Differential CpG DNA Methylation of Peripheral B, CD4 + T cells and Salivary Gland Tissues in IgG4-related Disease

doi:10.21203/rs.3.rs-1764394/v1

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Differential CpG DNA Methylation of Peripheral B, CD4 + T cells and Salivary Gland Tissues in IgG4-related Disease

https://doi.org/10.21203/rs.3.rs-1764394/v1

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published 07 Jan, 2023

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Objectives.

Immunoglobulin-G4-related disease (IgG4-RD) is a distinct systemic autoimmune-mediated disease that characterized by tissue fibrosis. The purpose of this study is to investigate the epigenetic modifications in IgG4-RD.

Methods.

A genome-wide DNA methylation study was performed in B cells, CD4⁺ T cells and salivary gland tissue from IgG4-RD patients and matched controls using the Illumina HumanMethylation 850K BeadChip.

Results.

We identified differentially methylated CpG sites including 44 hypomethylated and 166 hypermethylated differentially methylated probes (DMPs) in B cells, 260 hypomethylated and 260 hypermethylated DMPs in CD4 + T cells from 10 IgG4-RD patients compared with 10 healthy controls. We also identified 36945 hypomethylated and 78380 hypermethylated DMPs in salivary gland tissue of 4 IgG4-RD patients compared with 4 controls. We found that DPM2 (cg21181453), IQCK (cg10266221), ABCC13 (cg05699681, cg04985582) were hypermethylated and MBP (cg18455083) was hypomethylated in B cells, CD4⁺ T cells and tissue of IgG4-RD patients compared with controls. Also, we observed hypomethylated HLA class in both B cells and CD4⁺ T cells from IgG4-RD patients compared with controls. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DMPs in salivary gland of IgG4-RD patients demonstrated enrichment of pathways in regulation of immune cells responses and fibrosis.

Conclusion.

Our study is the first DNA methylation study in peripheral B cells, CD4⁺ T cells as well as salivary gland tissues from patients with IgG4-related disease. Our findings highlighted the role of epigenetic modification of DNA methylation and identified several genes and pathways that might involve in the pathogenesis of IgG4-RD.

IgG4-RD

DNA methylation

B cells

CD4+ T cells

salivary gland tissues

Immunoglobulin-G4-related disease (IgG4-RD) is a distinct systemic autoimmune-mediated disease characterized by infiltration of IgG4 + plasma cells into one or multiple organs and tumor-like masses development¹. Chronic activation of B cells, T cells and macrophage accumulate in fibrotic lesions of IgG4-RD². An estimate incidence of 0.28–1.08 per people and 336-1,300 newly diagnosed patients per year has been reported³. Systemic corticosteroid administration and B cell depletion are the main therapeutic strategies and could both significantly ameliorate IgG4-RD. However, due to the glucocorticoid-induced toxicity and high percentage of relapse treated with rituximab (RTX)⁴, the pathogenesis of IgG4-RD still requires further study.

Epigenetic mechanisms are found to contribute to the risk of developing various autoimmune diseases^{5, 6, 7}. DNA methylation is a well-studied epigenetic modifications that regulates gene expression⁸. So far, a number of studies have provided evidence of aberrant DNA methylation profiles in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and sjogren’s syndrome (SS) patients^{9, 10, 11, 12, 13, 14, 15, 16, 17, 18}. The DNA methylation changes in IgG4-RD patients are poorly understood.

In the present study, B cells and CD4⁺ T cells were purified from 10 IgG4-RD patients and 10 age-, sex-matched heathy controls. DNA methylation was assayed using a genome-wide Illumina 850K CpG promoter. Also, we performed DNA methylations analysis of salivary gland tissue biopsied from 4 IgG4-RD cases and 4 controls. Our findings demonstrated a pattern of peripheral B cells and CD4⁺ T cells and tissue DNA methylation in key genes and pathways associated with the pathogenesis of IgG4-RD patients.

Study cohort and Ethics

A total of 14 IgG4-RD patients were enrolled in our study. The diagnosis was performed according to the 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4- related disease and the 2011 comprehensive diagnostic criteria for IgG4- related disease^{19, 20}. Peripheral blood samples were obtained from 10 patients and 10 healthy blood donors who were matched for age, sex, and ethnicity. Salivary gland biopsies were obtained from 8 individuals that were examined for a possible IgG4-RD diagnosis. The biopsies which showed no inflammation and negative serology served as case controls. Demographic and clinical characteristics of the study participants are shown in Supplementary Table 1. Diagnostic score was calculated according to the 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4- related disease. Disease activity was assessed by the IgG4-RD responder index (RI)²¹.

This study was approved by the ethics board of Peking Union Medical College Hospital (No.JS-3389). All participants have signed a written informed consent.

Isolation of B cells and CD4+ T cells

Peripheral blood mononuclear cells (PBMCs) were isolated from fresh peripheral blood samples using density gradient centrifugation (Ficoll-Paque, Dakewe, China). CD4⁺ T cells and B cells were separated from PBMCs using the CD4+ T Cell Isolation Kit (Miltenyi Biotec, Cambridge, MA) and the B Cell Isolation Kit II（Miltenyi Biotec, Cambridge, MA）according to the manufacturer’s protocol. The purity of isolated CD4⁺ T cell and B cells were confirmed> 95% by flow cytometry, respectively.

DNA methylation profiling

DNA was extracted from cells or tissues (Qiagen, Valencia, California, USA) according to manufacturer’s instruction. DNA methylation was assayed using Infinium Human Methylation 850 BeadChips (Illumina, San Diego, USA). These steps were performed by Novogene Company (Beijing, China).

Analysis of DNA methylation data

DNA methylation files were processed in the R environment using the Minfi (V1.30.0) statistical analysis package for background signal correction and normalization of each channel to control probes included in each array. For each sample, (1) CpG sites with a p value more than 0.01; (2) Probes with SNPs or their single base extension, X chromosome and Y chromosome at the CpG site were excluded from the analysis.

The methylated and unmethylated probe values were used to calculate b value ratio using the following formulae: b value = (Methylated)/(Methylated + Unmethylated + 100). The mean-difference b-value (Db) and adjusted p value between HCs and IgG4-RD patients for each CpG sites were calculated using CHAMP packages (V2.14.0). For B cells or CD4⁺ T cells isolated from PBMCs, adjust p value <= 0.05 or Db > 0.05 was considered statistically significant. For tissue samples, adjust p value < 0.05 and Db >= 0.2 was considered statistically significant. Differential methylation regions (DMRs) were analyzed using DMRcate (V1.20.0) package with FDR-corrected p values < 0.05 considered as statistical significant.

Pathway analysis

The gene lists found to be statistically significant were used to perform further the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene ontology analysis (GO). ClusterProfiler package (V3.12.0) was used for pathway enrichment analysis²².

Global DNA methylation patters in peripheral blood and tissues from IgG4-RD patients and controls

DNA methylation profile of B cells and CD4⁺T cells from 10 HCs and 10 IgG4-RD patients was analysed. DNA methylation of salivary gland tissues from 4 IgG4-RD patients and controls was also assayed. The workflow was shown in Figure 1A. The overall DNA methylation beta value displayed similar distribution patterns between two groups (Figure 1B). 44 sites were hypomethlated and 166 sites were hypermethylated in B cells and 260 sites were hypomethylated and 112 sites were hypermethylated in CD4⁺ T cells from IgG4-RD patients compared to healthy controls (Figure 1C). A total of 36945 sites were hypomethylated and 78370 sites were hypermethylated in salivary gland tissues of IgG4-RD patients compared with controls (Figure 1C).

Next, genes and DMPs (Differential Methylation Probes) of salivary gland tissues were obtained and compared with those from B cells and CD4⁺ T cells in IgG4-RD patients. As presented in Figure 2A, 15 DMPs were common to the three cell types. To further identify the methylated status of common genes in three cell types, the delta beta value were calculated. We found that DPM2 (cg21181453), IQCK (cg10266221), ABCC13 (cg05699681, cg04985582) were hypermethylated and MBP (cg18455083) was hypomethylated in B cells, CD4⁺ T cells and tissue of IgG4-RD patients compared with controls (Figure 2B). Although TMEM108 (cg18478854) and LOC441897 (cb18346412) were hypermethylated in both B cells and CD4⁺ T cells, they were found hypomethylated in tissues of IgG4-RD patients compared with controls (Figure 2B).

DNA methylation status in B cells from IgG4-RD patients

Nexted, we analysed CD19⁺ B cells from 10 IgG4-RD patients and 10 healthy controls and identified 166 hypermethylated and 44 hypomethylated probes (Figure 3A). Among them, the majority of DMPs were present within intergenic regions (IGR) or within gene body (Figure 3A). The top associated hypomethylated and hypermethylated probes with annotated genes are shown in table S2 and table S3. IQCK, UMODL1, AHDC1, LARS2, RASA3, USP16, BTBD11, CLECL1, LOC441897 and ABCC13 genes showed hypermethylated, TMEM9B, CLIC6, MIR492, ARNTL, TNN, MBP, CDK15, PIGL, HLA-DRB1 and MYO1D showed hypomethylated at CpG sites in B cells from IgG4-RD patients.

GO analysis of the DMPs revealed enrichment for multiple categories . Among those, interferon-gamma-mediated signaling pathway (related genes: TRIM68, HLA-DRB1, HLA-DQB2 and IFNGR2), regulation of canonical Wnt signaling pathway (related genes: STK4, BICC1, KANK1, ARNTL, TNN and PSMD5) were shown to be enriched (Figure 3B).

DNA methylation status in CD4⁺ T cells from IgG4-RD patients

Furthermore, we examined CD4⁺ B cells from 10 IgG4-RD patients and 10 healthy controls and identified 112 hypermethylated and 260 hypomethylated probes (Figure 3C). Similar with B cells, the majority of DMPs of CD4⁺ T cells were also present within intergenic regions (IGR) or within gene body (Figure 3C). The top associated hypomethylated and hypermethylated probes with annotated genes are shown in table S4 and table S5. MAST4, AHDC1, BICC1, USP16, IQCK, LOC727677, MYO1D, LOC441897, CAV2 and TGFBR2 genes showed hypermethylated, TMEM9B, CLIC6, CCS, PAWR, FIP1L1, ARHGAP15, ARHGAP26, PKD1L1, HLA-DRB1 and HLA-DQB2 showed hypomethylated at CpG sites in CD4⁺ T cells from IgG4-RD patients.

GO analysis of the DMPs revealed enrichment for multiple categories . Among those, cellular response to oxidative stress (related genes: FUT8, ARNTL, CFLAR, PTPRK, ETS1, TRAP1, FOXO1, OXR1, PAWR, PRR5L, CCS, PYROXD1 and MIR21), T cell activation (related genes: CLECL1, TGFBR2, ZMIZ1, EOMES, CD3E, TIGIT, CLEC7A, PAWR, KIF13B, CD300A, FZD7 and MIR21) and Wnt-activated receptor activity (related genes: LRP5 and FZD7) were shown to be enriched (Figure 3D)..

Identified DMPs and DMRs in salivary gland tissue of IgG4-RD patients

Furthermore, we studies the DNA methylation status in the affected organ, the salivary gland of the IgG4-RD. A total of 78370 hypermethylated and 36945 hypomethylated probes were identified in tissues of IgG4-RD patients compared with healthy controls (Figure 4A-C). Among them, the majority of DMPs were also present within intergenic regions (IGR) or within gene body (Figure 4C). The top 25 associated hypomethylated and hypermethylated probes with annotated genes are shown in table S6 and table S7. LOH12CR1, PFKP, ARSB, SNX29, TBCD, STARD13, GALNT10, EIF4E3, VGLL4, TGFBR3, GLG1, RBM34, EPAS1, ITPKB, TBS22D1, SLC44A2, TRIOBP, ACAD11, KCNAB2, PDE4D, RERE, ARID1B, UAP1, LGALS3 and LOC102724933 genes showed hypermethylated, CD69, RUNX1, TMEM229B, JAZF1, SLC7A6, FAM69A, EVL, CYTIP, WIPF1, TNFSF8, LOC102724, NCKAP1L, SETBP1, KIAA0748, PPP1R16B, GRAP2, CASP8, ARSG, ITGB2-AS1, MGAT1, CD37, MAP2K2, TNFAIP8L2 and RCSD1 showed hypomethylated at CpG sites in tissues from IgG4-RD patients.

KEGG pathway analysis identified “Calcium signaling pathway” ,“cAMP signaling pathway” ,“MAPK signaling pathway”, “Oxytocin signaling pathway”, “Rap1 signaling pathway”, “Hippo signaling pathway”, “VEGF signaling pathway” and “cGMP-PKG signaling pathway” in the differentially methylated genes in tissues from IgG4-RD patients (Figure 4D). GO analysis of the DMPs revealed enrichment for positive regulation of cell adhesion, T cell activation (Figure 4E).

Finally, we characterized the most significant DNA Methylation Regions (DMRs) in salivary gland of the IgG4-RD patients (table S8). To better characterize genes that were detected in the DMRs, GO and KEGG pathway analyses were performed. KEGG pathway analyses identified genes involved in the cAMP signaling pathway, Calcium signaling pathway, PI3K-Akt signaling pathway, PPAR signaling pathway, Rap1 signaling pathway and Ras signaling pathway (Figure 5A). GO analyses revealed genes were most enriched in extracelluar matrix organization and ion channer activity (Figure 5B).

The epigenetic modifications in IgG4-related disease are poorly understood currently. In the present study, we perfomed an genome-wide DNA methylation analysis of peripheral B cells, CD4⁺ T cells as well as salivary gland tissues of IgG4-RD patients. We idenfied a set of differentially methylate probes, regions and involved pathways in IgG4-RD patients compared with controls. Our observations in DNA methylation patterns provided new insights into epigenetic modifications of peripheral immune cells and tissue-specific differences that might involve in the pathogenesis of IgG4-RD patients.

We found that MBP (cg18455083) was uniformly hypomethylated in B cells, CD4⁺ T cells and tissue of IgG4-RD patients compared with controls. Myelin basic protein (MBP) is the major target of T cells in lesions of multiple sclerosis (MS) patients and its animal model, experimental autommune encephalomyelitis (EAE)²³. A number of previous studies have demonstrated the role of myelin-reactivity of T cells in MS^{24, 25, 26}. A recent study by Catriona A. Wagner et. al also found that myelin-specific CD8⁺ T cells exacerbated brain inflammatin in CNS autoimmunity²⁷. Currently, there is no literature about whether myelin plays a role in the pathogenesis of IgG4-RD. Since CD4⁺ cytotoxic T lymphocytes have been demonstrated clonally expanded and implicated in the pathogenesis of IgG4-related disease^{28, 29}, it is interesting to explore whether myelin-specific B cells or T cells contribute to the development of IgG4-RD in our future study.

Previous study by Japanese group suggested the involvement of HLA class in the IgG4-related pancreatitis³⁰. Another study by another Japanese group found six HLA class associatd variants, namely rs1143146 (HLA-A), rs1050716 (HLA-C), c.759_763delCCCCCinsTCCCG (HLA-C), rs1050451 (HLA-C), rs4154112 (HLA-DQB1) and rs1049069 (HLA-DQB1) associated with relapse of IgG4-related pancreatitis³¹. In accordance with GWAS study, We also found hypomethylated HLA class in both B cells and CD4⁺ T cells from IgG4-RD patients compared with controls. We showed that HLA-DRB1 was hypomethylated in B cells and HLA-DRB1, HLA-DQB2 were hypomethylated in CD4⁺ T cells from IgG4-RD patients.

Several differentially methylated genes that play important roles in the immune cells regulation or fibrosis have been identified in the tissues of IgG4-RD patients in our present study. GALNT10 encodes for GALNT10, is found to be associated with the increased regulatory CD4⁺ T cells infiltration and decreased granzyme B expression in CD8⁺ T cells in tumor tissues³². TGFBR3 encodes for the TGF-beta type III receptor (TGFBR3), is an essential constituent of the TGF-beta signaling, regulated both immune responses and fibrosis^{33, 34}. ITPKB encodes for inositol 1,4,5-trisphosphate 3-kinase, is important for B cell survival, development and function as well as T cell maturation in thymus^{35, 36}. LGALS3 encodes for galectin-3, has been implicated in various autoimmune disease through modulating T cells functions^{37, 38}. CD69 encodes for CD69, which is the activated markers for B cells and T cells, play a pivotal for in autoimmunity³⁹. RUNX1 encodes for RUNX1 (Runt-related transcription factor 1), a transcription factor that regulate fibrosis⁴⁰. CD37 encodes for CD37, is a B-cell surface antigen widely expressed on mature B cells⁴¹. A recent study found the tetraspanin CD37 orchestrates the α4β1 integrin-Akt signaling axis and supports long-lived plasma cell survival⁴².

KEGG pathway analysis revealed enrichment of “Calcium signaling pathway”, “MAPK signaling pathway” and “Hippo signaling pathway” in tissues of IgG4-RD patients. Chronic calcium signaling in IgE⁺ B cells limits plasma cell differentiation and survival⁴³. A recent study by Sai-Nan Min et.al found that intraglandular injection if IL-4 into mouse submandibular glands could promote fibrogenesis in IgG4-related sialadenitis through the ROS-p38 MAPK-p16^INK4A. Although, there was no literature about the role of Hippo signaling pathway in the IgG4-RD development, yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), transcriptional effectors of the Hippo pathway, has been identified as key matrix stiffness-regulated coordinator of fibroblast activation and matrix synthesis⁴⁴.

The main limitation of these data is limited sample size, especially tissue specimen since IgG4-RD is a rare disease. Therefore, Longitudinal studies would be required to enlarge sample size and additional functional assays should be performed to fully elucidate the role of DNA methylation in IgG4-related disease.

In conclusion, we are the first study to identify DNA methylation changes in peripheral B cells, CD4⁺ T cells as well as salivary gland tissues from patients with IgG4-related disease. Our data indicate the anormal DNA methylations and emphasize the potential role of DNA methylation changes in the pathogenesis of IgG4-RD. Our study demonstrated differentiation methyation of MBP, hypomethylated HLA class, and other key genes and pathways involved in the pathogenesis of IgG4-RD and provided potential therapeutic targets for clinical IgG4-RD therapy.

IgG4-RD

Immunoglobulin-G4-related disease

KEGG

Kyoto Encyclopedia of Genes and Genomes

Rheumatoid Arthritis

SLE

Systemic Lupus Erythematosus

Sjogren’s Syndrome

PBMCs

Peripheral Blood Mononuclear Cells

DMRs

Differential Methylation Regions

Gene Ontology

DMPs

Differential Methylation Probes

MBP

Myelin Basic Protein

Multiple Sclerosis

EAE

Experimental Autommune Encephalomyelitis

TGFBR3

the TGF-beta Type III Receptor

ITPKB

Inositol 1,4,5-Trisphosphate 3-kinase

RUNX1

Runt-related transcription factor 1

YAP

Yes-associated protein

TAZ

Transcriptional Coactivator with PDZ-binding Motif.

Competing interests

The authors declare no conflict of interests.

Contributors

WZ and YF conceived and designed the study. MW, JZ, LP, YZ, XZ, YF and WZ recruited participants. AW performed experiments with help from YP, YC, JL, ZL and HL. XW performed data analysis. WX, YF and WZ wrote the manuscript with input from all authors. WZ acts as the guarantor responsible for the overall content of the present work. All authors approved the final version of the manuscript.

Acknowledgement

none

Funding

This work was supported by the National Natural Science Foundation of China (81971545, 81971544, 82071839) and CAMS Innovation Fund for Medical Sciences (CIFMS 2021-1-I2M-003, 2020-I2M-C & T-A-002).

Ethical approval

This study was approved by the ethics board of Peking Union Medical College Hospital (No.JS-3389). All participants have signed a written informed consent.

Data availability statement

Data are available upon reasonable request. Not applicable

Patient and Public Involvement

Not applicable

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No competing interests reported.

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Differential CpG DNA Methylation of Peripheral B, CD4 + T cells and Salivary Gland Tissues in IgG4-related Disease

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