisms and Host Factors 3. NKT cells produce TH 1 and TH 2 cytokines (IFN𝛾 and IL4. various cytokines which are able to support a fibrotic response have been found at disease sites in patients with sarcoidosis (e. transforming growth factor-𝛽 (TGF-𝛽). Apart from TNF. familial aggregation of sarcoidosis can be seen worldwide. a commonly implicated antigen for sarcoidosis. vesicle trafficking. bilateral hilar lymphadenopathy. erythema nodosum. HLA class II are cell surface proteins that prime the adaptive immune system to antigens.1. Since L¨ofgren’s syndrome is often associated with disease remission. This led to the discovery of butyrophilin-like 2 (BTNL2). However. the macrophages of patients with pulmonary fibrosis. the host’s immune status. particularly in patients with active disease. cell division. NKT cells are mostly CD4+ and express an invariable TCR [33]. TH 2 cytokines such as IL-13 increase TGF-𝛽 production (Figure 1). 37]. therefore suggesting that NKT cells exert regulatory activity which prevents disease progression [43]. High levels of IL-17+ /CD4+ T lymphocytes have been found in the BALF and granulomas of sarcoidosis patients. Moreover. Twin studies prove that monozygotic twins are more concordant for sarcoidosis than dizygotic twins. HLA-DRB1∗ 01 and HLA-DRB1∗ 04. Both family and genetic host studies have recognised genes that are responsible for this genetic susceptibility. HLA-DRB1∗ 14 and HLA-DRB1∗ 15 have been shown to increase the risk of sarcoidosis. studies investigating other candidate genes (polymorphisms in the complement receptor 1 gene. whereas HLADRB1∗ 03. 3. It has been proposed that a switch from TH 1 to TH 2 cytokine predominance may occur in chronic sarcoidosis in response to persistent inflammation.5-fold increased risk of having sarcoidosis [48].g. 40]. TGF-𝛽 recruits. resp. NOD. it is highly likely that the development of a sarcoidosis reaction to an antigen depends on a combination of genetic polymorphisms. 3. and insulin growth factor-1 (IGF-1)) [35. activates.1. The immunological mechanisms leading to a fibrotic outcome remain undetermined. Recently. 36]. Therefore. TNF𝛼 is an essential mediator for granuloma formation. Nonetheless. Although the majority of studies have used the TH 1/TH 2 model to explain the immunopathogenesis of sarcoidosis. The annexin A11 gene regulates calcium signalling. its dysfunction or deletion may implicate apoptotic pathways in sarcoidosis [46]. Richmond and colleagues [42] verified the specificity of TH 17 cells for mycobacterial antigens. when stimulated with a glycolipid stimulator. are negatively associated with sarcoidosis. enhances fibroblast survival. Finally. They infiltrate the lungs after being recruited from the blood by the chemokine CCL20 [41]. Single nucleotide polymorphisms (rs2076530 G → A) in BTNL2 may affect T-cell regulation and activation [45]. 2. by focusing solely on this model. The genome-wide association study conducted by Hofmann and colleagues [46] revealed an association for the annexin A11 gene located on chromosome 10q22. 2. Findings on Genome-Wide Association. there is a propensity to oversimplify the immunological process and divert research efforts away from other mechanisms. Disease remission occurs with the suppression of macrophage and T-helper cell activity by IL-10 or when the presumptive antigen has been completely cleared (Figure 1) [4]. variations in the gene that encodes for RAGE (a transmembrane receptor) have been associated with an increased risk of sarcoidosis. The multicentre study entitled A Case Control Etiologic Study of Sarcoidosis (ACCESS) demonstrated that sarcoidosis patients were 5 times more probable than controls to report a parent or sibling with sarcoidosis [45].3.2. These findings suggest a possible role of TH 17 in sarcoidosis disease progression. Moreover. and transforms fibroblasts into myofibroblasts which have been strongly implicated in the development of fibrosis [17. and exposure to environmental agents [44].). arthritis. TH 17 is a novel CD4+ effector T-cell population. Human Leukocyte Antigen (HLA) Genes. Sarcoidosis is associated with the DR subtypes of class II antigens. and CCR2 genes) were inconclusive and had poor reproducibility between populations [49–52]. Non-HLA Genes. express CCL18 chemokines which facilitates lung remodelling via fibrosis [39. it has been speculated that one or more antigenic stimuli may be involved in the pathogenesis of sarcoidosis. 47]. HLA-DRB1∗ 11. Putative Aetiology of Sarcoidosis The aetiology of sarcoidosis remains unclear. MMP. showed diminished levels of IFN𝛾.1. the HLA-DRB1∗ 1501/DQB1∗ 0602 haplotype was associated with severe and chronic pulmonary sarcoidosis [6.4. Moreover. 3.1. blood NKT cells from sarcoidosis patients. A myriad of observations have supported the notion that sarcoidosis can International Journal of Chronic Diseases be caused by environmental and infectious agents. under the influence of the TH 2 cytokine milieu. Persistent granulomatous inflammation can lead to fibrosis. Role of Other T Lymphocytes (T𝐻17 and NKT Cells). In some populations.4 exhibiting L¨ofgren’s syndrome (acute sarcoidosis characterised by uveitis. and fever) [33]. a costimulatory molecule within the MHC locus. Genetic linkage studies on German families revealed a strong linkage to chromosome 6p. Moreover. and apoptosis.

[90]. spatial crowding of unrelated sarcoidosis cases suggests that sarcoidosis can also be a result of exposure to environmental agents [1. After BALF CD4+ lymphocytes were stimulated with ionomycin and phorbol 12-myristate acetate. The TH 1/TH 2 model is under scrutiny as it oversimplifies the immunopathogenesis of sarcoidosis [56]. there are increased numbers of CD4+ IFN𝛾+ cells in both BALF and induced sputum of patients with sarcoidosis [88. There is a subpopulation of T cells (AV2S3+ (V𝛼2. The following segment clarifies this debate. the proportion of CD4+ T cells expressing IL-4 and IFN𝛾 obtained from the peripheral blood of sarcoidosis patients did not differ significantly from that of healthy controls [57. TH 1 and TH 2 chemokines (interferon-inducible protein-10 (IP-10) and thymus and activationregulated chemokine (TARC)) were both increased in the serum of sarcoidosis patients. 3. it has been suggested that TH 2 cell preponderance occurs in the peripheral blood of sarcoidosis patients and that this. only 80% and 40% of CD4+ IL-4+ cells concurrently produce IFN𝛾 and IL-2 respectively. Under unstimulated conditions. T Cell Receptor (TCR) Genes. or 𝛾𝛿+ TCR genes in blood. . There were no associations between polymorphisms in genes for vitamin D receptor or serum angiotensinconverting enzyme [45. This was in agreement with previous findings that demonstrated elevated BALF and peripheral blood IL-13 (a TH 2 cytokine) mRNA levels [92].International Journal of Chronic Diseases proximity of this gene to the MHC region makes it difficult for one to ascertain if this association is due to linkage with neighbouring HLA genes [53]. Nonetheless the evidence supporting specific infectious and environmental factors varies significantly (Table 1) [3]. following stimulation. further studies investigating the cytokine profiles in blood lymphocytes of patients versus healthy controls are required to assess the TH 1/TH 2 balance. the difference in the percentages of IL-4 and IFN𝛾 secreting CD4+ lymphocytes in BALF and peripheral blood of sarcoidosis patients is insignificant [57. V𝛽. Lower ratios were demonstrated in scleroderma and in patients with idiopathic pulmonary 5 fibrosis. lung. some studies report that after lymphocyte stimulation. suggesting that AV2S3+ T cells may offer some protective function against sarcoidosis [6]. To further explore this dichotomy of blood TH 1/TH 2 equilibrium. compared with controls. After stimulation. It needs to be supported by histological evidence showing noncaseating granulomas. there are lower levels of IL-17A gene expression in CD4+ T cells in patients with L¨ofgren’s syndrome compared to healthy controls [94]. the regulatory mechanisms in the peripheral blood of sarcoidosis patients. Ex Vivo Stimulation of BALF and Peripheral Blood Lymphocytes Preliminary ex vivo studies that employed flow cytometry to investigate peripheral blood lymphocytes in sarcoidosis patients demonstrated a greater activation of nonstimulated CD4+ and CD8+ BALF T cells compared to peripheral blood lymphocytes. together with data showing heightened TH 1 cytokine expression at disease sites. 54]. motivating researchers to look for other novel methods of diagnosing the disease. increased cytokine profiles have been verified by increased BALF IFN𝛾+ /IL-4+ CD4+ T cell ratios in sarcoidosis patients. interestingly. Extrinsic Factors. emphasising the systemic nature of the disease. Moreover. there is an increase in TH 17 related cytokine levels in both BALF and peripheral blood [41]. Nureki and colleagues [59] showed that under unstimulated conditions. it has been shown that the amount of AV2S3+ BALF T cells at the onset of sarcoidosis correlates positively with prognosis. Moreover. 89]. together with the generalised intensification of TH 1 activity. indicate that TH 17 cells have a systemic role in patients with non-L¨ofgren’s disease and is involved in sarcoidosis progression [14]. The T-cells at sites of inflammation in sarcoidosis exhibit a restricted repertoire of TCR 𝛾𝛿 or 𝛼𝛽 genes. there was an appreciable increase in secreted IFN𝛾 but a decrease in IL-4 expression in sarcoidosis patients compared to controls [87]. 5. It has also been shown that upon stimulation. Exhaled Breath Condensate: Detection of Immunological Markers The diagnosis of sarcoidosis is never secure. these findings reflect the systemic nature of sarcoidosis. IL-12R and IL-18R) than CD4+ T cells in the peripheral blood. Numerous pathogens have been implicated and investigated in the etiology of sarcoidosis.2. Clinicoradiological findings alone are often insufficient to confirm the diagnosis of sarcoidosis. Therefore.4. CCR5. 3].3) CD4+ T cells) from BALF of HLA-DR∗ 0301 sarcoidosis patients which is unique to sarcoidosis. 3. gives the appearance of an increase in both TH 1 and TH 2 circulating cytokine expression in sarcoidosis patients compared to healthy controls [59]. Other studies showed higher TH 1 and TH 2 levels of cytokine positive CD4+ T cells compared to healthy controls [59. 58]. Flow cytometry data indicate that after stimulation. concurrent production of TH 1 and TH 2 cytokines [91]. thus demonstrating that activated BALF lymphocytes of sarcoidosis patients are capable of a complex. Nonetheless. This showed that the sarcoid immune response is largely compartmentalised to disease sites [55]. Another study also indicated that. These data. 58]. and the functional significance of TH 17 cells. For instance.1. after stimulation. This makes diagnosing sarcoidosis a vexing clinical challenge. TH 17 cells have also been implicated in the induction of granuloma formation [93]. This warrants a tissue biopsy which is invasive [12]. 60]. 4. more T cells express TH 1 than TH 2 cytokines in both the BALF and peripheral blood of sarcoidosis patients and more CD4+ T cells in BALF express TH 1 receptors (CXCR3. Moreover. Although CD4+ T cells largely express TH 1 cytokines. and at sites of Kveim-Siltzbach skin reactions implies that sarcoidosis is an antigen-driven disorder. The expression of specific V𝛼. Therefore.

(ii) A nonspecific polyclonal hypergammaglobulinemia. 65. and Epstein-Barr virus) were elevated in patients with sarcoidosis [72]. mycobacteria may not be the sole cause of sarcoidosis [3]. (v) Granulomatous reactions resulting from spirochetes. and 16 were found in the lymph nodes and sera of sarcoidosis patients [67]. 66]. Tropheryma whipplei. (i) Acid-fast stains and cultures of sarcoid specimens do not routinely demonstrate the presence of mycobacterium species. Evidence for (i) Immunohistochemical studies showed possible remnants of cell wall deficient mycobacteria [61]. in genetically different individuals. (iii) An antibody response to P. Additionally. (ii) P. tuberculostearic acid. (ii) A mycobacterial cell wall component. (iii) Techniques such as enzyme-linked immunospot assay (ELISpot) and polymerase chain reactions (PCR) have shown increasing evidence for mycobacteria in the mediastinal lymph nodes and peripheral lung tissues of sarcoidosis patients [63]. Evidence against Table 1: List of infectious and noninfectious agents and the evidence for and against them. may explain the increased antibody titre for these viruses [73]. acnes has been found in up to 78% of sarcoidosis sample cultures [69]. compared to healthy controls. herpes simplex virus. (iii) Mycobacterial nucleic acid and antigens are not detected in many sarcoid specimens. and Borrelia species infection can be difficult to discriminate from sarcoidosis [75]. (ii) The mere presence of the mycobacterial antigens in sarcoid specimens is not proof of a causal relationship. (iii) Viruses do not cause the epithelioid granulomas of sarcoidosis [74]. acnes proteins has been observed in 40% of BALF samples (compared to 5% in healthy controls) [70]. fungi. Mtb-hsp 16 can induce an autoimmune response in sarcoidosis. 6 International Journal of Chronic Diseases . therefore. (iv) The mechanism for granuloma formation by molecular mimicry after viral exposure remains undetermined [74].Infective Nature Viruses and other infectious pathogens Propionibacterium Mycobacterium Causative agent (i) Serum antibodies to herpes-like viruses (human herpes virus-8. (i) Significant proportions of the general population have also been previously exposed to herpes-like viruses. (iv) Mycobacterium tuberculosis DNA: mycobacterium tuberculosis catalase-peroxidase protein (mKatG) and circulating IgG for mKatG have been identified in sarcoidosis patients [64]. (i) It has been shown to be able to induce a granulomatous reaction [68]. sarcoidosis patients have amplified T-cell responses in the peripheral blood and lungs to mKatG and mycobacteria antigens [65. common in sarcoidosis. (vi) Dubaniewicz and colleagues (2013) suggested that. (v) Mycobacterial heat-shock proteins (Mtb-hsp)70. (i) Cultures from healthy controls also yield this commensal organism [71]. was found in sarcoid specimens [62].

Evidence against (vi) The notion that cell-wall deficient organisms like mycobacteria. (i) Wood stoves and fireplaces have been associated with an increased risk of sarcoidosis [80]. (ii) Fire rescue workers. metals. (i) The ACCESS study failed to identify risk factors that accrue a greater than two-fold risk (odds ratio). and chlamydia species cause sarcoidosis is founded on limited data. and musty odours can increase one’s risk of sarcoidosis. International Journal of Chronic Diseases 7 . dusts. wood dust. (i) Immune dysregulation following allogeneic hematopoietic cell transplantation has been shown to promote sarcoidosis in patients with susceptible HLA subtypes [76]. These antigenic peptides include vimentin. ATP synthase. There is a shortage of conformation from well-controlled epidemiological and laboratory studies [75]. (ii) The BALF of HLA-DRB1∗0301-positive sarcoidosis patients with L¨ofgren’s syndrome had antigenic peptides that were bound to HLA-DR molecules of lung cells that have the TCR AV2S3+ gene segment. (iii) IFN𝛾 enzyme-linked immunospot assays revealed a strong T-cell response to the cytoskeletal peptides of vimentin from the peripheral blood of patients with HLA-DRB1∗0301. thought to be autoantigens in various conditions [85]. (iii) An increased incidence of sarcoidosis in closed populations may suggest an infection-related disease. it has been postulated that these autoantibodies are most likely the product of general B-cell stimulation in the progression of T-cell stimulation by antigens [1]. 82]. and silica) and sarcoidosis [1. The disease-specific autoantibody profile has not been described. Thus. Lastly. military personnel. pesticides.. this suggests a possible autoimmune response in patients with HLA-DRB1∗0301. The same was observed for ATP synthase and lysyl tRNA synthetase from BALF.g. insecticides. it had inadequate power to ascertain the sarcoidosis risk among fire rescue workers. it failed to prove an association between previously hypothesised exposures (e.5) that workplace exposure to organic solvents. and healthcare workers. (ii) Individuals have developed granulomatous inflammation post lung and heart transplant from patients with sarcoidosis [77–79]. rickettsia. contributing to sarcoid granulomatous inflammation [86]. Therefore. Reduced risk was associated with exposures to animal dander and other allergic (TH 2) responses [83]. 3]. and healthcare workers who were exposed to the dust from the destruction of the World Trade Centre in New York were found to have a higher risk of developing sarcoidosis [81. Evidence for Table 1: Continued.Noninfectious Nature Autoantigens Environmental Transplants Causative agent (i) Sarcoidosis patients express low titre levels of autoantibodies. (iii) Findings from the ACCESS study showed the modest positive odds ratios (∼1. (iv) Nanoparticles of common minerals and metals can elicit a dysregulated immune response [84]. and lysyl tRNA synthetase. Moreover. military personnel. (i) The pathological significance of autoantibodies in sarcoidosis remains unclear.

miR-29a and miR-29b were found to be downregulated in IFN𝛾-secreting T cells. IL-8 and vascular endothelial growth factor in sarcoid EBC. chitotriosidase. The propensity of IL-6 to form complex molecular forms of higher molecular weight could account for this discrepancy [100]. Abnormal levels of microRNA have been associated with the pathogenesis of cancers and fibrotic and obstructive lung diseases [117–119]. BALF remains the most relevant biological material. requires little instrumentation. leukotrienes. To date. It has also been implicated in the fibrotic progression of sarcoidosis [120]. Given the multifactorial nature of sarcoidosis.8 Exhaled breath condensate (EBC) has been subjected to intensive research as it provides a noninvasive alternative for sampling the airway and alveolar space a promising source of biomarkers for a variety of lung conditions [95–97]. the small sample size and the failure to make comparisons with healthy controls limited the usefulness of this study [101]. Conversely. neutrophils. PAI-1. 8-isoprostane (8-IP)) and cysteinyl leukotrienes were also found to be elevated in the BALF and EBC of sarcoidosis patients [102]. neopterin. nitric oxide. does not introduce foreign substances into the lung or cause inflammatory changes. the lack of reliable markers and the inability of EBC to sample specific compartments of the lungs undermine these International Journal of Chronic Diseases One-way mouth piece that the subject exhales into Glass tube Saliva trap Stopper Lid EBC Ice/ice chamber Vacuum Figure 2: Schematic diagram of the EBC collecting apparatus. Crohn’s disease [125]. there exists no sufficiently sensitive and specific marker for diagnosing and predicting the prognosis of sarcoidosis [99]. only a few have been shown to be sufficiently sensitive and specific [110]. MicroRNAs are noncoding RNA that can inhibit the production of mRNA. coeliac disease [124].g.g. TGF-𝛽. carbon monoxide and hydrocarbons) diffuse as gases from the alveoli and bronchi to the mouth. MicroRNA-29 (miR-29) and T-bet have been shown to modulate its production [114. 116]. They are joined by nonvolatile molecules (e. This reduction skews the immunological response towards a TH 1 lineage by initiating a positive feedback loop which enhances IFN𝛾 production. PAI-1. 122. it is elevated and measurable in the BALF of sarcoidosis patients and could therefore serve as a sarcoid biomarker [112].. and soluble IL2 receptor [108. Amongst these four.. 6. it could serve as a prognostic marker [103]. 104–107]. 123] in patients with multiple sclerosis [114]. water evaporation droplets and volatile molecules (e. no ideal markers for detecting and monitoring the clinical course of sarcoidosis exist. During exhalation. Moreover. The exhaled breath is channelled into a refrigerated collecting container. Although EBC has advantages over BAL (it is noninvasive. therefore. Cellular and molecular biomarkers previously discovered in BALF and serum of sarcoidosis patients could also serve as biomarkers. and cytokines) from the airway lining fluid and condense via a refrigeration device to give EBC (Figure 2) [95. Interferon Modulators: Novel Immunological Markers IFN𝛾 plays a pivotal role in the immunopathogenesis of sarcoidosis. However. It is very likely that a combination of markers will be required. Kerbs von Lungren 6 antigen. 40. These include eosinophils. 115]. high initial levels of 8-IP were shown to correlate with disease persistence. T-bet expression has been shown to correlate with IFN𝛾 expression [16. and can be repeatedly performed in sick patients) [113]. 109]. Other more novel markers include lysozyme. However. Serum levels of these biomarkers were said to reflect increased parenchymal infiltration and lymphocytic alveolitis in sarcoidosis and can thus serve as potential EBC biomarkers. and Behc¸et’s disease [126. It binds to a number of enhancers and to the promoter region of the IFN𝛾 gene to promote IFN𝛾 transcription [121]. IL-6 levels were negatively correlated with that which is in BALF. The subject blows into the mouth piece which is a one-way valve. TNF𝛼. TNF𝛼. 57. prostanoids. The miR-29 family is made up of four members. In a later study.g. T-bet is a transcription factor necessary for IFN𝛾 production. and the chemokine ligand (CCL18) [28. As previously mentioned (see immune reactions in sarcoidosis). This also suggests that the up-regulation of miR-29a and miR-29b can mitigate IFN𝛾 expression [115. benefits. and IGF-1 levels in EBC were closely positively correlated with BALF samples from sarcoidosis patients. Exhaled eicosanoids (e. 98].. Nonetheless. 127]. A number of immunological biomarkers have been recognised in EBC. Amongst the above-mentioned biomarkers. ACE is the most contentious as it has been shown to have poor sensitivity and specificity [111] and its activity is subject to the effects of gene polymorphisms. Another study detected TGF-𝛽1 . T-bet mRNA . urea. serum angiotensin converting enzyme (ACE). Nevertheless.

[5] E.. 6. A. 1400–1417. . “IL-12 and IL-18 are increased and stimulate IFN-𝛾 production in sarcoid lungs. B. However.International Journal of Chronic Diseases has been shown to be elevated in the BALF lymphocytes of patients with pulmonary sarcoidosis [128]. 130]. References [1] E. 2011. [13] Y. M. S. Mathew. no. Thomas.” Journal of Experimental Medicine. 2007. vol. W.” Clinics in Chest Medicine. Fontana. R. Sanchez. Mazzi. 305.” Journal of Immunology. BAL. no. Zaba. N. 445–458. pp. 200. 2. 5. Eklund. 2. “Recent advances in sarcoidosis. 32– 39. vol. 2004. 183. 2002. Oliver. 701–709. vol. vol. S. 4.” American Journal of Respiratory and Critical Care Medicine. “The potential of the immunological markers of sarcoidosis in exhaled breath and peripheral blood as future diagnostic and monitoring techniques. pp. vol. given its variable clinical manifestation and the lack of a reliable diagnostic test with uniformed reference values and measurements. mRNA levels are poor proxies for protein levels [129. pp. no. 2003. G. and P. 1. no. Ohmichi et al. “Dendritic cells in the pathogenesis of sarcoidosis. vol. Wakefield. Dighe. Knox. 166. Rosen. Miyara. Conclusion Despite nearly 140 years of extensive research. R. pp. D. 1. 457–467. “Sarcoidosis: clinical presentation. K. Gripenb¨ack. “T-lymphocyte activity in HLA-DR17 positive patients with active and clinically recovered sarcoidosis. A. 1. and R. H. 746–755. Sotirchos. 139. N. A. 42. C. [6] A. Noor and K. A. P. no.” Nature Reviews Rheumatology. vol. and G. “The anergic state in sarcoidosis is associated with diminished dendritic cell function. Besides being a potential immunological biomarker of sarcoidosis. D. L. “The immune paradox of sarcoidosis and regulatory T cells.” Sarcoidosis Vasculitis and Diffuse Lung Diseases. and therapeutics. Amoura. 2. [23] S. vol. 2011. B. Parizot et al. J. [9] M. 2008. Teirstein. 2. no. [10] G. and J.” Journal of Physiology and Pharmacology. 1. S. Shigehara. Prystowsky. no. 2009. no. vol. no. 120. no. 11. vol. Chui. vol. EBC could be used as a noninvasive method to diagnose sarcoidosis. Chen and D. 7. Shijubo. 59. C. 19. Moreover. Spilianakis. Iannuzzi and J. M. 55–68. G. Amsen.” Current Opinion in Pulmonary Medicine. Research on these fronts can offer novel insights into the “immune paradox” associated with sarcoidosis and can pave the path for novel therapeutic strategies for the disease. pp. 185. no. Phan. 85. Flavell. 174–182. [15] H. no. 7.” Inflammopharmacology. pp. the literature is currently deficient of studies that measure T-bet protein levels in sarcoidosis patients and studies that juxtapose miR29 and T-bet protein levels at sarcoidosis disease sites and in the peripheral blood. 357. 5. 2008. no. pp. vol. 1. 2011. S. vol. 8. B. 2011. no. Gyetko. vol. Szabo. 2010. Y. R. Morgenthau and M. interferon modulator levels in EBC and the peripheral blood can be compared to elucidate the regulatory mechanisms in the peripheral blood. Saidha. pp. Agostini. Eckstein. Hunninghake. Ahmadzai. and C. 2012. Judson. pp.” Journal of the American Medical Association. 133–141. Bargagli. 49–57. 2009. “Localization of the immune response in sarcoidosis. and E. Rybicki. Unfortunately. no. Culver. Ahmadzai. C. Bauer. 28. Rottoli. J. Young Jr. 29. “Recent advances in molecular targets and treatment of Idiopathic Pulmonary Fibrosis: focus on TGF𝛽 signaling and the myofibroblast. A. Given that the majority of sarcoidosis patients have pulmonary involvement. 25. pp. Hu. Stasiak-Barmuta. 2153–2165.. P. and P. pp. J. [17] M. [16] D. Korniluk. 21. Iannuzzi. Mroz. C. 181. Cameron. and K. 2011. Ehrenstein. vol. “Regulation of the interleukin (IL)-12R 𝛽2 subunit expression in developing T helper 1 (Th1) and Th2 cells. R. 277–285. 2007. D. Semenzato. S. pp. vol.” Chest. G. Results from such studies may also explain the pathology underpinning the peripheral anergy seen in sarcoidosis. S. 5. vol. Wakefield.” American Journal of Respiratory Cell and Molecular Biology. no. [18] A. immunopathogenesis. vol. [2] M. 359–370. Singh et al. [21] C. [14] H. “Pathology of sarcoidosis. and S. sputum. Gubler. Conflict of Interests The authors do not have any financial conflict of interest related to this paper. J. due to posttranscriptional regulation and disparities in protein and mRNA turnover rates. Fulmer.” Current Medicinal Chemistry. and M. 21. D. 1997. A. pp. diagnosing sarcoidosis remains a clinical conundrum for many physicians.. 2008. pp. 153–160. [11] A. “Peripheral blood responses to specific antigens and CD28 in sarcoidosis. the aetiology and pathogenesis of sarcoidosis and the mechanisms that regulate the immune reactions in the peripheral blood remain undetermined. A.” Journal of Experimental Medicine. [22] K. and R. “A concise review of pulmonary sarcoidosis. 2001. [12] R. “T-lymphocytes and cytokines in sarcoidosis.. no. S.” Clinics in Dermatology. A. U. E. 106. Smith. Thomas. and M. no. pp. 203.” Journal of Immunology. pp. no. and S. 1979. S. [7] M. 9 [8] S. 3. 110–117. vol. pp. [3] S. 642–649. “Etiology of sarcoidosis: does infection play a role?” Yale Journal of Biology and Medicine. urine. 817–824. “How are TH1 and TH2 effector cells made?” Current Opinion in Immunology. and A. 36–52. Fischoeder. [19] L. 507–513. Baughman. and exhaled gas. Katchar. “Immunopathogenesis of sarcoidosis. C. J. Grunewald. pp. Iannuzzi. M. [20] R. and P. M. J. 2006. no. 2007. “Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNF𝛼 therapy. M. 3. 3. 20. A. Z. “Sarcoidosis. “Increased levels of interleukin-12 and interleukin18 in bronchoalveolar lavage fluid of patients with pulmonary sarcoidosis. 16. 573–581.” New England Journal of Medicine. pp. A. pp. Bhardwaj. Gharaee-Kermani. S. K. Planck. 391–399. pp. vol. D. vol. C. “Sarcoidosis—scientific progress and clinical challenges. vol. Murphy. 8. no. pp. C. 250–258.” Respiratory Medicine. 2012. vol. S. 435–440. pp. A. no. Meneghin.” American Review of Respiratory Disease. 1. A. Lloyd.” Seminars in Respiratory and Critical Care Medicine.” Journal of Experimental Medicine. 5. Moller. Chyczewska. 1. Evans. no. “Markers of inflammation in sarcoidosis: blood. [4] M.

. 1997. vol. R.. Z. pp. Abken. B. pp. no. Pechkovsky.. K. 2085–2091. 20. A. 2. pp. S. 5. 2.” Rejuvenation Research. vol. 71–83. D. J. Sk¨old. Franke. A. 215–222. “L¨ofgren’s syndrome: human leukocyte antigen strongly influences the disease course.” Seminars in Respiratory and Critical Care Medicine. no. Ho. [48] I.. vol. vol. 2009. 10. vol. P. 151. A. M.” American Journal of Respiratory and Critical Care Medicine. 5. M. D. 140. [30] E. “Stimulation of human T-cell proliferation by specific activation of the 75-kDa tumor necrosis factor receptor. pp. [43] S..” Respiratory Medicine. 2001. Cabrelle. Zissel. A. A. 168. A. [29] E. 4. no.. Rappl. tumor necrosis factor. “Matrix metalloproteinases and tissue inhibitor of metalloproteinase-1 in sarcoidosis and IPF. pp. vol. [55] J. vol. “Sarcoidosis is a Th1/Th17 multisystem disorder. vol. 41. and S. 5. pp. 1990. 2003.” Journal of Clinical Immunology. [35] M. 339–346. I. M. C. pp. A. Teramo et al.” American Journal of Respiratory and Critical Care Medicine. no. Prasse. C. no.” Thorax. no. J. no.” Sarcoidosis Vasculitis and Diffuse Lung Diseases.” International Immunology. no. 1999. Patterson. Grunewald. no. 144– 150. 2004. A. vol. Zorzetto et al. and B. 2013. D. I. no. 2012. D. Bargagli. 27. vol. no. . Eklund. D. pp. Olivieri. 173. H. Fischer et al. [47] M.” Thorax. Romani.. [38] A. 2011. 35. “Sarcoidosis. Eklund. no. “Immunologic response of sarcoidosis. 4. Kaneko. “The immunology of sarcoidosis. Frederick et al. Magi. vol. 27. K. M. [26] N. vol. and IL2. C.. International Journal of Chronic Diseases [40] A. no. N. “The clinical and immunologic features of pulmonary fibrosis in sarcoidosis. “Generation of mature dendritic cells from human blood An improved method with special regard to clinical applicability. Medica. no. “Genome-wide association study identifies ANXA11 as a new susceptibility locus for sarcoidosis. pp. 156. 160. Kastrin. 487–511. 145. pp. and T. 2008. and A. vol. B. 3340–3347. vol. 2008. McMichael. 748–754.. “Sarcoidosis Th17 cells are ESAT-6 antigen specific but demonstrate reduced IFNgamma expression. 137–151. 1062–1072. “Control of IL2 receptor-𝛼 expression by IL-1. no. 4637–4641.” Journal of Immunological Methods. [46] S. no. Thickett. vol. Hunninghake. pp. vol. 2. M¨uller-Quernheim. M. 7. 4. 9464. J. vol. “Complement receptor 1 gene polymorphisms in sarcoidosis. “Extensive amplification of human regulatory T cells alters their functional capacities and targets them to the periphery. M. 40. Willett et al. 2008. Maver. O. “Phenotypic analysis of lymphocytes and monocytes/macrophages in peripheral blood and bronchoalveolar lavage fluid from patients with pulmonary sarcoidosis. A. 2011. and P. H. P. T. no. K. Zorzetto. pp. “Pathogenesis of sarcoidosis.” European Respiratory Journal. 324–330. W. C. Pabst. pp. 9. 66. 1220–1227. M. 4. vol. Grunewald and A. [54] A. 307–312. 321–331. [49] H. Hofmann.” Clinics in Chest Medicine. 264. no. vol.” Translational Research. pp. 2002. “Expression of receptor for advanced glycation end products in sarcoid granulomas. Spagnolo. vol. no.. 1103–1106. [51] P. Berlin. M. Iannuzzi. “Role of genetic polymorphisms in ACE and TNF-𝛼 gene in sarcoidosis: a metaanalysis. 32. 31. McMahon. Y.” American Journal of Respiratory and Critical Care Medicine. no. vol. J. Valentonyte. “A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18. “HLA-DR predicts the prognosis in Scandinavian patients with pulmonary sarcoidosis. 2002. [52] M. Seino et al. vol. Lario et al. 2. T. Richmond. R. 2012. 16. [32] G. M.” Journal of Immunology. no. Plaetinck. [27] C. 5. C. 446–455. Reider. Bombieri. A. A. 52. Ferrarotti et al. “CARD15/NOD2 polymorphisms are associated with severe pulmonary sarcoidosis. 3. 2. 4. A. 431–435. Henry. Chen. Morbini. A. C.. 2006. G. 181. Van Den Bosch. Wahlstr¨om. J. A. 22. 2003. and G. [31] G. Mauch. C. pp. 5. B. no. [33] L.” Clinical Immunology. [25] L. no. Sato. Schwinger. T. 17–23. J. 2011. [41] M. 1601– 1605. 2.” European Respiratory Journal. 910–918. Facco.. “Analysis of serum amyloid A in sarcoidosis patients. [36] G. Prasse. M. IL-2.10 [24] G.. 54. E. pp. C.” Lancet. K. Husain. 360–373. Sperling. “CARD15 gene mutations in sarcoidosis. “Familial aggregation of sarcoidosis. [50] M. Heuer et al. Corthesy et al. Landi.. 29. Combe. 915–933. K. Grutters. J. Facco et al. 1996. vol. and J. Urban. and J. “Regulatory T cells with reduced repressor capacities are extensively amplified in pulmonary sarcoid lesions and sustain granuloma formation. A. and H. Kobayashi. “Serum amyloid a regulates granulomatous inflammation in sarcoidosis through tolllike receptor-2. [53] I. pp. C. Rottoli. 5. 1. “Deficiency of a subset of T cells with immunoregulatory properties in sarcoidosis.. 379–390. 2010. “Impaired IFN-𝛾 production of V𝛼24 NKT cells in non-remitting sarcoidosis. pp. “Angiotensin II receptor type 1 1166 A/C and angiotensin converting enzyme I/D gene polymorphisms in a Dutch sarcoidosis cohort. no.” Journal of Immunology. Hogarth.” Immunology and Allergy Clinics of North America. Niewold. 147–152.” American Journal of Respiratory Cell and Molecular Biology. pp.-C. Williams. M¨uller-Quernheim. vol. Tartaglia. C. 2012. no. [37] A. Schreiber. Song. 781–792. S. A Case-Control Etiologic Study of Sarcoidosis (ACCESS). Isom et al. vol. 179. 11. [42] B. J. H. pp. Agostini. vol. 105. A. pp. Rybicki. pp. S. Xaubet. 175.-P. 5. 4. 1993. 498–506. Zissel.” American Journal of Respiratory and Critical Care Medicine.. Bianchi. 836–847. P. Campo. Sato. no.” Presse Medicale. vol. 2007. Peterlin. 1996. Rappl. and their receptors in the development of T cell alveolitis in pulmonary sarcoidosis. pp. 196. and J. Marin-Arguedas. no. A. [44] D. J. “Role of IL-15. A. 10. pp. M¨ullerQuernheim. 2010. vol. B. O. no. Wigzell.” American Journal of Respiratory and Critical Care Medicine. Goeddel. 775–780. vol. R. no. A. “A common haplotype of the C-C chemokine receptor 2 gene and HLA-DRB1∗0301 are independent genetic risk factors for L¨ofgren’s syndrome. 2008. 433–441. [34] J. Grunewald et al. Fogdell-Hahn. Eklund. 2007. pp. Mackarel et al. 2010. Hampe.” Journal of Human Genetics.” Journal of Immunology. Berlin.-I. [39] K. pp. pp.” American Journal of Respiratory and Critical Care Medicine. Sch¨urmann. 9. Gerke and G. no.” Nature Genetics. 2010. [28] J. pp. Complex regulation via elements in the 5’ flanking region. Ruven. 2005. N. vol. 365. Grunewald. Kruit. “Transforming growth factor-𝛽1 gene polymorphisms are associated with disease progression in idiopathic pulmonary fibrosis. Culver. Trentin. V. Davies.” American Journal of Respiratory and Critical Care Medicine. A. H. L. Prasse. 2. 164. Hombach. H. 6. vol. Toews et al. 11. e275–e287. 390–403. pp. R. no.” European Respiratory Journal. Olerup. pp. 33. 157. [45] B. pp. vol. M. Reynolds et al.” Journal of Internal Medicine. 1. Riemann et al. V. pp. Schmidt.. M. 5.. no. Ploetze. and J. Spagnolo et al. A.

vol. J.” Journal of Clinical Investigation. E162–E166. and G. [81] “Sarcoidosis among U. pp. 23. [61] H. 75. [85] J. 102. Ando et al. no. E. vol. no. X. vol. and S. 3. I. Ishige.” Morbidity and Mortality Weekly Report.. Wigzell. J. [73] D. K.” Chest. 101–104. 2012. M. A. Prezant. P. vol. 11. vol. Navy Enlisted Men. pp. Shoemaker. Kim.. vol. pp. “Cellular recognition of Mycobacterium tuberculosis ESAT-6 and KatG peptides in systemic sarcoidosis. 3. 1975. 117. Schilstra. 30. pp. Aggarwal. L. T. no. “Pulmonary granulomas caused experimentally in mice by a recombinant trigger-factor protein of Propionibacterium acnes. no. pp. 46. 2006. no. M¨ollers. 2007. A. S. 2001. P. Teirstein. Hunt. 11. vol. Das. S. no. [68] J. Georges. Takemura et al. 115– 121. Hoffner. 5. D. [80] D. Stjernberg. S. [69] Y. “Etiology of sarcoidosis. 2003. 1183–1193. 209–216. vol.” Clinical and Experimental Immunology. L. Palva. [65] W. A. [64] Z. R. J. [67] A. [58] A. “Intracellular cytokine repertoire in different T cell subsets from patients with sarcoidosis. 7. A. “Antibodies to Epstein Barr virus and some other herpesviruses in patients with sarcoidosis. Newman. M. Alavi and E. Y. vol. [57] N. 11 [71] I.S. vol. vol.. 5. pp. Singh. 2. 2005.” Sarcoidosis Vasculitis and Diffuse Lung Diseases. and E. vol.. [66] K. 1. and S. pp. 22. [75] A. Eishi. Katchar.” Clinics in Chest Medicine. and J. A. Mascher. pp. 5. K¨ampfer.” American Journal of Respiratory and Critical Care Medicine. 337–344. O. pp. Suga. Winqvist et al. Goldstein et al. 1. Greenlee et al.” Journal of Allergy and Clinical Immunology. [72] J. Y. R. 11.” Infection and Immunity. N. 50. “Case studies to explore the pitfalls in the diagnosis of sarcoidosis. 265–274. B. 2. “Propionibacterium acnes DNA detected in bronchoalveolar lavage cells from patients with sarcoidosis. Persson et al. H. Aries. Hannuksela.. [86] J. Hiramatsu. M. “Molecular evidence for the role of mycobacteria in sarcoidosis: a metaanalysis. S. vol. “TH1/TH2 and TC1/TC2 profiles in peripheral blood and bronchoalveolar lavage fluid celin pulmonary sarcoidosis. S. 1965–1993. no. G. pp. no. B. no. J. K. D. Dhason. 2007. Dengjel.. “A case control etiologic study of sarcoidosis: environmental and occupational risk factors. J. Nadaf et al.” Tuberculosis. no. 6. “Sarcoidosis-associated MHC Ags and the development of cutaneous and nodal granulomas following allogeneic hematopoietic cell transplant. L. Beachboard. Heffner. “The cause of sarcoidosis: the Centurial enigma solved. no. 133. P.” Journal of Medical and Dental Sciences. . [70] J. Nureki. 18–24. H. 111.. T. vol. 11. “Tuberculostearic acid in lymph nodes from patients with sarcoidosis. C. 201. 527–530. 487–493. T. 2005. no. 2007. no. Austin. pp. 1974.” Sarcoidosis Vasculitis and Diffuse Lung Diseases. no. Wahlstr¨om. 3. Lackland. Dengjel. no. [60] J. pp. A. N. pp. S. 163. and M. [79] B. 19. 107. Van Suylen. Olerup. J. Marzilli. “Antibody to herpes like virus in sarcoidosis.” Sarcoidosis.” Journal of Clinical Microbiology. 2001. 2004. pp. pp. 1999.International Journal of Chronic Diseases [56] M. K. C.” Journal of Experimental Medicine. Mitchell. vol. 3. 2. A. vol. M. no. “Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis. 1997. no. Miyazaki. and M. E. Song. 60–67. 46. and K.. vol. vol. S. 3. pp. A. R. prevalence. 1032–1034. no. 40. 1. 6. no. 197–203. pp. Agarwal. no. K. Braun. no. 2. 239–247. vol. Lomago. 29. Y. L. Dhala. Wahlstr¨om. “Donor-acquired sarcoidosis. N. D. vol.. 1. [62] A. J. D. Chen and D. Mikhail. 11. Odham. “Recurrent sarcoidosis in lung transplant allografts: granulomas are of recipient origin. B. 2008. 1987. 2001. Heimer. Minami. vol. Nakata et al. Grunewald. 2007. Ionescu. 4. M. A. M. 1. “Multiple mycobacterial antigens are targets of the adaptive immune response in pulmonary sarcoidosis. pp. Ishige et al.” Histology and Histopathology. [83] L. Mascio. Hahn et al. 539–543. Gupta. vol. 6. 56. 142– 152. H. 508– 516. N. Wahlstr¨om. 755–767.. pp.. [63] D. Oswald-Richter. Jindal. vol. J. Eishi. 3. pp. Moller.-I. 2006. Zhan et al. 2002. 365–377. no. O. Suda. 2000.” Respiratory Medicine. V. “Autoimmune T cell responses to antigenic peptides presented by bronchoalveolar lavage cell HLA-DR molecules in sarcoidosis. A.” Sarcoidosis Vasculitis and Diffuse Lung Diseases. 23. pp.” Annals of Diagnostic Pathology. and M. vol. and H. 33–42. no. Ishige et al. C. Drent.” European Respiratory Journal. [74] E. Biller et al. no. pp. Dr¨omann. [82] D. 683– 694. Eklund. 2. no. [84] D. Westerdahl. vol. Y. “A current assessment of rurally linked exposures as potential risk factors for sarcoidosis. 2010. Chida. T. “Serum antimycobacterial heat shock proteins antibodies in sarcoidosis and tuberculosis.” Sarcoidosis Vasculitis and Diffuse Lung Diseases. J. pulmonary tuberculosis and erythema nodosum. Rose. “Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis. 2001. and G. 880– 882. E. M. “Analysis of intracellular cytokines in CD4+ and CD8+ lung and blood T cells in sarcoidosis. pp.” Pediatric Transplantation. vol. pp. D. P. 116.. Galluzzi. Judson. “Circulating levels of both Th1 and Th2 chemokines are elevated in patients with sarcoidosis. B. Dalhoff. pp. vol. [59] S. 1996. pp. Nakamura. “Severe calcification of the aorta (porcelain aorta) associated with sarcoidosis in a pediatric heart transplant recipient. 2005. 353–363. L. Drake. no. article 161.” Thorax. Hanngren. and severity of sarcoidosis in New York City firefighters. 2008. 12. 14. and A. 3576–3582. pp. 111–117. P. 2. Yousem. L.. “Immunolocalization of cellwall-deficient forms of Mycobacterium tuberculosis complex in sarcoidosis and in sinus histiocytosis of lymph nodes draining carcinoma. 20.. no. 122. Kajdasz. vol.” American Journal of Respiratory and Critical Care Medicine. 135–140. A.” Scandinavian Journal of Infectious Diseases. R. S. vol. Nikoskelainen. vol. Mohr Jr. vol. 16. pp. Bresnitz et al. Prasse. Inui. McCarthy. Padilla. 2.-I. 198–204.” Bone Marrow Transplantation. “The incidence.” Clinical Immunology. “Th1 cytokine pattern in sarcoidosis is expressed by bronchoalveolar CD4+ and CD8+ T cells. C. and T. 2011. 140–145. 1324–1330. 86. K. Moscovic. Kataoka. no. A. 2002. G. Pukiat. [78] M. pp.” Annals of Epidemiology. Jacobs. C. 241–248. Eishi. E. “Propionibacterium acnes is the most common bacterium commensal in peripheral lung tissue and mediastinal lymph nodes from subjects without sarcoidosis. no. Dubaniewicz.” Diagnostic Molecular Pathology. Eklund. 3. 1. pp. Rottoli. 2003. G. [76] S. “Identification of HLA-DR-bound peptides presented by human bronchoalveolar lavage cells in sarcoidosis. 2009. Schilero. 4. A.” The American Review of Respiratory Disease.” Respiratory Research. McSwiggan.. no. [77] D. 170.

Campbell. 2007. 63. 2. Mulder. vol. 3.” Inflammation Research. no. Nakamura. pp. vol. vol.” Respiration. 2008. vol. and P. Ste¸pniewska et al. 139–146. and J. Caggiula et al..” Journal of Translational Medicine. pp. pp. . Xu. G.” Thorax. [89] I. “Does the cellular bronchoalveolar lavage fluid profile reflect the severity of sarcoidosis?” European Respiratory Journal. “No evidence of altered alveolar macrophage polarization. 101. Article ID 217518. Jacobs. M. 10.” European Respiratory Journal. Czerniawska et al. “Utility of exhaled breath condensates across respiratory diseases.. 2009. 26. Sandrini. [92] H. “Is analysis of exhaled breath condensate an equivalent to bronchoalveolar lavage fluid in sarcoidosis patients?” Hirosaki Medical Journal. Kowalska. vol. An overview. M. pp.. Bettelli. Abdallah. A. E. K. du Bois. W.” American Journal of Respiratory and Critical Care Medicine. A. pp. and D. N.. [88] P. pp. Nagate. Wodzig. no. P. 325–332. Bouwman. “Inflammatory markers in the exhaled breath condensate of patients with pulmonary sacroidosis. vol. no. and L. 2006. 132. Drent. 32.” Scandinavian Journal of Clinical and Laboratory Investigation. Lamers. 2006. A. Korn. Y.. H. [98] Y.” Nature. R. F. M. vol. 9.” Chest. 2012. K. A..” Proteomics. “Intracellular cytokine profiles and T cell activation in pulmonary sarcoidosis. K. 2005. Barter. P. 222– 227. Pantelidis. Kyriakou et al. 519–524. 4.” Nature Immunology. Kawanishi. “Potential biomarkers for diagnosis of sarcoidosis using proteomics in serum. J. 12–20. Liu et al. A. Rothkrantz-Kos. 589–596. 1999. no. S. “Comparative evaluation of serum markers in pulmonary sarcoidosis. Danso-Abeam.. J.” BMC Pulmonary Medicine. no. Eklund. M. 2. van Dieijen-Visser. 1027–1036. 2012. Nasuhara. J. Al Hayja. 2003. 791–792. Hunt.” Cytokine. Israel. E. 69. J. A. 3. pp. W. 42. A. J. 2012. Liang. 57. pp. S. 704–714. 7198. [99] J. Wahlstr¨om. vol. no.-P. Kuchroo. H. “Cytokine profile and proteome analysis in bronchoalveolar lavage of patients with sarcoidosis. A. [97] K. T. 68. [91] A. “MicroRNA-29 in the adaptive immune system: setting the threshold. Gholami. vol.. “Comparison of biomarkers in exhaled breath condensate and bronchoalveolar lavage. and M. Schlaak.” Cellular and Molecular Life Sciences. 564–571. Oukka. “Gene polymorphisms of ACE and the angiotensin receptor AT2R1 influence serum ACE levels in sarcoidosis. 2007. S. pp.” The Scientific World Journal. Z. Thomas. G´orski. I. 2013. 58. E. De Vries. 10. R. Shigemura. 6. “Bronchoalveolar and serological parameters reflecting the severity of sarcoidosis. Grunewald. C. J. and J. “Exhaled 8-isoprostane as a prognostic marker in sarcoidosis.” Nature Reviews Genetics. but reduced expression of TLR2. Van Dieijen-Visser. no. vol. pp. 335–340. Croce. Yeligar. 12. Wik´en. 3. 2008. T. Pierce. vol. M. 137. “Effects of molecular structural variants on serum Krebs von den Lungen-6 levels in sarcoidosis. 1. no.” BMC Pulmonary Medicine. Ohyashiki. H. 6. Kurmanowska. S. vol. G. Dooley. pp. 2010.” Journal of Internal Medicine. article 23. vol. E. 2005. no. vol. S. Montpetit. 21. [101] A. pp.” American Journal of Respiratory and Critical Care Medicine. D. Kasuga. Lightman. 62. and J. J. 2. 2007. no. Nawrocka. Spagnolo. [96] S. H. “Eicosanoids in exhaled breath International Journal of Chronic Diseases [103] [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] [116] [117] condensate and BAL fluid of patients with sarcoidosis. Chow. 69. 11. no. “Th1/Th2 cytokine pattern in bronchoalveolar lavage fluid and induced sputum in pulmonary sarcoidosis.” Respiratory Medicine. I. Tsiligianni. pp. and W. 2010.” Clinical Chemistry. 479–483. M. S. Rothe. “Exhaled breath condensate. and G. vol. M. Kadowaki et al. 5. no. P. vol. C. Liston. supplement. “Chitotriosidase and soluble IL-2 receptor: comparison of two markers of sarcoidosis severity. Konno et al. Gaede. Ma. and T-bet expression in peripheral blood mononuclear cells from relapsing-remitting multiple sclerosis patients correlates with disease activity. Davis. vol. M¨uller-Quernheim. Miyoshi. no. and V. no. M. “Causes and consequences of microRNA dysregulation in cancer. 6.” Respiratory Research. 84. S. 1051–1057. pp. article 8. Mariman. A. 2012. 2012. pulmonary fibrosis associated with systematic sclerosis and idiopathic pulmonary fibrosis. A. J. “Induction and effector functions of TH17 cells. 1510–1517. G. Hill. F. Batzella et al. P. C. pp. vol. article 111. J. 2009. article 121. Brown. pp.” Pneumonologia i Alergologia Polska. 363–375. G. Bargagli. 3. Rottoli. [102] W. 5. Margollicci et al. Ruprecht. no. Marczak. 54–59. Wouters. M. vol. H. [90] K. 2003.12 [87] T. M.. Drent. 1391–1397. Idali. “The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-𝛾. 5. Kunisawa.. J. in bronchoalveolar lavage cells in sarcoidosis. no.” Immunology and Allergy Clinics of North America. Kazani and E. 7 pages. K. 2003. [94] M. Zissel. pp.” Chest. pp. pSTAT3. 1687–1695. 155–164.” Journal of Neuroscience Research. 8. 13. and J. vol. 356–362. vol. 78. Liem.” Journal of Physiology and Pharmacology. Jackson. Paone. pp. no. Piotrowski. “Expression of Th1 markers by lung accumulated T cells in pulmonary sarcoidosis. 2002. M. J. A.” Sarcoidosis. Grunewald. vol. 2012. 1423–1430. M. “Potential usefulness of inflammatory markers to monitor respiratory functional impairment in sarcoidosis. Frisullo. E. [100] A. Papadopoulou. “Increased interleukin-13 expression in patients with sarcoidosis. and C. 2003. pp. A short term follow-up. 10. F. 2012. 3. A. 9.” Sarcoidosis Vasculitis and Diffuse Lung Diseases. Rozy. A. F. “Exhaled breath condensate: a promising source for biomarkers of lung disease. S. S. and R. 6. pp. 453. vol. 407–413. [93] E. 1992. vol. no. Katchar. 2008. 5. Marczak. vol. and E. B. A. Piotrowski. J. Bianchi. no. X. 21. R. Mikuniya. vol. 8. Antoniou. 254. vol. pp. 10. Pus’cin’ska. A. B. no. Z. Bons. M. and J. no. 1.. Meyer. 175. K. D. D. no. M. and A. Ziegenhagen. Takanashi et al. 9. Tago. 289–292. 2010. “pSTAT1. S. P. Antczak. Y. 185. “Use of discriminant analysis in assessing pulmonary function worsening in patients with sarcoidosis by a panel of inflammatory biomarkers. “Angiotensinconverting enzyme in bronchoalveolar lavage fluid in sarcoidosis. 861–869. Yates. 3533–3541. vol. Magi. and K. Allen. no. S. 49. pp. Angelucci. no. pp. no. F. S. Eklund. H. Pforte. A. Czerniawska. 2011. pp. M. “Markers of fibrosis and inflammation in exhaled breath condensate (EBC) and bronchoalveolar lavage fluid (BALF) of patients with pulmonary sarcoidosis—a pilot study. 5. M. 6. and P. Perari et al. vol. Drent. D. vol. A. M. A. M. “Direct demonstration of the productive capability of cytokines at the single cell level in lung sarcoidosis using multicolor cytometry. A. Leone. vol. Hauber. G´orski. A. M¨ullerQuernheim. 2010. M. [95] M. Biller. no. Hamada. Antczak. G. 1338–1344. P. S. I. pp. Kurmanowska.

no.. 145–153. Cho et al. E.. Kriegova. [127] R. pp. Ge. 87. vol. 8. H. 3. 13 . vol. A. 53. Negreanu. 2007. 2012. pp. vol. and B. and T. no. Ansel. N. Wang. [120] E. X. [126] B. Tomankova et al. vol.-P. 5. Li. Hack. Inoue. 10. pp. vol. 38. pp. 2003.” Nature Immunology. pp. Yang et al.” Methods. 53. 2004. T. no.. 2. “Molecular mechanisms in Behc¸et’s disease. Holtmann and M. no. vol. “Role of transcription factor T-bet and Eomes in IFN-gamma secretion of different human T cell subsets. 35. Zhou et al. “More than just a T-box: the role of T-bet as a possible biomarker and therapeutic target in autoimmune diseases. pp. A. Rao. 31–34. 417. [122] N. 1199–1200. and K. Liu. pp. Li. vol.-T.” Thorax. no. Ji. H.” Chinese Journal of Cellular and Molecular Immunology. 8.” British Journal of Ophthalmology. 2010. “T-bet upregulation and subsequent interleukin 12 stimulation are essential for induction or Th1 mediated immunopathology in Crohn’s disease.” European Respiratory Journal.” Journal of Experimental Medicine. Levanon.” Biochemical and Biophysical Research Communications.-Q. “T helper cell polarisation in coeliac disease: any (T-)bet?” Gut. [129] B.International Journal of Chronic Diseases [118] M. no. no. Groner. “Erratum: Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. 2011. Rao. P.-H. Djuretic. Sosa. vol. “T-helper cell type-1 transcription factor T-bet is upregulated in pulmonary sarcoidosis. 8. Ezzie. F. T. Kislinger. pp. [119] G. [128] E. 3. Neurath. 1. pp. pp. 1065– 1067. D. Xue. pp. 3. 435– 441. vol. 10.” Briefings in Functional Genomics & Proteomics. Julian. [130] C. M. 67. 1303–1308. 9. Fillerova. “Integrated transcriptome and proteome data: the challenges ahead. no. [124] M. “Differential expression of microRNA and predicted targets in pulmonary sarcoidosis. 87. T. 1264–1267. no. J. no. R. 1589–1597. [121] I. D. 2004. Y. 2003. [123] H. Crawford et al. A. Y. J. 122–131.-S. Cox. M. 2005. [125] K. 3. W. “T-bet expression is upregulated in active Behc¸et’s disease. R. and A. 303–314. Sato et al. “Gene expression networks in COPD: microRNA and mRNA regulation.. M. Crawford. “Integrating gene and protein expression data: pattern analysis and profile mining.” British Journal of Ophthalmology. 1136–1144. no. Emili. M.” Immunotherapy. pp. 3. vol. 2. Friggeri. 2010. vol. Forsthuber. 2011.” Gut. V.. 212–219. 26. no. “miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. 2012. Crouser. 207. no. Matsuoka. Z. vol. G. 2. Yang. pp. A.. Rajendram and N. 886–891. vol. 2004. M.

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