Salivary glands of primary Sjogren's syndrome patients express factors vital for plasma cell survival

Ewa A Szyszko,Karl A Brokstad,Roland Jonsson,Kathrine Skarstein,Malin V Jonsson,Gunnvor Oijordsbakken

doi:10.1186/ar3220

Ewa A Szyszko, Karl A Brokstad + Show 4 more

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https://doi.org/10.1186/ar3220

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Abstract

IntroductionThe presence of circulating Ro/SSA and La/SSB autoantibodies has become an important marker in the classification criteria for primary Sjögren's syndrome (pSS). Plasma cells producing these autoantibodies are mainly high affinity plasma cells originating from germinal centre reactions. When exposed to the right microenvironment these autoimmune plasma cells become long-lived and resistant to immunosuppressive treatment. Since autoimmune plasma cells have been detected in the salivary glands of SS patients, we wanted to investigate if the glandular microenvironment is suitable for plasma cell survival and if glandular residing plasma cells are the long-lived plasma cell subset.MethodsSingle, double and triple immunohistochemistry as well as immunofluorescence staining was performed on minor salivary gland tissue retrieved from pSS, chronically inflamed and normal subjects.ResultsWe detected significant numbers of CD138+, non-proliferating, Bcl-2 expressing plasma cells in the salivary glands of pSS patients with high focus score (FS). Furthermore, we demonstrated that CXCL12 and interleukin (IL)-6 survival factors were highly expressed in pSS salivary gland epithelium and by focal mononuclear infiltrating cells. Notably, adipocytes when present in the salivary gland tissue were an important source of CXCL12. We clearly demonstrate that plasma cells are localised in close proximity to CXCL12 and IL-6 expressing cells and thus that the environment of salivary glands with high FS provide factors vital for plasma cell survival.ConclusionsPlasma cells residing in the salivary glands of pSS patients with high FS showed phenotypic characteristics of the long-lived plasma cell subtype. Furthermore, the pSS salivary gland microenvironment provided niches rich in factors vital for plasma cell survival.

Highlights

The presence of circulating Ro/SSA and La/SSB autoantibodies has become an important marker in the classification criteria for primary Sjögren’s syndrome
We demonstrated that CXCL12 and interleukin (IL)-6 survival factors were highly expressed in primary Sjögren’s syndrome (pSS) salivary gland epithelium and by focal mononuclear infiltrating cells
We clearly demonstrate that plasma cells are localised in close proximity to CXCL12 and IL-6 expressing cells and that the environment of salivary glands with high focus score (FS) provide factors vital for plasma cell survival

Summary

Introduction

The presence of circulating Ro/SSA and La/SSB autoantibodies has become an important marker in the classification criteria for primary Sjögren’s syndrome (pSS). Sjögren’s syndrome (SS) is a heterogeneous autoimmune disease characterized by focal mononuclear cell infiltration in the exocrine glands and high serum titres of Ro/ SSA, La/SSB and rheumatoid factor (RF) autoantibodies Plasma cells producing these autoantibodies are primarily class-switched, somatically mutated IgG plasma cells that origin from germinal centers (GCs) reactions [1]. Together with the fact that both Ro and La antigens have been detected in the salivary glands of SS patients [16,17] there exists a possibility that autoimmune plasma cells are produced at the site of inflammation Another possibility is that the glandular microenvironment comprises factors necessary for prolonged plasma cell survival and that autoantibodies are being produced by plasma cells independently of activation and differentiation of new B-cells. The bone marrow subset of plasma cells is often referred to as a long-lived plasma cell subset

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