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Med Sci (Paris). 34: 121–133.
doi: 10.1051/medsci/201834f121.

Exploring the dynamic changes between pulmonary and cutaneous sarcoidosis based on gene expression

Youyu Sheng,1# Yuxin Yang,2# Yun Wu,3# and Qinping Yang1*

1Department of Dermatology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai200040, China
2Department of Dermatology, The People’s Hospital of Jianyang City, Sichuan Province, China
3Department of Dermatology, The First Hospital of Jiaxing, Zhejiang Province, China
Corresponding author.
#These authors contributed equally to this work.
* Corresponding author: Qinping Yang qpyang_shhs1@126.com

Sarcoidosis is a disease involving the growth of abnormal inflammatory granulomas and affecting multisystems. It has an unknown etiology. The lung and the skin are the most commonly involved organs. Although large amounts of research have focused on the pathogenesis of sarcoidosis, little is known about the link between cutaneous sarcoidosis and pulmonary sarcoidosis. Moreover, the gene expression profiles provide a novel way to find diagnostic or prognostic biomarkers. Therefore, the aim of this study was to analyze the differentially expressed genes (DEGs) in pulmonary sarcoidosis and cutaneous sarcoidosis patients and to compare them to healthy individuals. DEGs and their biological functions are dynamically dysregulated, and several common disease-related genes and mutual disease progression-related genes were identified which linked pulmonary sarcoidosis and cutaneous sarcoidosis together. The biological functional pathways regulated by these DEGs may allow to define the common mechanism shared by different type of sarcoidosis, providing novel insight into the common pathogenesis of sarcoidosis and opening the way to the development of new therapeutic strategies.

Keywords: biological pathways, common diseaserelated genes, cutaneous sarcoidosis, progression-related genes, pulmonary sarcoidosis


Sarcoidosis is a multi-organ disease characterized by the presence of immune granulomas with uncertain etiology [1, 2]. The pulmonary involvements account for 90% to 95% of cases [3], and skin lesions are present in at least 20% of sarcoidosis cases [4, 5] and are the initial disease manifestation in nearly one third of these subjects [6]. The severity of sarcoidosis may range from an asymptomatic stage to a life-threatening condition. In a minority of cases, sarcoidosis may cause fibrosis of involved organs, leading to permanent organ damage that will not respond spontaneously or poorly to treatments [7- 9]. Sarcoidosis is rarely fatal with an age- and sex-adjusted mortality rate of less than 5/1,000,000 in the United States. However, it appears that the death rate from sarcoidosis is rising [10]. The majority of deaths result from pulmonary sarcoidosis where pulmonary fibrosis and/or pulmonary hypertension developed [11, 12], although it usually progresses slowly over decades [13].

Mounting research has focused on the pathologic mechanisms of sarcoidosis. It is suspected that exposure to one or more extrinsic antigens in a genetically susceptible individual leads to the overactivation of inflammatory pathways that promote the formation of sarcoidal granulomas. Studies have found an elevated risk of sarcoidosis in individuals who have been exposed to microbial agents [14, 15] and environmental substances [16, 17]. Disease susceptibility may be genetically determined, and several genes affecting the prevalence and course of sarcoidosis have been identified. Specifically, human leukocyte antigen (HLA) genes have been shown to influence the development and progression of sarcoidosis [18]. Cytokines like TNF-α, IL-12 and interferon gamma (IFN-γ) have been revealed to be involved in the formation of sarcoidosis [1, 19]. TGF-beta/Smad pathway is involved in the pathogenesis of pulmonary sarcoidosis [20]. The known mechanisms include inflammation, granuloma formation, genetic polymorphism etc., but the primary cause of sarcoidosis remains unclear.

Modern experimental technologies, such as microarray, have facilitated research in discovering novel pathogenetic mechanisms of sarcoidosis. Large amounts of information, specifically with regard to the microarray-based mRNA expression analysis of pathological tissues including lung, lymph nodes and blood cells of sarcoidosis patients, have been used to find potential pathogenic mediators and novel biomarkers [9, 21] such as Matrix metalloproteinase 12 (MMP12). Unsupervised bioinformatics analyses of gene expression data can identify highly regulated molecular pathways that are likely to promote abnormal granulomatous inflammation. Up-regulated hypoxia inducible factor-1A (HIF-1A) and vascular endothelial growth factor (VEGF) genes have been linked to acknowledged negative prognostics [22].

In this study, we utilized the gene expression profiles of different staged cutaneous sarcoidosis (shorten as CSC) and pulmonary sarcoidosis (abbreviated as PSC) as well as normal controls, to identify specific and mutual gene expression patterns as well as signaling pathways involved in disease occurrence and development and to search relevant biomarkers, reliable endpoints as well as potential efficient treatments.

Material and methods
Study datasets
The gene expression profiles of pulmonary sarcoidosis (PSC) were downloaded from the GEO [23] (http://www.ncbi.nlm.nih.gov/geo/). In GSE19976, there were eight patients with active but self-limiting pulmonary sarcoidosis and seven with active, progressive, fibrotic pulmonary disease [9]. The gene expression profile was based on the GPL6244 [HuGene-1_0-st] Affymetrix Human Gene 1.0 ST Array [transcript (gene) version]. GSE16538 was based on the GPL570 [HG-U133_Plus_2] Affymetrix Human Genome U133 plus 2.0 Array including six active pulmonary sarcoidosis (n=6) and six normal lung anatomy [24]. In GSE32887, there were 15 samples of sarcoidosis with skin lesions, 11 unaffected skin from patients with cutaneous sarcoidosis (CSC) and 5 normal samples [21]. We marked the self-limiting pulmonary sarcoidosis as “SL_PSC”, the fibrotic pulmonary sarcoidosis as “F_PSC”, sarcoidosis with skin lesions as “TL_CSC” and unaffected skin from patients with CSC as “NL_CSC”.
Data analysis
With the “MetaDE” package of R project, we merged the GSE19976 and GSE16538, and finally acquired 8 samples of SL_PSC, 13 samples of F_PSC and 6 normal samples. To explore the pathogenesis of PSC, we considered the SL_PSC and F_PSC as the test groups and the normal samples as control groups. Through the “limma” package of R project, the genes with p-value <0.05 were considered as the differentially expressed genes (DEGs). We performed the function enrichment to find the significant pathways and biological functions with the “Database for Annotation, Visualization and Integrated Discovery” (DAVID) (http://david.abcc.ncifcrf.gov/). The functions with p-values for enrichment scores less than 0.05 were extracted.
Functional dynamic deviation scoring
Differentially expressed genes of the three groups were linked to different biological progresses. We used the Euclidean distance of quantitative method to calculate each significant GO term relative to the normal state of the skin, the dynamic functional variety under the stages of non-lesion and lesion sarcoidosis [25].

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A (P) represented deviation score of function P; N showed the number of differentially expressed genes in that function; Xi was the mean expression level of gene i in the non-lesion/lesion sarcoidosis; Yi was the mean expression level of gene i in normal skin. Through calculating the Euclidean distance and cumulative sum of all the genes in function P under the non-lesion/lesion sarcoidosis and normal skin, the degree of function P deviating from the normal state under the non-lesion/lesion sarcoidosis was figured out.

Feature selection
The intersections of disease-related genes and disease progression-related genes between PSC and CSC were applied as features, the gene expression levels were applied as feature values and both were combined with machine learning RFE algorithm for feature selection. Feature set was obtained through combination of a number of iterative features extracted in the process of selection. Feature set number increased gradually, thus making it possible to evaluate efficiency of the highest corresponding feature set, enabling feature selection.
Construction of a SVM classification model
The genes optimized by feature selection were applied as biomarkers to classify patients with PSC or CSC, using the classification of support vector machine (SVM) model. A five-fold cross-validation was performed. All samples were randomly divided into five groups, four of which being used as training set, the other one as test set. Each sample was then used as test set for prediction. A ROC curve was finally used to evaluate the effectiveness of the model.
Analysis of mRNA expression profiles
We found 1,903 differentially expressed genes (DEGs) between CSC patients and normal control, and 1,498 DEGs between TL_CSC and NL_CSC patients. For the PSC, there were 1,058 DEGs between disease and normal samples, and 80 DEGs between F_PSC and SL_PSC samples. The DEGs are shown in Table 1.

Twelve DEGs were significantly expressed at different stages of CSC ( Figure 1A) whereas 2 genes were found significantly deregulated at different stages of PSC ( Figure 1B). Between CSC and PSC, we found 97 common disease-related genes ( Figure 1C), and 13 common progression-related genes ( Figure 1D).

Functional analysis
Functional enrichment analysis was performed to better understand the role of these DEGs. Our data show that DEGs between F_PSC and normal tissue are significantly enriched in genes encoding proteins involved in cellular protein catabolic process, protein catabolic process, modification-dependent macromolecule catabolic process, sterol biosynthetic process, etc. ( Figure 2A). By contrast, DEGs between SL_PSC and normal tissue were significantly enriched in genes encoding molecules involved in chemotaxis, positive regulation of translation, angiogenesis, protein kinase cascade, etc. ( Figure 2C). Moreover, the DEGs in F_PSC and SL_PSC mainly regulate phosphorylation, protein kinase cascade, protein modification process, regulation of immune effector process etc. ( Figure 2B).

Regarding to CSC, the DEGs between NL_CSC and normal tissue were significantly enriched in genes encoding DNA metabolic process, spermatogenesis, negative regulation of transcription etc. ( Figure 2D). By contrast, DEGs between TL_CSC and normal tissue were markedly enriched in immune cell-related functions including T cell activation, positive regulation of cell activation and of leukocyte activation etc. ( Figure 2E). Furthermore, DEGs in TL_CSC and NL_CSC mostly modulate T cell activation, positive regulation of immune response, positive regulation of cell activation etc. ( Figure 2F).

In addition, we also carried out a functional enrichment on the mutual disease-related genes and disease progression-related genes ( Figure 3). Results showed that the common disease-related genes between CSC and PSC are involved in the sterol biosynthetic process, steroid biosynthetic process and so on ( Figure 3A). The common progression-related genes mainly regulate the intracellular signaling cascade, phosphorylation, regulation of erythrocyte differentiation, protein modification process, protein kinase cascade ( Figure 3B).

Dynamic functional changes
CSC According to the deviation scores, 149 biological functions impacted were defined. These biological functions are differentially regulated during the transition from normal to non-invasive sarcoidosis and to skin lesion sarcoidosis (Supplement Table 1). The following biological processes changed markedly ( Figure 3A): immune response-activating signal transduction, immune response-regulating signal transduction, activation of immune response. The most significant differentially expressed genes are involved in apoptosis, T cell receptor signaling, B cell receptor signaling, viral myocarditis, antigen processing and presentation, Fcgamma R-mediated phagocytosis ( Figure 3B).

Changes in biological functions were also suggested when the gene expression between normal lung to minor lesion PSC and F_PSC was compared (Supplement Table 2). Biological processes such as the positive regulation of antigen receptor-mediated signaling, the regulation of antigen receptor-mediated signaling, the regulation of lymphocyte activation, the regulation of leukocyte activation, lymphocyte differentiation etc., were significantly impacted ( Figure 4A). Several signaling pathways are also remarkably changed, such as that involved in Primary immunodeficiency, in T cell receptor signaling pathway, in cytokine-cytokine receptor interaction, and in Natural Killer (NK) cell-mediated cytotoxicity ( Figure 4B).

Biomarker screening based on feature selection
Feature selection was performed on the intersections of disease-related genes and disease progression-related genes from PSC and CSC. Through iterative feature extraction, three biomarkers (CLDN7, NUDT11 and FAM73A) were obtained from the disease-related genes, and two biomarkers (TAP1 and TAP2) were acquired from the disease progression-related genes ( Figure 6AB). The selected biomarkers were used as features to construct SVM classifier for the supervised classification of patients with PSC or CSC. Combined with a five-fold cross-validation, a ROC curve was generated to evaluate the effectiveness of the model. Our results indicated that the classification model constructed on the basis of disease-related and disease progression-related biomarkers, optimized by feature selection, could effectively distinguish patients with PSC or CSC, with efficiencies of 87% and 92%, respectively ( Figure 6CD).


Sarcoidosis is a multiple system granulomatous disease of unknown etiology [1, 2, 26]. The exact pathogenesis of sarcoidosis is still not fully understood and the link between the CSC and PSC remains unknown [27]. In the recent years, many researches have focused on the pathogenesis of CSC and PSC [26, 28]. Despite these efforts, it is still unclear how these two diseases correlate. Identifying the specific biomarkers closely associated with both CSC and PSC could largely contribute to early clinical diagnosis of the different types of sarcoidosis and to prevent CSC – PSC transition. Therefore, in this study, we have analyzed and compared the expression profiles of different staged CSC and PSC, identifying specific genes and the related impacted biological functions of the CSC and PSC, respectively. Moreover, the shared genes and functional pathways between CSC and PSC were also analyzed. 97 common disease-related genes and 13 mutual disease progression-related genes were identified. Further analysis showed that these common disease-related genes encode proteins mainly involved in sterol biosynthetic process and steroid biosynthetic process; by contrast, the mutual disease progression-related genes mostly regulate intracellular signaling cascade, phosphorylation, erythrocyte differentiation, protein modification process, and protein kinase cascade. We propose that these common genes and their related functions could represent the common features between CSC and PSC, and represent also potential markers for the diagnosis of the CSC-PSC transition. In addition, through feature selection, 3 disease-related biomarkers (CLDN7, NUDT11 and FAM73A) and 2 disease progression-related biomarkers (TAP1 and TAP2) were identified. Moreover, SVM classifier constructed on the basis of these features could effectively distinguish patients with PSC or CSC.

We considered that the shared genes are simultaneously involved in different types of sarcoidosis. Therefore, they are conservative genes significantly associated with sarcoidosis. Abnormal expression of these genes can lead to sarcoidosis. However, their expression is probably affected by other factors, such as distribution, genetic background [29- 31] and environmental stimulation [32], as well as other related genes [21, 33]. The intersection of DEGs embodies the universality of sarcoidosis while the specific genes defined in CSC and PSC represent the specificity of these two diseases. Because the specific genes are only differentially expressed in one type of sarcoidosis, these DEGs could represent clinically relevant diagnostic markers to distinguish different types of sarcoidosis. In addition, we also analyzed the differences in patients with sarcoidosis at different stages, identifying disease-related genes and progression-related genes. The abnormal expression of these genes fully displayed the dynamic nature of disease progression. Thus, utilizing these genes as diagnostic markers to evaluate a dynamic disease will contribute to identify the turning point of the disease, and could help preventing disease progression and improving the response to treatment.

During the functional analysis, we found that disease-related genes in both CSC and PSC are involved in a number of important biological functions, such as sterol biosynthesis and steroid biosynthetic process. During the occurrence of sarcoidosis, some important biological pathways are dysregulated. Correction of these abnormalities during the disease process could prevent disease progression and improve the efficacy of treatment. As the disease progresses, more downstream genes and biological functions are abnormally induced. Our results have identified common progression-related genes regulating intracellular signaling cascades, phosphorylation, regulation of erythrocyte differentiation, protein modification, and protein kinase cascade. Thus, the specific dysregulated functions probably reveal the biological mechanisms accompanying different types of sarcoidosis. This may help the identification of the etiology of the disease and the development of effective therapeutic strategies.

Data analyses have also demonstrated that several biological processes defined by DEGs contribute to the occurrence of CSC and/or to the development of the disease into cutaneous CSC. For example, T cell activation and the positive regulation of leukocyte activation may mark the occurrence of CSC. Moreover, T cell activation and a set of genes encoding proteins involved in the regulation of immune response were significantly differentially regulated by DEGs in TL_CSC and NL_CSC. It suggests a mechanism of development of the disease from non-lesion CSC to skin lesion CSC. Regarding to PSC, biological processes such as chemotaxis, positive regulation of translation, angiogenesis, protein kinase cascade, were remarkably differentially regulated by the DEGs in self-limiting PSC as compared to normal tissue, which may reveal the occurrence of PSC. DEGs in fibrotic PSC and normal tissue were enriched in genes encoding proteins involved in catabolic processes, in sterol biosynthetic process, showing the PSC progressed to a more serious stage. We also discovered that phosphorylation, protein kinase cascade, protein modification process, regulation of immune effector process, are dysregulated between F_PSC and SL_PSC, indicating that these biological processes play significant roles in the fibrotic progress of PSC. Consistent with our findings, previous researches have reported that persistent stimulation of the immune system plays a major role in granuloma formation and maintenance [26, 34]. Some immune-related cells such as macrophages, dendritic cells, lymphocytes and regulatory T cells, as well as immune-related factors are all closely involved in the cellular and molecular mechanisms of granuloma formation [8, 19, 35] and in the immune-pathogenesis of sarcoidosis [34]. Recent research indicated that immune-relevant factors such as IL-33 are important factors in sarcoidosis, making them potential biomarkers [36, 37]. Moreover, IFN-γ plays an important role in granuloma formation in this disease [37]. Although immunological events may determine the granuloma fate, other signaling pathways and factors also play important roles in pathogenesis and/or developmental process of sarcoidosis. Angiogenesis regulated by HIF-1A/VEGF/inhibitor of growth protein 4 (ING-4) axis may be crucial for the course and outcome of sarcoidosis [22]. Despite these advances, there are no clinically useful biomarkers that can assist the clinician in diagnosis, prognosis or assessment of treatment effects [17, 28, 38].

Disease progression is a dynamic process and we used a dynamic functional scoring algorithm to identify and analyze the differential functional pathways at different stages of disease progression. We found that functional pathways display a gradient dynamic change during disease progression. The functional pathways were mostly close to normal at the early stage of the disease, while the disease progression made the abnormalities of pathways increasing and finally greatly deviating from the normal levels. The correlations of function and disease stimuli were therefore ranked according to the extent of functional variation. The more obvious the dysfunction was, and the closer the correlation with the disease was. Thus, these dysregulated functions may be the key players in the mechanisms that drive the disease, and the genes encoding molecules involved in these functional pathways might represent therapeutic targets.

Furthermore, three disease-related biomarkers (CLDN7, NUDT11 and FAM73A) and two disease progression-related biomarkers (TAP1 and TAP2) were identified by feature selection. Claudin-7 has been previously reported to be expressed in sarcoidosis [39]. NUDT11 belongs to a subgroup of phosphohydrolases that preferentially attack diphosphoinositol polyphosphates [40]. Dysregulation of NUDT11 may contribute to the abnormal metabolism observed during the occurrence of sarcoidosis. However, there was no report on the role of FAM73A in sarcoidosis. The transporter associated with antigen processing (TAP) may be involved in determining sarcoidosis susceptibility [41, 42]. Previously, serum amyloid-A was reported to be potentially helpful for detecting the activity of sarcoidosis, and it has been also reported that soluble interleukin-2 receptor (sIL2-R) measurement could be useful in exploring the extra-pulmonary organ involvement [43]. Despite these, no single biomarker can be reliably used for a correct diagnosis or an exclusion of sarcoidosis [44,45]. Our results indicate that the use of these five biomarkers (CLDN7, NUDT11, FAM73A, TAP1, and TAP2) as features to construct SVM classifier, could effectively distinguish patients with PSC or CSC. Certainly, further clinical confirmations are needed.

To conclude, DEGs in pulmonary sarcoidosis and cutaneous sarcoidosis patients as well as in healthy individuals were analyzed to identify common disease-related genes and mutual disease progression-related genes which linked pulmonary sarcoidosis and cutaneous sarcoidosis together. DEGs and their biological functions are dynamically dysregulated. The biological functional pathways regulated by these DEGs may help defining the common mechanism shared by different types of sarcoidosis. They are encoding proteins likely involved in the pathogenesis of sarcoidosis and could serve as disease markers. Our study provides a novel insight into the common pathogenesis of sarcoidosis and could help developing new therapeutic strategies.

Disclosure statement

The authors disclose no conflict of interest.

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