Background
Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to the selective loss of insulin-producing β-cells by activating the T cells [
1]. The co-stimulatory and co-inhibitory pathways modulate T cells activation and hence play a vital role in T1D. Scientists had made several advances in the past to understand how co-stimulatory and co-inhibitory pathways affect T1D, such as CD28/B7.1, CD40/CD40L, ICOS/ICOSL and PD1/PD-L1 [
2‐
6]. B7-H3, as a co-stimulatory molecule, which belongs to the B7 immunoglobulin superfamily, is frequently increased in response to the autoantigens and pathogens during host T cell immunoregulation [
7].
The biological effect of B7-H3 for its co-stimulatory and co-inhibitory properties remains controversial [
8,
9]. There are studies revealing the capability of B7-H3 in promoting CD4
+ and CD8
+ T cell proliferation, cytotoxic T lymphocytes (CTLs) induction and interferon-gamma (IFN-γ) secretion in vitro [
8,
10]. However, some studies speculated that B7-H3 may also have the inhibitory function. B7-H3 could inhibit the proliferation of CD4
+ and CD8
+ T cells and crucial transcription factors namely nuclear factor of activated T-cells (NFAT), nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1) [
10‐
12]. In neuroblastoma, B7-H3 exerted a protective role and thereby downregulated natural killer (NK) cell function [
13]. Additionally, it was reported that the soluble and membrane form of B7-H3 could inhibit NK cell-mediated lysis in glioma [
14]. Recently, we demonstrated the upregulated expression of sB7-H3 in T1D patients and found the correlation with gender as well as serum levels of creatinine (Cr), blood urea nitrogen (BUN), albumin to creatinine ratio (ACR) and high-density lipoprotein (HDL) [
15]. Nevertheless, the expression and function of B7-H3 in T1D remains unknown.
In the present study, we analyzed the expression of B7-H3 and its clinical significance in T1D patients. We aimed to investigate four single nucleotide polymorphisms (SNPs) of B7-H3 genes to determine its associations with T1D risk in order to find the correlations among B7-H3 haplotype, secretion of soluble B7-H3 and biochemical parameters in T1D.
Discussion
Immune system and disease development are closely related and immune response can protect the body against different types of diseases. Therefore, it is critical to understand the co-stimulatory and co-inhibitory signals on multiple immune cell types in T1D. In this study, our research demonstrated that the expression of mB7-H3 on monocytes was significantly higher than healthy controls. The B7-H3-T-A-C-T polymorphism variant was associated with a decreased risk of T1D and furthermore was correlated with the secretion of sB7-H3 in serum.
The B7 family, including the CD28/B7 axis, ICOS/ICOSL pathway, receptors like TIM3 and B7-H4, is important for the regulation of immune responses mediated by antigen-specific T cells and also has a significant impact on T1D [
21‐
25]. As an important member of the B7 family, the role of B7-H3 (CD276) in T1D remains unclear. B7-H3 was identified in 2001 as a cell surface molecule in the B7 immunoglobulin superfamily, which played an important role in the initiation and termination of immune cell responses as well as cancer development [
8]. However, its receptor has not been identified.
One study found the involvement of B7-H3 in the innate immune monocyte/macrophage-mediated inflammatory response and confirmed that B7-H3 was associated with human sepsis and could augment the inflammatory responses [
26]. In line with the study above, our previous experiments showed that B7-H3 was not expressed on T cells [
18]. In addition to the investigation of the expression of mB7-H3 on CD14
+ monocytes, we also observed increased levels of sB7-H3 in T1D patients when compared with healthy controls. A variety of co-stimulatory molecules exist both in soluble and membrane forms. Soluble co-stimulatory molecules could be produced by proteolytic cleavage and/or splicing of mRNA [
27,
28]. Therefore, soluble form of B7-H3 in T1D may due to the cleavage of its membrane form. High mB7-H3 levels on monocytes along with the upregulation of sB7-H3 in patients suggested its co-stimulatory function, which stimulated the self-tolerance breakdown and thus led to the autoimmunity. Our results revealed that B7-H3 played a stimulatory role in T1D. The basic mechanism of controlling and regulating its production in different types of cells remains to be elucidated.
Since monocytes are the key producers of inflammatory factors and several studies also demonstrated that the intermediate CD14
+ monocytes produced TNF-α in abundance and monocytes may play an essential role in promoting the inflammatory response in T1D [
29,
30]. Previous studies have shown the association of B7-H3 with inflammatory reactions [
26]. B7-H3 could amplify LPS, NF-κB p65 and MAPK p38 signals and make them participate in monocyte/macrophage-mediated inflammatory responses [
26,
31]. B7-H3 also participated in the progression of asthma and augmented the inflammatory response independent of the Toll-like receptor 2 (TLR2) pathways [
32]. Consistent with the above results, our study indicated the proinflammatory role of B7-H3 in the progression of T1D.
In addition, we studied the relationship between clinical features and levels of mB7-H3 in T1D patients. The expression of mB7-H3 was significantly correlated with the secretion of IFN-γ and TNF-α. We accorded these results with initial studies where B7-H3 synergistically promoted the secretion of cytokine IFN-γ and moderately upregulated the TNF-α. Significant correlation of the expression B7-H3 in T1D and the remaining clinical features could be explained with the co-stimulatory effect. Compared with the above results, our former study reported that sB7-H3 and renal function (Cr, BUN, ACR) was positively correlated and assumed that the soluble form may engage in the progression of diabetic nephropathy [
15]. With all these results discussed above, we hypothesized that B7-H3 might act as a co-stimulator of innate immunity, which led to pathological damage by activating inflammatory response as well as enhancing T cell- mediated immune response. The upregulation of B7-H3 in the pathogenesis of T1D resulted in the pancreatic islet suffering autoimmune destructions. Previously, our group reported that patients suffering from rheumatoid arthritis (RA) had a higher frequency of T-A-T-C haplotype of B7-H3, and confirmed that it was associated with RA risk and affected the release of the soluble form from the cell surface [
17]. Herein, B7-H3-T-A-C-T was observed to associate with the protective role of T1D, and similarly, with soluble B7-H3 expression.
Despite the above findings, our research has some shortcomings due to the lack of human samples. In addition, we could not speculate possible answers when having less samples. More detailed study is recommended with larger samples to investigate the existence of a haplotype-dependent distribution pattern for B7-H3 expression in Chinese individuals and T1D patients.
Conclusions
In this study, we found a significant upregulation of mB7-H3 on monocytes and its correlation with several clinical features including ALT, fast C-peptide 120 min, HbAlc, IFN-γ, IL-6 and TNF-α in T1D patients. Moreover, the B7-H3 haplotype T-A-C-T was less frequently observed in T1D patients and was correlated with the decreased levels of soluble form but not the membrane form of B7-H3. Therefore, the B7-H3-T-A-C-T polymorphism variant was associated with less risk of T1D as well as the release of sB7-H3. The findings of this study indicated that B7-H3 might act as a potential biomarker related to the pathogenesis of T1D.
Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit
http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (
http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.