Diminished CXCR5 expression in peripheral blood of patients with Sjögren's syndrome may relate to both genotype and salivary gland homing
L. A. Aqrawi
Rheumatology Unit, Department of Medicine, the Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen
Department of Oral Surgery and Oral Medicine, Institute of Clinical Odontology, University of Oslo, Oslo, Norway
Search for more papers by this authorM. Ivanchenko
Rheumatology Unit, Department of Medicine, the Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorA. Björk
Rheumatology Unit, Department of Medicine, the Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorJ. I. Ramírez Sepúlveda
Rheumatology Unit, Department of Medicine, the Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorJ. Imgenberg-Kreuz
Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Search for more papers by this authorM. Kvarnström
Rheumatology Unit, Department of Medicine, the Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorP. Haselmayer
Global Early Development, Merck KGaA, Darmstadt, Germany
Search for more papers by this authorJ. L. Jensen
Department of Oral Surgery and Oral Medicine, Institute of Clinical Odontology, University of Oslo, Oslo, Norway
Search for more papers by this authorG. Nordmark
Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Search for more papers by this authorK. Chemin
Rheumatology Unit, Department of Medicine, the Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorK. Skarstein
Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen
Department of Pathology, Haukeland University Hospital, Bergen, Norway
Search for more papers by this authorCorresponding Author
M. Wahren-Herlenius
Rheumatology Unit, Department of Medicine, the Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
Correspondence: M. Wahren-Herlenius, Rheumatology Unit, Department of Medicine, Centre for Molecular Medicine, the Karolinska Institute, 171 76 Stockholm, Sweden. E-mail: [email protected]Search for more papers by this authorL. A. Aqrawi
Rheumatology Unit, Department of Medicine, the Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen
Department of Oral Surgery and Oral Medicine, Institute of Clinical Odontology, University of Oslo, Oslo, Norway
Search for more papers by this authorM. Ivanchenko
Rheumatology Unit, Department of Medicine, the Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorA. Björk
Rheumatology Unit, Department of Medicine, the Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorJ. I. Ramírez Sepúlveda
Rheumatology Unit, Department of Medicine, the Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorJ. Imgenberg-Kreuz
Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Search for more papers by this authorM. Kvarnström
Rheumatology Unit, Department of Medicine, the Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorP. Haselmayer
Global Early Development, Merck KGaA, Darmstadt, Germany
Search for more papers by this authorJ. L. Jensen
Department of Oral Surgery and Oral Medicine, Institute of Clinical Odontology, University of Oslo, Oslo, Norway
Search for more papers by this authorG. Nordmark
Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Search for more papers by this authorK. Chemin
Rheumatology Unit, Department of Medicine, the Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorK. Skarstein
Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen
Department of Pathology, Haukeland University Hospital, Bergen, Norway
Search for more papers by this authorCorresponding Author
M. Wahren-Herlenius
Rheumatology Unit, Department of Medicine, the Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
Correspondence: M. Wahren-Herlenius, Rheumatology Unit, Department of Medicine, Centre for Molecular Medicine, the Karolinska Institute, 171 76 Stockholm, Sweden. E-mail: [email protected]Search for more papers by this authorSummary
Genetic investigations of Sjögren's syndrome (SS) have identified a susceptibility locus at p23.3 of chromosome 11, which contains the CXCR5 gene. C-X-C motif chemokine receptor 5 (CXCR5) is a chemokine receptor expressed on B and T cell subsets, and binds the chemotactic ligand C-X-C motif chemokine ligand 13 (CXCL13). In this study we aimed to link the genetic association with functional effects and explore the CXCR5/CXCL13 axis in SS. Expression quantitative trait loci analysis of the 11q23.3 locus was performed using B cell mRNA expression data from genotyped individuals. Lymphocyte surface markers were assessed by flow cytometry, and CXCL13 levels by a proximity extension assay. CXCR5+ and CXCL13+ cells in minor salivary glands were detected using immunohistochemistry. Our results demonstrated that SS-associated genetic polymorphisms affected the expression of CXCR5 (P < 0·01). Notably, a decreased percentage of CXCR5+ cells, with lower CXCR5 expression, was observed for most circulating B and T cell subsets in SS patients, reaching statistical significance in CD19+CD27+immunoglobulin (Ig)D+ marginal zone (P < 0·001), CD19+CD27+IgD– memory (P < 0·05) and CD27-IgD double-negative (P < 0·01) B cells and CD4+CXCR3–CCR6+ Th17 cells (P < 0·05). CXCL13 levels were increased in patient plasma (P < 0·001), and immunohistochemical staining revealed expression of CXCL13 and higher numbers of CXCR5+ cells (P < 0·0001) within focal infiltrates and interstitially in salivary glands of SS patients. In conclusion, we link a genetic susceptibility allele for SS to a functional phenotype in terms of decreased CXCR5 expression. The decrease of CXCR5+ cells in circulation was also related to homing of B and T cells to the autoimmune target organ. Therapeutic drugs targeting the CXCR5/CXCL13 axis may be useful in SS.
Supporting Information
Additional Supporting information may be found in the online version of this article at the publisher's web-site:
| Filename | Description |
|---|---|
| cei13118-sup-0001-suppinfo1.docx12 KB |
Table S1. Overview of antibodies used in flow cytometry. |
| cei13118-sup-0002-suppinfo2.tiff2.9 MB |
Fig. S1. Gating strategy for B cells. |
| cei13118-sup-0003-suppinfo3.tiff2.9 MB |
Fig. S2. Gating strategy for T follicular helper (Tfh) cells. |
| cei13118-sup-0004-suppinfo4.tiff2.9 MB |
Fig. S3. Gating strategy for T helper type 17 (Th17) cells. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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