A bibliometric analysis of IL-35 research from 2009 to 2018

Background Interleukin-35 (IL-35) is a recently discovered cytokine that plays a role in immune suppression and has therefore been the subject of a great deal of research. A bibliometric analysis of the global research concerning IL-35, however, is rare. Objectives The aim of this research was to assess the international scientific output of IL-35 research and explore its hotspots and frontiers from 2009 to 2018 by bibliometric analysis. Methods Publications about IL-35 research from 2009 to 2018 were retrieved from the Web of Science Core Collection (WoSCC). Citespace V was used to analyze years, journals, countries, research institutions, areas of exploration, research hotspots, and trends of publication. Results We retrieved a total of 416 publications and observed a trend of publications increasing over the past decade. Original articles (351) were the most frequently occurring document type. The largest number of publications belonging to one country and one institution, respectively, was China (202) and Tianjin Medical University (17). Trending keywords may indicate frontier topics, including “infectious tolerance,” “autoimmune,” and “central nervous system.” Conclusion This study provides valuable information on the study of IL-35 so that researchers may identify new research fields.


INTRODUCTION
In 1997, a study reported that the Epstein-Barr Virus-Induced Gene 3 Protein (EBI3) associated noncovalently with the p35 subunit of interleukin −12 to form a heterodimeric hematopoietin in vivo (Devergne, Birkenbach & Kieff, 1997). The EBI3-p35 heterodimer has been named IL-35 by the International Union of Immunological Societies (IUIS) Subcommittee. The cytokine IL-35 has been identified as a member of the IL-12 family. Other IL-12 family cytokines include IL-12, IL-23, and IL-27.

IL-35 is secreted by regulatory T cells and B cells
Interest in research on IL-35 has increased dramatically in recent years, and as a result, many journals have published articles on IL-35. The rapid growth of IL-35 literature renders identifying new developments and emerging trends in IL-35 research difficult. Few attempts, however, have been made to systematically analyze the knowledge, intellectual turning points, and key points in this field.
CiteSpace is a tool for visualizing and analyzing trends and patterns in scientific papers (Chen, 2004). CiteSpace provides a variety of functions to help understand network and historical patterns, including identifying rapidly growing subject areas, finding citation hotspots, decomposing networks into clusters, and automatically labeling clusters with citation terms (Chen, 2006). Here, we used bibliometric analysis to qualitatively and quantitatively evaluate IL-35 studies from 2009 to 2018. It is expected, therefore, that CiteSpace could be used to identify the emerging trends and hotspots of IL-35 research.

METHODS
All of the data obtained from the Web of Science Core Collection (WoSCC) of Thomson Reuters on February 27, 2019 was used in this study. The data retrieval strategy was: topic: (Interleukin-35) OR topic: (IL-35), index = SCI-EXPANDED, time span = 2009-2018 (retrieved date February 27, 2019). The following search string was used: document type: (Article OR Review). Web of Science database was used to analyze the characteristics of the literature, including the countries or regions in which it was conducted, the organization that researched IL-35, the journals it was published, as well as the research areas. The downloaded document records were exported to CiteSpace V for the further analysis.

General information
We collected 416 papers on IL-35 the WoSCC. Of these, 351 (84.38%) were original articles. The number of published research papers increased during the years from 2009 (n = 6) to 2018 (n = 89). The number of citations of these papers also increased dramatically from 2009 (n = 11) to 2018 (n = 2,171) ( Fig. 1), reaching a total of 8166. There were 350 (84.13%) papers that had been cited at least once. Table 1 shows the 10 most frequently cited publications.

Journal analysis
A total of 191 different journals published these articles. The maximum number of papers published in Cytokine was 19, followed by PLoS One (n = 16), the Journal of Immunology (n = 14), and Frontiers in Immunology (n = 10) ( Table 2). These publications were cited by 1326 journals. Frontiers in Immunology had the largest number of citations (n = 223), followed by PLoS One (n = 167), the Journal of Immunology (n = 136) and Scientific Reports (n = 82).

Country and institution analysis
Research on IL-35 was found to have been conducted in 41 countries. China was the country with the largest number of published papers (n = 202), followed by the USA (n = 91), and Germany (

Research area analysis
A total of 50 research field were represented, with the majority of publications focusing on immunology (n = 171), cell biology (n = 65), and biochemistry-molecular biology (n = 60). Figure 2 shows the top 10 research fields in IL-35 papers from 2009 to 2018.

Co-citation analysis
The map analysis was shown by a literature co-citation network. The network contains 225 nodes and 446 links. The Modularity Q was 0.8258 (>0.5), meaning that the clusters of networks were reasonable. The Mean Silhouette was 0.5107, indicating that the homogeneity of clusters was, on average, acceptable. As shown in Fig. 3, nodes represent referenced documents. The largest cluster in the visualization is #0 job profile, followed  by #1 antitumor activity, #2 turning promiscuous protein, and #3 IL-12 family cytokine. These clusters were also shown in a timeline view (Fig. 4).

Keywords analysis
We used CiteSpaceV to analyze keywords. Over a period of time, a knowledge map of the cooccurrence of keywords may reflect hot topics, whereas trending keywords may indicate frontier topics. Generating a visual knowledge map of keyword cooccurrence resulted in 130 nodes and 431 links (Fig. 5). The strongest citation bursts keywords were as follows: ''central nervous system,'' ''dendritic cell,'' and ''IL-27'' (Fig. 6).

DISCUSSION
In this study, we analyzed the structure of the citation network and the trends in topics of recent research involving IL-35. An analysis of the literature published about IL-35 over the past 10 years showed a high growth rate of publications related to IL-35 with frequent citations, indicating that the study of IL-35 was a hot topic. The top 10 institutions that were engaged in IL-35 research contributed to 118 publications, accounting for 28.37% of the total number of research papers. Of the top ten, six institutions were from China. Over the past 10 years, China has been the leading country in IL-35 research, indicating China's great progress in the life sciences. In order to compare the reception of each publication, we also analyzed the citation frequency of the papers. The results showed that an article published in Nature Immunology (Collison et al., 2010) was the most frequently cited article, indicating that ''IL-35-mediated induction of a potent regulatory T cell population'' was an important publication to reference in IL-35 research.
The co-citation knowledge map refers to a network of co-citation publications to determine research frontiers. These nodes represent different documents, marked by the year of publication and the author of the publication. The size of the node is proportional to the number of references cited in specific time periods. The red citation ring indicates a sudden increase of citations over a period of time. Trending citations provide an effective way to track research hotspots. Furthermore, we analyzed the characteristics related to clusters of references and constructed a visual map of this research that contained 225 nodes and 446 links. The color of the node indicates how recently the relevant literature had been published. The dark color corresponds to older research, the yellow or orange color to new research (Chen et al., 2012). Among the 14 clusters, Cluster 0 (job profile) is the largest. The topics of Cluster 1 (antitumor activity), Cluster 2 (turning promiscuous protein), Cluster 4 (emerging role), and Cluster 7 (regulatory B cell) were the newest research . The publications that comprised Cluster 1 (antitumor activity) focused on the role of IL-35 in cancer, including the severity of the malignancy, the clinical stage of the tumor, the promoting of tumor growth, the autocrine growth factor, and the limited antitumor immunity (Zeng et al., 2013;Wang et al., 2013;Nicholl et al., 2014;Turnis et al., 2016). Cluster 2 (turning promiscuous protein) publications focused on unconventional proteins, including unconventional modes of signaling, and the suppression of autoimmune disease and responsive anti-inflammatory cytokines (Li et al., 2012;Collison et al., 2012;Wang et al., 2014).
The cluster 4 (emerging role) research reported that the low serum level of IL-35 is related to both active systemic lupus erythematosus and active rheumatoid arthritis (Li et al., 2012;Collison et al., 2012;Wang et al., 2014). Interestingly, some studies reported that IL-35 promotes chronic inflammation (Filková et al., 2015;Thiolat et al., 2014).
The publications corresponding to cluster 7 (regulatory B cell) focused on the function of the regulatory B cell, including inflammation, autoimmunity, and the maintenance of the fine equilibrium required for infectious tolerance (Iwata et al., 2011;Yoshizaki et al., 2012;Mauri & Bosma, 2012;Flores-Borja et al., 2013).
Bursts of keywords provide a reasonable forecasting of the research frontier. Citespace detected several bursts which were regarded as an indicator of the frontiers of IL-35 research. In the Fig. 6 , the blue line represents the time interval. The start to the end of each burst interval is indicated by a red line. Therefore, the top three research frontiers of IL-35 were as follows: (1) ''infectious tolerance'': Infection tolerance is an in vivo process in which tolerance is transferred from one group of lymphocytes to another. In this way, short-term treatment aimed at producing infection tolerance may lead to long-term, self-sustaining immune homeostasis in clinical settings (Kendal & Waldmann, 2010). IL-35 plays an important role in infection tolerance (Olson, Sullivan & Burlingham, 2013;Tao et al., 2015).
(2) ''autoimmunity'': Studies have found abnormal expression of IL-35 in patients suffering from autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, diabetes mellitus type 1, psoriasis, autoimmune hepatitis, multiple sclerosis, and experimental autoimmune uveitis (Choi et al., 2015;Su et al., 2018). An autoimmune disease is a pathophysiological state; the immune response directly targets and damages the body's own tissues.
(3) ''central nervous system'': Through the study of a mouse model, IL-35 was found to be associated with central nervous system demyelination, autoimmune encephalomyelitis, and the control of host responses following central nervous system viral infection (Zandian et al., 2011;Tirotta et al., 2013;Xie et al., 2016). A study suggested that the level of IL-35 in patients with neuromyelitis optica spectrum disorders was low. This might be an important biomarker of the severity of neuromyelitis optica spectrum disorders .

CONCLUSIONS
This study will help researchers understand the trends of IL-35 research. Infectious tolerance and autoimmune diseases may be the latest research frontiers. The molecular biological mechanisms of IL-35 need further exploration.

ADDITIONAL INFORMATION AND DECLARATIONS Funding
The authors received no funding for this work.