Interleukin-35 Prevents Development of Autoimmune Diabetes Possibly by Maintaining the Phenotype of Regulatory B Cells

The anti-inflammatory role of regulatory B cells (Breg cells) has been associated with IL-35 based on studies of experimental autoimmune uveitis and encephalitis. The role of Breg cells and IL-35+ Breg cells for type 1 diabetes (T1D) remains to be investigated. We studied PBMCs from T1D subjects and healthy controls (HC) and found lowered proportions of Breg cells and IL-35+ Breg cells in T1D. To elucidate the role of Breg cells, the lymphoid organs of two mouse models of T1D were examined. Lower proportions of Breg cells and IL-35+ Breg cells were found in the animal models of T1D compared with control mice. In addition, the systemic administration of recombinant mouse IL-35 prevented hyperglycemia after multiple low dose streptozotocin (MLDSTZ) injections and increased the proportions of Breg cells and IL-35+ Breg cells. A higher proportion of IFN-γ+ cells among Breg cells were found in the PBMCs of the T1D subjects. In the MLDSTZ mice, IL-35 administration decreased the proportions of IFN-γ+ cells among the Breg cells. Our data illustrate that Breg cells may play an important role in the development of T1D and that IL-35 treatment prevents the development of hyperglycemia by maintaining the phenotype of the Breg cells under an experimental T1D condition.

Download Full-text

The role of regulatory B cells in the development of autoimmune diabetes in NOD mice

10.5353/th_b5194749 ◽

2013 ◽

Author(s):

Yang Liu

Keyword(s):

B Cells ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Regulatory B Cells

Download Full-text

Interleukin 12 Protects from a T Helper Type 1–mediated Autoimmune Disease, Experimental Autoimmune Uveitis, through a Mechanism Involving Interferon γ, Nitric Oxide, and Apoptosis

Journal of Experimental Medicine ◽

10.1084/jem.189.2.219 ◽

1999 ◽

Vol 189 (2) ◽

pp. 219-230 ◽

Cited By ~ 156

Author(s):

Teresa K. Tarrant ◽

Phyllis B. Silver ◽

Jennifer L. Wahlsten ◽

Luiz V. Rizzo ◽

Chi-Chao Chan ◽

...

Keyword(s):

Nitric Oxide ◽

T Cells ◽

Interferon Γ ◽

Effector T Cells ◽

T Helper ◽

Experimental Autoimmune Uveitis ◽

Ifn Γ ◽

Helper Type ◽

Experimental Autoimmune

Pathogenic effector T cells in experimental autoimmune uveitis (EAU) are T helper type 1–like, and interleukin (IL)-12 is required for their generation and function. Therefore, we expected that IL-12 administration would have disease-enhancing effects. Mice were immunized with a uveitogenic regimen of the retinal antigen interphotoreceptor retinoid-binding protein, treated with IL-12 (100 ng/d for 5 d), and EAU was assessed by histopathology. Unexpectedly, IL-12 treatment failed to enhance EAU in resistant strains and downregulated disease in susceptible strains. Only treatment during the first, but not during the second, week after immunization was consistently protective. High levels of interferon γ (IFN-γ) were present in the serum during IL-12 treatment, but subsequent antigen-specific IFN-γ production in protected mice was diminished, as were IL-5 production, lymph node cell proliferation, and serum antibody levels. Treated mice had fewer cells and evidence of enhanced apoptosis in the draining lymph nodes. Unlike wild-type mice, IFN-γ–deficient, inducible nitric oxide synthase (iNOS)-deficient, and Bcl-2lck transgenic mice were poorly protected by IL-12, whereas IL-10–deficient mice were protected. We conclude that administration of IL-12 aborts disease by curtailing development of uveitogenic effector T cells. The data are compatible with the interpretation that IL-12 induces systemic hyperinduction of IFN-γ, causing activation of iNOS and production of NO, which mediates protection at least in part by triggering Bcl-2 regulated apoptotic deletion of the antigen-specific T cells as they are being primed.

Download Full-text

Regulatory Role of Peritoneal B Cells in EAE

Serbian Journal of Experimental and Clinical Research ◽

10.1515/sjecr-2015-0048 ◽

2016 ◽

Vol 17 (2) ◽

pp. 87-92

Author(s):

Bojana Stojanović ◽

Jelena Milovanović ◽

Aleksandar Arsenijević ◽

Marija Milovanovic ◽

Miodrag L. Lukic

Keyword(s):

Multiple Sclerosis ◽

B Cells ◽

Experimental Autoimmune Encephalomyelitis ◽

Regulatory Role ◽

Disease Development ◽

Regulatory B Cells ◽

Autoimmune Encephalomyelitis ◽

Inflammatory Stimuli ◽

Experimental Autoimmune

Abstract B cells play a dual role in the pathogenesis of autoimmune diseases. In experimental autoimmune encephalomyelitis (EAE), an experimental model for multiple sclerosis, B cells contribute to disease progression, while their regulatory role predominates in the initial phases of disease development. Several studies have identified different subsets of regulatory B cells, mostly in the spleen, which are all sources of IL-10. However, peritoneal regulatory B cells are also important producers of IL-10, can migrate towards inflammatory stimuli, and could have an immunoregulatory function. As we have observed expansion of regulatory B cells in the peritoneum of resistant mice after EAE induction, herein we discuss the regulatory roles of B cells in EAE pathogenesis and the possible role of peritoneal regulatory B cells in resistance to EAE induction.

Download Full-text

Defective Regulatory B Cells Are Associated With Thyroid-Associated Ophthalmopathy

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2018-01812 ◽

2019 ◽

Vol 104 (9) ◽

pp. 4067-4077 ◽

Cited By ~ 1

Author(s):

Guo Chen ◽

Yungang Ding ◽

Qian Li ◽

Yanbing Li ◽

Xiaofeng Wen ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Healthy Controls ◽

Regulatory B Cells ◽

Peripheral Blood Mononuclear ◽

Thyroid Associated Ophthalmopathy ◽

Ifn Γ

Abstract Purpose To investigate the change in IL-10–producing regulatory B cells (Breg), which suppress peripheral immune responses, in patients with thyroid-associated ophthalmopathy (TAO). Methods Peripheral blood mononuclear cells (PBMCs) were isolated from healthy controls (n = 54), patients with Graves disease (n = 26), and patients with TAO (N=125), and stimulated with CpG/CD40L. The frequency of IL-10–producing Bregs and the expression of IL-10 in response to TSH stimulation were measured by flow cytometry. CD4+ T cells were cultured with Breg-depleted PBMCs to elucidate the function of Bregs in patients with TAO. The potential immunoregulatory mechanism was also investigated by Western blot and chromatin immunoprecipitation assays. Results Patients with active TAO had higher baseline levels of Bregs in their peripheral blood than both healthy controls and inactive patients. TSH promoted Bregs. Bregs from patients with TAO were defective in suppressing the activation of interferon (IFN)-γ+ and IL-17+ T cells in vitro. Conclusions Regulatory B cells in patients with TAO are functionally defective, suggesting that the defective Bregs might be responsible for the pathogenesis of TAO.

Download Full-text

The role of CD19+CD24highCD38high and CD19+CD24highCD27+ regulatory B cells in patients with type 1 autoimmune pancreatitis

Pancreatology ◽

10.1016/j.pan.2014.02.004 ◽

2014 ◽

Vol 14 (3) ◽

pp. 193-200 ◽

Cited By ~ 39

Author(s):

Kimi Sumimoto ◽

Kazushige Uchida ◽

Takeo Kusuda ◽

Toshiyuki Mitsuyama ◽

Yutaku Sakaguchi ◽

...

Keyword(s):

B Cells ◽

Autoimmune Pancreatitis ◽

Regulatory B Cells ◽

Type 1 Autoimmune Pancreatitis

Download Full-text

Analysis of Regulatory B Cells in Experimental Autoimmune Uveitis

Methods in Molecular Biology - Regulatory B Cells ◽

10.1007/978-1-0716-1237-8_23 ◽

2021 ◽

pp. 437-450

Author(s):

Jin Kyeong Choi ◽

Charles E. Egwuagu

Keyword(s):

B Cells ◽

Regulatory B Cells ◽

Experimental Autoimmune Uveitis ◽

Autoimmune Uveitis ◽

Experimental Autoimmune

Download Full-text

MBD2 acts as a repressor to maintain the homeostasis of the Th1 program in type 1 diabetes by regulating the STAT1-IFN-γ axis

Cell Death and Differentiation ◽

10.1038/s41418-021-00852-6 ◽

2021 ◽

Author(s):

Tiantian Yue ◽

Fei Sun ◽

Faxi Wang ◽

Chunliang Yang ◽

Jiahui Luo ◽

...

Keyword(s):

Dna Methylation ◽

Type 1 Diabetes ◽

Adoptive Transfer ◽

Nod Mice ◽

Transcriptional Level ◽

Clinical Settings ◽

Cpg Dna ◽

Ifn Γ

AbstractThe methyl-CpG-binding domain 2 (MBD2) interprets DNA methylome-encoded information through binding to the methylated CpG DNA, by which it regulates target gene expression at the transcriptional level. Although derailed DNA methylation has long been recognized to trigger or promote autoimmune responses in type 1 diabetes (T1D), the exact role of MBD2 in T1D pathogenesis, however, remains poorly defined. Herein, we generated an Mbd2 knockout model in the NOD background and found that Mbd2 deficiency exacerbated the development of spontaneous T1D in NOD mice. Adoptive transfer of Mbd2−/− CD4 T cells into NOD.scid mice further confirmed the observation. Mechanistically, Th1 stimulation rendered the Stat1 promoter to undergo a DNA methylation turnover featured by the changes of DNA methylation levels or patterns along with the induction of MBD2 expression, which then bound to the methylated CpG DNA within the Stat1 promoter, by which MBD2 maintains the homeostasis of Th1 program to prevent autoimmunity. As a result, ectopic MBD2 expression alleviated CD4 T cell diabetogenicity following their adoptive transfer into NOD.scid mice. Collectively, our data suggest that MBD2 could be a viable target to develop epigenetic-based therapeutics against T1D in clinical settings.

Download Full-text

P0523PROTECTIVE ROLE OF REGULATORY B CELLS ON THE RENAL TISSUE REPAIRMEN AFTER ISCHEMIA REPERCUSSION INJURY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0523 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Yokota Yunosuke ◽

Goh Kodama ◽

Sakuya Itou ◽

Yosuke Nakayama ◽

Nobukazu Komatsu ◽

...

Keyword(s):

Flow Cytometry ◽

Renal Function ◽

B Cells ◽

Interleukin 10 ◽

Renal Tissue ◽

Protective Role ◽

Regulatory B Cells ◽

Tubulointerstitial Injury ◽

Iri Model

Abstract Background and Aims Acute kidney injury (AKI), even if followed by renal recovery, is a risk factor for the future development of chronic kidney disease (CKD) and end- stage renal disease. It has been postulated that interleukin-10 (IL-10)-producing Regulatory B cells (Breg) play an important role for the tissue repairment in several tissues and organs. Basically, protective role of Breg has been reported in inflammatory bowel disease. In the kidney, it has been shown that IL-10 suppresses renal function decline and improves renal prognosis in IRI model, a typical model of AKI. However, the identity of Breg in the kidney and their origin have not been clarified. Further, how the Breg works during the transition from AKI to CKD is not known. Therefore, first we investigated whether Breg existed in renal tissue on the progression from AKI to CKD in IRI model mice. Further, we performed splenectomy, and examined the renal injury, Breg, and plasma IL-10 levels in this model. Method To examine the existence of Breg in the kidney of IRI model, we used 8-10 weeks-old GFP / IL-10 mice based on C57BL / 6J mice. They are reporter mice for IL-10 producing cells, and can visualize IL-10 producing cells under a fluorescence microscope without fluorescent immunostaining. We prepared following three groups, sham, IRI (unilateral), and IRI + SN (splenectomy) groups. Mice were anesthetized with chloral hydrate (4 g/kg,, intraperitoneal). After making a midline incision, exposed a blood vessel of the left renal pedicles and clamped it for 30 min by clips. one day, 7 days, and 14 days after the surgery, mice were sacrificed, and renal function and plasma IL-10 levels as well as tissue damages by PAS and Masson’s Trichrome staining were assessed. Tissue IL-10-producing cells were detected by flow cytometry. Results There was no difference of plasma IL-10 levels and renal tubulointerstitial injury in IRI group and IRI+SN group on day 1 after IRI. However, on day 7 and day 14, plasma IL-10 levels became gradually higher in IRI group, and SN decreased the increase in IL-10 levels. Tubulointerstitial injury was induced by IRI and SN further worsened tubular damages. Serum Cr and BUN levels were not different in three groups due to normal right kidney. On day 1, number of IL-10-producing B cells increased in the spleen and renal medulla in IRI group confirmed by flow cytometry, which was completely diminished by SN, suggesting that origin of the infiltrated Breg might be spleen, thereby being involved in the protective role in IRI injury in the kidney. Conclusion We report for the first time that Breg might be recruited from spleen by AKI, which may be one of the mechanisms to prevent the progression to CKD.

Download Full-text