As we all know,dental implants have become a common method of choice to complete oral restorations in partially and completely edentulous patients,on account of the advantages of dental implants: minimally invasive painless, no side effects, safety and stability, small size and long-term maintenance.Although the survival of dental implants is high, the prevalence of peri-implant diseases is also very significant.
Peri-implantitis is a pathological illness linked to plaque that affects the tissues surrounding dental implants. It is characterized by inflammation of the peri-implant mucosa and a consequent progressive loss of the bone that supports the implant. In addition to radiographic bone loss, peri-implantitis sites show clinical signs of inflammation, bleeding on probing and/or suppuration, increased probing depths, and/or recession of the mucosal margin. The implants may even become loose and fall off. [3]. Shuman M et al showed that the effectiveness of the dental implant was adversely affected by smoking, diabetes, history of periodontal diseases and multiple placements of implants[ 15]. Patients in SPT(supportive periodontal therapy ) developing re-infections are at greater risk for peri-implantitis and implant loss than periodontally stable patients[16]. These studies suggest that the occurrence of peri-implantitis is related to the body's immune response. One of the principle factors prompting implant failures is immunologically mediated rejection. Milad Baseri et al demonstrated that immune cells, especially macrophages and dendritic cells, almost increased in the patients with implant failure,also including mast cells, Langerhans cells (LCs),and neutrophils[ 17]. Zizzi A et al[ 18]indicates MCs are key cell types actively involved in the pathogenesis of periodontal and peri-implant inflammation.MCs reside close to T-cells, can undergo phagocytosis and process bacterial antigens, and minate adaptive immune responses by presenting antigens to T-cells and are a source of Th 1- and Th2- inducing cytokines MC(mast cell)cytokines increase inflammatory peri-implant response promoting infiltration of inflammatory cells and tissue destruction.The MMPs, and tryptase and chymase MC production could contribute to connective tissue breakdown, granuloma-associated angiogenesis and related bone resorption in peri-implantitis. According to Yakun, Han, and colleagues, compared to T and other lymphocytes, gingiva B cells produce more RANKL and support greater osteoclastogenesis, and this capability was enhanced in periodontitis. The ability to produce RANKL is strongest in memory B cells. Surprisingly, memory B cells from animals with periodontitis expressed noticeably more RANKL than healthy controls. The number of osteoclasts was larger in cultures with memory B cells obtained from periodontitis animals than in those from healthy ones. Memory B cells enhanced osteoclast development in vitro in a RANKL-dependent way. Other B-cell subsets only slightly affect the development of osteoclasts[ 19]. And TGF-b and IL-17 levels were higher in peri-implantitis patients, according to research by MFD Arajo et al., demonstrating that these cytokines are directly engaged in the inflammatory process.In order to increase the longevity of the implant, new therapies could be developed to suppress the manufacture of IL-17 and encourage the synthesis of IL-13 in the peri-implant tissue. This would be possible by understanding the role of cytokines in the development of peri-implantitis. To increase osseointegration, prevent and treat peri-implant disease, and monitor the number of innate immune cells may be helpful in preventing rejection, we should develop strategies focused on the potential use of drugs to inhibit and/or influence MC activation and/or secretion (e.g., HIR antagonists, like Terfenadine, Cetirizine, Rupatadine, or Serine proteases inhibitors, such as Ketotifin or Zincchelation [20] .
Gene expression refers to the process in which a specific gene on a DNA molecule is activated and transcribed into mRNA, and a protein is synthesized from it, under the action of certain regulatory factors, that is, the process of gene transcription and translation. And cytokine (CK) is a general term for small molecular proteins with a wide range of biological activities that are synthesized and secreted by cells (immune cells, non-immune cells) stimulated ,exerting their effects in the form of autocrine and paracrine. Therefore, genes regulate the body through certain signaling pathways through cytokines.
Due to the rapid expansion of transcriptome studies, microarray analysis research is spreading quickly, which is leading to an increased understanding of the molecular mechanisms underlying oral diseases[21, 22]. We can discover important genes that can be used as biomarkers for the diagnosis and prognosis of peri-impantitis by the integration of multiple related datasets, and we can determine the association between important genes and immune cells.
This study screened the differentially expressed regular mRNAs and mRNAs related to chromosome between peri-implantitis and normal tissues and we constructed the corresponding mRNA network to identify the key hub genes in peri-implantitis, evaluated the content of immune cells in normal tissues and peri-implantitis, and explored the relationship between core genes and immune cells between normal tissues and peri-implantitis, and found the target drug related to peri-implantitis, to guide the clinical diagnosis and treatment of peri-implantitis. Firstly, we conducted GO and KEGG enrichment analysis of DEGs, and we found that these differentially expressed genes were mainly associated with inflammatory
processes. By re-weighted analysis of hub genes and differential genes,wo got our core genes (CD38 and IRF4).Next, we got 32 hub genes related to chromosome in the same way,and found the relationship between immune cells and the hub genes.Then,we explored the association between the chromosomal gene expression peri-implantitis of and systemic diseases through DO analysis,and found the target drug to guide the clinical diagnosis and treatment of peri-implantitis.
Numerous cell types express CD38, a 300 amino acid protein that is a 45 kDa type II transmembrane glycoprotein that is encoded by homologous genes on chromosomes 4 and 5 of mice and humans, respectively. Through the non-substrate ligand CD31, it affects T cell activation and proliferation, B cell differentiation, and cell adhesion[23]. Researchs have shown a human anti-CD38 monoclonal antibody Daratumumab mediates myeloma Killing, and it is an anti-differentiation cluster 38 (anti-CD38) monoclonal antibody (MoAb) that downregulates Tregs CD38+, for the use of anti-CD38 immunotherapy to inhibit osteoclast formation[23, 24]. In this study, it was found that CD38 was associated with four 10 types of immune cells, especially with the highest correlation with immature B cells and activated B cell (P༜0.001). CD38 is shown to be highly expressed in B cells, macrophages, dendritic cells (DCs), innate lymphoid cells (ILC), natural killer (NK) cells, T cells, neutrophils, and monocytes, according to Piedra-Quintero Z L et al. [25]. The processes of cell differentiation, cytokine release, migration, and death are all influenced by CD38. After activation, immune cells express CD38 strongly, which controls infection-induced inflammatory processes from cell recruitment through the generation of adaptive immunological responses. Nevertheless, as seen in a transcriptional comparison between species, the degree of CD38 expression among these populations may vary between mouse and human. Human astrocytes induced by HIV-1 and/or IL-1b were tested for CD38 expression by Kow W et al, and human brain tissues were examined. Astrocyte stimulation by IL-1b and HIV-1 increased CD38 mRNA levels. In IL-1b-activated astrocytes, there was an increase in CD38 immunoreactivity and adenosine 50-diphosphate (ADP)-ribosyl cyclase activity. Production of pro-inflammatory cytokines and chemokines by astrocytes was significantly reduced after CD38 was knocked down using specific siRNAs.[26] .
IRF4(Interferon regulatory factor 4) is a member of the IRF family,a transcription factor protein with a molecular weight of 52 kD, and is abundantly expressed on mature B cells (plasma cells) and plays an important "role" in the differentiation of B cells.As a transcription factor, IRF4 plays a major role in regulating immune responses as well as immune cell proliferation and differentiation,and plays an important role in the function of B cells, T cells(Treg, Th2, Th9 and Th 17 cells) and macrophages[27]. Xuanzong Li et al demonstrated a close association between IRF4 and immune infifiltration, and IRF4 could be used as a prognostic marker in patients with LUAD[28]. IRF4 is a transcription factor that is indispensable for TH2 effector cell differentiation[29]. Soo-Jin Park et al suggested that tilianin attenuates HDM-induced allergic airway inflammation by inhibiting Th2-mediated inflammation through the selective inhibition of the IRF4-IL-33 axis in dendritic cells[27]. Wen Chao Han et al indicated the expression of serum TLR-4, TLR-5 and IRF4 was significantly higher in the severe group than in the moderate group, and significantly higher in the moderate group than those the in mild group, and significantly higher in the mild group than those in the suspected mild group about knee osteoarthritis.And TLR- 4, TLR- 5 and IRF4 were related to disease activity and inflammatory factors and could be diagnostic markers of knee osteoarthritis in the middle-aged and elderly.In this study, we found that IRF4 was associated with four 10 types of immune cells, especially with the highest correlation with immature B cells ,activated B cell and Gamma.delta.B.cell (P༜0.001) in treat group. This is in line with the results of previous researches.
At last,we found that 32 hub genes related to chromosome about peri-implantitis was associated with 16 types of immune cells and 13 immune response processes. We also found the 10 target drugs through the Drug Signature Database and the top 10 target miRNA by the Target Scan.Moreover, we found that chromosomal genes related to implants are also highly expressed in some systemic diseases though the DO analysis,such as autosomal dominant disease and heredirary breast ovarian cancer.At present, the relationship between cancer and chromosomal genes has been studied,and epigenetics has emerged as a means of elucidating critical regulation in cancer[34] .But the correlation between peri-implantitis and chromosomes was first proposed by us.A large number of studies have shown that IRF4 and CD38 are also closely related to the occurrence of cancer.There are a number of studies showing that IRF4 is related to the treatment of cancer.Junke Wang et al showed increased IRF4 gene expression is associated with increased risk of denovo AML and MDS (OR = 3.90, 95% CI, 2.36–6.44, Pmeta = 1.0 × 10 − 7 ). The identifification of IRF4 by both GWAS and TWAS contributes valuable insight on the role of genetic variation in AML and MDS susceptibility[30]. Qingyan Huang et al demonstrated high expression of IRF4 shown better prognostic outcome for breast and colorectal cancers. IRF4 was associated with immune inflitration in breast and colorectal cancers. Therefore, IRF4 maybe serve as a potential prognostic biomarker in breast and colorectal cancers with immune inflitration. Daniel A. Rauchet al showed that interferon regulatory factor 4 could act as a therapeutic target in adult T-cell leukemia Lymphoma[31]. But there are a number of studies showing that CD38 is related to the development of cancer, a multifunctional protein contributing to cancer progression. It is identifified as a prognostic factor of acute myeloid leukemia, chronic lymphocytic leukemia, prostate cancer pancreatic cancer, acute B lymphoblastic leukemia, lung cancer, hepatocellular cancer,colorectal cancer, nasopharyngeal carcinoma,and triple-negative breast cancer[32]. Bar Ben Baruch 1 et al show that in vitro paracrine effects of CAF-CD38 fostered tumor cell migration and invasion as well as endothelial cell tube formation. Mechanistically, we report that CAF-CD38 drives the protein expression of an angiogenic/ pro-metastatic signature, which includes VEGF-A, FGF-2, CXCL- 12, MMP-9, and HGF. Data suggest that CAF-CD38 fosters tumorigenesis by enabling the production of pro-tumoral factorsthat promote cell invasion, migration, and angiogenesis[33] .