Periodontitis is a multifactorial chronic inflammatory disease associated with dysbiosis of the oral microbiota, and approximately 50% of adults suffer from this chronic disease (1), which is characterized by gingival inflammation and irreversible destruction of periodontal attachments (i.e., cementum, periodontal ligament, and alveolar bone). Recent advances suggest that periodontal disease initiation and propagation occur through dysbiosis of the commensal oral microbiota (dental plaque), which then interacts with the immune defenses of the host, leading to inflammation and disease (2).

In recent decades, there has been interest in the possibility that the presence of periodontal disease may be a causative or aggravating factor in some systemic diseases (3). Three mechanisms currently support a link between periodontitis and systemic disease: metastatic infections, dissemination of bacterial toxins and immunological injury (3). The first two mechanisms suggest the transmission of bacteria and their bacterial products from the oral cavity to the systemic level. The third theory suggests that systemic damage is the result of an inflammatory cascade response that begins in the oral cavity.

IgA nephropathy (IgAN) is the most prevalent glomerular disease worldwide and is associated with a poor prognosis (4). The pathogenesis of IgAN is complex and may involve a variety of different pathways (5). Studies indicate that infection may play a major role in the pathogenesis of IgAN (6). It is well known that upper respiratory tract infections often worsen IgAN, particularly acute tonsils. IgAN is thought to be a tonsillion-related disease caused by a breakdown in the immune tolerance of the resident bacteria in the tonsil (7), and several bacterial species have been reported as antigens in the pathogenesis of IgAN (8–10). Bacteria involved in chronic oral infections may be pathogenic candidates. Negasawa el. indicated that P. gingivalis (the main pathogenic bacteria of periodontitis) in tonsils was detected with significantly higher prevalence in IgAN patients than in habitual tonsillitis patients (11). Moreover, Misaki el al suggested that harboring C. rectus in the oral cavity could be associated with proteinuria in IgAN patients (12). The complete elimination of oral infection lesions can optimize the treatment effect of tonsillectomy plus methylprednisolone (MP) pulse therapy and promote the recovery of IgAN (13).

At present, the relationship between periodontitis and IgAN requires further investigation, especially in terms of cellular and molecular mechanisms. With the rapid development of microarray and high-throughput sequencing technology, bioinformatics techniques are often used to study the crosstalk between diseases. In this study, we used bioinformatics methods to explore the potential crosstalk genes between periodontitis and IgAN and evaluated the interaction between these potential crosstalk genes and infiltrating immune cells to gain a deeper understanding of the pathophysiological processes that may link periodontitis and IgAN.

In this study, we integrated the transcriptomes of periodontitis and IgAN and used WGCNA for the first time to explore the common mechanism between the two, revealing potential crosstalk genes, shared pathways, and associated immune cells. By taking the intersection of WGCNA important module genes and DEGs, we found that the SPAG4, CCDC69, KRT10, CXCL12, HPGD, CLDN20 and CCL187 genes were the most important cross-talk genes between periodontitis and IgAN, and these genes may be related to kinase regulator activity. Finally, CXCL12 and CCDC69 were identified as diagnostic markers with good value. The immune infiltration results revealed that T cells and B cells play an important role both in the pathogenesis of periodontitis and IgAN.

The results of this study suggest that the core cross-talk genes between periodontitis and IgAN are associated with kinase regulator activity. Kinases are enzymes that catalyze the transfer of phosphate groups, usually from ATP to substrate molecules. Periodontal pathogens play a critical role in the development and progression of periodontitis. Porphyromonas gingivalis is a keystone pathogen of periodontitis, whose main virulence factors include gingipain proteases and peptidylarginine deiminase (PPAD), and the phosphorylation of virulence factors is crucial for their processing and secretion (16). In addition, α-hemolytic streptococcus, as one of the main bacterial groups in the oral cavity, can promote the expression of homeodomain-interacting protein kinase 2 (HIPK2) in tonsil lymphocytes, which may mediate IgA1 glycosylation (17). Thus, periodontal or oral pathogens induced kinase regulator activity may play an important role in the common pathophysiology of the two diseases.

In this study, the possible immune relationship between IgAN and periodontitis was preliminarily explored, and it was found that the immune pattern was significantly different in the periodontitis and IgAN groups compared to the control group, and B and T cells increased more significantly in both periodontitis and IgAN samples. Primary IgAN is characterized by IgA deposition in the mesangial region of the glomerulus (18). The subclass of IgA in this deposition is IgA1, which may be produced in the mucosal region of the upper respiratory tract, including the tonsils or mucosal tissues in the oral region (19). The tonsil parenchyma consists of lymphoid follicles dominated by B cells and T-cell-dependent interfollicular regions (20, 21). Tonsillar focal infection may elevate the generation of CD8 T cells and the aberration of immunoglobulin production (22). Recent studies have suggested that chronic oral bacterial infections, especially red complexes of periodontopathic bacterial species, may be involved in the pathogenesis of IgAN (11).A recent review article highlighted that in the crypt of the tonsil, macrophages/dendritic cells engulf antigens, such as oral bacteria, and present them to helper T cells; activated helper T cells stimulate and activate mature B cells in the tonsillar germinal center to produce Gd-IgA1, and then the produced Gd-IgA1 enters the systemic circulation through the lymphatic system and causes kidney injury (23).In addition to tonsils, chronic infection during periodontitis may also stimulate mature B-cell proliferation in mesenteric lymph nodes and lead to increased IgA secretion through mucosal immune response, thus promoting the occurrence and progression of IgAN (24). Furthermore, T cells and their cytokines are involved in posttranslational modification of IgA1 hinge region (25). Some studies have found that the periodontal pathogen porphyromonas gingivalis can alter T cell response (26). Therefore, we speculated that periodontal infection might lead to abnormal IgA deposition through activation of T - and B-cell-mediated mucosal immunity.

In order to minimize the influence of overfitting and improve the quality of performance indicators, as many samples as possible should be selected for clinical biomarker discovery experiments (27). In our study, the GSE16134 dataset included a total of 198 gingival tissue samples and the GSE93798 dataset included 42 kidney tissue samples. The performance of a biomarker is often assessed using the area under the receiver operator curve (AUC). The value of AUC is between 0 and 1, and the higher the value, the better the overall performance of the test (28). In this study, ROC analysis found that the AUC of CXCL12 was 0.875 for predicting periodontitis and 0.759 for predicting IgAN, and the AUC of CCDC69 was 0.866 for predicting periodontitis and 0.966 for predicting IgAN. Therefore, both CXCL12 and CCDC69 have good predictive properties for periodontitis and IgAN.

As an important crosstalk gene between IgAN and periodontitis, CXCL12 (CXC chemokine ligand 12) is a potent chemoattractant that belongs to the CXC chemokine family. Widely expressed in many tissues during development, it is a powerful chemoattractant of hematopoietic cells, which has been shown to promote their migration across the endothelial barrier (29). CXCL12 levels increase during the development of periodontal disease and may recruit host defense cells to sites of inflammation, which may be involved in activating immune defense pathways during periodontal disease (30, 31). The following evidence suggests that it may be involved in the development and progression of IgAN mediated by periodontitis. It has been shown that GZMK CD8 memory T cells, mediated by CXCL12, have a prolonged residence time in the lytic region of neutrophils, which in turn can enhance antigen presentation (32). In some patients, CXCL12 can directly trigger effector T cells and affect their own migratory activity by secreting IL-15, causing rejection (33). In an airway infection model established by Pseudomonas aeruginosa, CXCL12 and HMGB1 binding was found to strongly promote the activation of downstream immune cells (34). Decreased expression and activation levels of CXCL12 were found in cyclosporin-immunosuppressed B cells as a mechanism for the treatment of autoimmune diseases by this class of drugs (35). Therefore, we assume that CXCL12 may be involved in both pathologies by mediating processes such as post-infection T-cell activation in tonsils and mucosa, systemic migration of effector T cells, and secretion of B-cell-deficient IgA. In addition, it has been speculated that in IgAN patients, abnormal expression of chemokines and/or chemokine receptors causes IgA-producing cells destined for the secretory mucosal lamina propria to be mistakenly transferred to nonsecretory sites, such as the tonsil, bone marrow, and spleen (36). In IgAN, B cells may be involved in the production of galactose-deficient IgA1 (Gd-IgA1) and its antibodies (37), and the CXCL12-CXCR4 axis is thought to be a major player in B-cell precursor homeostasis in the bone marrow (38). In summary, a potential role for chemokines in the interaction between periodontitis and IgAN seems likely, but further data are needed.

Our study found that CCDC69 is also an important crosstalk gene between IgAN and periodontitis; however, there are currently few studies on CCDC69. Pal et al. noted that CCDC69 acts as a scaffold to regulate the recruitment of midzone components and the assembly of the central spindle, which plays a crucial role in cell division (39). CCDC69 is also involved in the immune response. The expression of CCDC69 is positively correlated with immune cells (B cells, CD8+ cells, neutrophils, dendritic cells and lymphocytes) around the tumor, which can reflect the infiltration of immune cells (40). In this study, CCDC69 and CXCL12 had a significant positive correlation with central memory CD4⁺ T cells and immature B cells in both periodontitis samples and IgAN samples. This will highlight the common pathophysiology at the immune level and may be a key factor in understanding the relationship between periodontitis and IgAN.

Our study has several strengths. We first used the comprehensive and complex bioinformatics analysis as a new approach to understand the association between the two diseases. LASSO regression algorithm was performed to identify the potential shared diagnostic genes. Validation of external datasets improves the accuracy of predictions. There are also some limitations in this study. Our finding relied on different patient cohorts and were not validated in the same individual. A model of the combination of periodontitis and IgAN needs to be established to verify the potential relationship between the two diseases in the future. In addition, data on age, sex, medication, and comorbidities of patients in the samples were not considered in this study, which may be reliable for the current results.

This study is the first to use bioinformatics tools to explore the close genetic relationship between periodontitis and IgA nephropathy. The SPAG4, CCDC69, KRT10, CXCL12, HPGD, CLDN20 and CCL187 genes were the most important cross-talk genes between periodontitis and IgAN. T-cell and B-cell-driven immune responses may play an important role in the association between periodontitis and IgAN.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

XG conceived of the procedure for the research and wrote the manuscript. ZG and PW helped analyse the study data. ZL and ZW revised the draft. All authors read and approved the final manuscript. All authors contributed to the article and approved the submitted version.