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

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.

BAFF overexpression increases lymphocytic infiltration in Sjögren's target tissue, but only inefficiently promotes ectopic B-cell differentiation

“…In agreement with the latter studies, we demonstrated here using both cell surface immunophenotyping and gene expression analyses that B cell differentiation did not progress beyond the follicular stage in lacrimal glands from NOD mice, with no signs of GC or plasma cell differentiation markers and gene expression during disease progression. This observation contrasts with what was reported in the glands from pSS patients which show GC formation in 10 to 30% of the cases and striking accumulation of plasma cells with a long-lived phenotype within the target tissue [3][4][5].…”

“…Despite being the second most common rheumatic disease after rheumatoid arthritis, no disease-modifying drug is currently available to treat pSS patients. The histological hallmark of the disease is a multifocal nodular immune infiltration of the exocrine glands, predominantly composed of CD4 + T and B lymphocytes, but also CD8 + T cells and long-lived plasma cells [2][3][4]. In addition, ectopic germinal center (GC)-like structures were observed in 10 to 30% of patients [2,5]; their presence was associated with autoantibody seropositivity, disease activity, and higher risk of developing lymphoma [2,[5][6][7].…”

Sjögren’s syndrome pathological neovascularization is regulated by VEGF-A-stimulated TACE-dependent crosstalk between VEGFR2 and NF-κB

“…The angiogenic effects of VEGF-A may be responsible for the increased number of blood vessels observed in SS salivary glands. 22,23 The enhanced angiogenesis was associated with an increased VEGF-A/VEGFR2 signaling, as demonstrated by the observation of an increased amount of phosphorylated VEGFR2 in SS salivary glands biopsies. Given the critical role of VEGFR2 signaling in angiogenesis, antiRo/SSA Abs-regulated VEGFR2 activation may represent an important mechanism in the control of angiogenesis in SS.…”

Pathogenic Long-Lived Plasma Cells and Their Survival Niches in Autoimmunity, Malignancy, and Allergy

“…However, the role of CD28 might be controversial, as Njau et al (11) reported increased Ig titers and PC numbers in CD28 2/2 chimeras. Whereas the large majority of MPCs are localized in the bone marrow (5,12), LLPCs are also found in lymphatic organs such as spleen (13), lymph nodes (14), mucosa-associated lymphatic tissues (15), as well as in chronically inflamed tissues such as the synovium in rheumatoid arthritis (16), the CNS in induced multiples sclerosis (17), the kidneys in systemic lupus erythematosus (SLE) (18), the salivary glands in Sjögren's syndrome (19), or the lung during chronic airway inflammation in allergy/asthma (20,21). In secondary lymphatic tissues, PCs reside in extrafollicular areas such as the lamina propria of mucosa and the red pulp of spleen, and LLPCs are associated with APRIL, BAFF, and IL-6 sources in the vicinity (14,15,22,23).…”