CXCL12/SDF-1 in IgG4-Related Disease.

Riccardo Capecchi,Ilaria Puxeddu,Federico Pratesi,Cristina Croia,Andrea Cacciato,Luca Morelli,Daniela Campani,Ugo Boggi,Antonio Tavoni,Paola Migliorini

doi:10.3389/fphar.2021.750216

Riccardo Capecchi, Ilaria Puxeddu + Show 8 more

Open Access

https://doi.org/10.3389/fphar.2021.750216

Copy DOI

Abstract

Background: SDF-1/CXCL12 is a chemokine with pleiotropic functions in hematopoietic stem cell niche homeostasis, germinal center architecture, B cell maturation, neoangiogenesis, and fibrosis. Recently, the CXCL12/CXCR4/CXCR7 axis was associated with cancer metastasis and autoimmune diseases. The IgG4-related disease (IgG4-RD) is a pathological condition characterized by IgG4+ plasma cells infiltrating fibrotic lesions. The aim of this research is to investigate the relevance of SDF-1/CXCL12 in IgG4-RD. Materials and Methods: Peripheral blood samples were collected before therapy from a single-center cohort of 28 IgG4-RD patients, fulfilling the ACR-EULAR classification criteria. Clinical and serological data were obtained for each patient. In total, 14 healthy donors (NHS), 9 patients with pancreatic ductal adenocarcinoma (PDAC), and 9 with Sjogren syndrome (SSj) were recruited as controls and screened for circulating SDF-1/CXCL12 by ELISA. Moreover, paraffin-embedded pancreatic biopsies obtained from patients with IgG4-RD (n = 7), non-autoimmune pancreatitis (n = 3), PDAC (n = 5), and control tissues (n = 4) were analyzed to study the tissue expression and localization of SDF-1/CXCL12 and one of its receptors, CXCR4, and their potential relation with neutrophil extracellular traps (NETs). Results: IgG4-RD patients had higher serum levels of SDF-1/CXCL12 than normal controls (p = 0.0137). Cytokine levels did not differ between the IgG4-RD autoimmune pancreatitis (AIP) and retroperitoneal fibrosis nor between the single- and multiple-organ involvement. No correlation was seen with the IgG4-RD Responder Index, IgG4 levels, white blood cells, or inflammatory markers in the serum. When compared to SSj, the IgG4-RD AIP subgroup presents higher amounts of serum SDF-1/CXCL12 (p = 0.0275), while no differences are seen in comparison with PDAC. The expression of SDF-1/CXCL12 in the tissue was significantly higher in the IgG4-RD tissue than the normal pancreas, and the tissue with the high SDF-1/CXCL12 expression is characterized by the overall inflammatory cell infiltration, fibrosis, and high level of NETs. Conclusion: Modulating B cell development, neoangiogenesis and fibrosis, and SDF-1/CXCL12 may play a role in IgG4-RD. The higher levels observed in IgG4-RD, as compared to SSj, which closely mimics the disease, can be related to a different pattern of lesions, with prevalent fibrosis seen in IgG4-RD. Taken together, these findings suggest that drugs acting on the CXCL12/CXCR4/CXCR7 axis may affect IgG4-RD.

Highlights

IgG4-related disease (IgG4-RD) is a rare condition characterized by fibro-inflammatory lesions in one or many organs with peculiar histological features, such as tissue fibrosis with a storiform pattern, a diffuse lymphoplasmacytic infiltrate, obliterative phlebitis, mild to moderate eosinophil infiltrate, and abundance of IgG4+ plasma cells (Deshpande et al, 2012; Stone et al, 2012; Inoue et al, 2015).Oligoclonal somatically hypermutated plasmablasts that produce IgG4 are detected in the peripheral blood (Mattoo et al, 2014; Doorenspleet et al, 2016)
The levels of SDF-1/CXCL12 in the sera of IgG4-RD patients and controls were measured by ELISA (Human SDF-1/CXCL12 Quantikine, R&D Systems, Inc., Minneapolis, MN, USA), according to the manufacturer’s instructions
The results indicate that chemokine is overexpressed in the sera of IgG4-RD at levels comparable to what was observed in pancreatic ductal adenocarcinoma (PDAC) patients

Summary

Introduction

IgG4-related disease (IgG4-RD) is a rare condition characterized by fibro-inflammatory lesions in one or many organs with peculiar histological features, such as tissue fibrosis with a storiform pattern, a diffuse lymphoplasmacytic infiltrate, obliterative phlebitis, mild to moderate eosinophil infiltrate, and abundance of IgG4+ plasma cells (Deshpande et al, 2012; Stone et al, 2012; Inoue et al, 2015). Oligoclonal somatically hypermutated plasmablasts that produce IgG4 are detected in the peripheral blood (Mattoo et al, 2014; Doorenspleet et al, 2016). This population of B cells may be considered as a biomarker of the disease and as a disease activity marker. The aim of this research is to investigate the relevance of SDF-1/CXCL12 in IgG4-RD

Objectives

Methods

Results

Discussion

Conclusion