B cells in Sjögren’s syndrome: from pathophysiology to therapeutic target

Mielle, Julie; Tison, Alice; Cornec, Divi; Daïen, C.; Pers, Jacques‐Olivier

doi:10.1093/rheumatology/key332

Cited by 30 publications

(34 citation statements)

References 146 publications

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“…We have been investigating the possible involvement of BAFF in the pathogenesis of pSS because BAFF plays a pivotal role in B cell activation [7,11,13,15] and is involved in the pathogenesis of diseases associated with antibody formation, such as pSS. For example, several groups have reported that BAFF levels are elevated in the serum of pSS patients [16][17][18] and that this elevation is correlated with the patients' serum IgG and autoantibody levels, such as anti-Ro/SSA and anti-La/SSB antibodies [19,20]. Moreover, BAFF is strongly expressed in lymphocytes that infiltrate the salivary glands [21,22].…”

Section: Introductionmentioning

confidence: 99%

Elevated expression of BAFF receptor, BR3, on monocytes correlates with B cell activation and clinical features of patients with primary Sjögren’s syndrome

et al. 2020

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Background: We reported that the production of BAFF (B cell-activating factor) and IL-6, both of which are involved in survival and differentiation of B cells, is dysregulated in monocytes of patients with primary Sjögren's syndrome (pSS). In this study, we investigate the relationship between possible aberrations of pSS monocytes and clinical features of pSS patients and the contribution of monocytes to B cell activation, a mechanism involved in the pathogenesis of pSS. Methods: Expression of BAFF-receptor (BR3) on peripheral monocytes from patients with pSS (n = 67) and healthy controls (HC: n = 37) was analyzed by FACS. Peripheral monocytes were stimulated with BAFF, and IL-6 production by the cells was measured by ELISA. Peripheral B cells were cultured with BAFF-stimulated monocytes in the presence or absence of anti-IL-6 receptor antibody, and IgG production by the cells was measured by ELISA. Patients' serological data were collected from their clinical records. Patients' disease activity was quantified based on their EULAR Sjögren's syndrome disease activity index (ESSDAI) scores. Results: The proportion of peripheral BR3-positive monocytes (BR3 + /CD14 +) was significantly increased in pSS patients compared to HC. Moreover, IL-6 production by BAFF-stimulated monocytes was remarkably higher than HC and was significantly correlated with BR3 + /CD14 + ratios of patients. In addition, BR3 expression on pSS monocytes was elevated in anti-Ro/SSA and/or anti-La/SSB positive compared to negative patients. Remarkably, BR3 expression on peripheral monocytes was positively and significantly correlated with patients' serum IgG and IgM levels and ESSDAI scores. Moreover, the amount of IgG produced by B cells was markedly higher in pSS patients compared to HC when the cells were co-cultured with BAFF-stimulated autologous monocytes in vitro. Notably, addition of anti-IL-6 receptor antibody into the co-culture system led to inhibition of IgG production by B cells.

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Section: Introductionmentioning

confidence: 99%

Elevated expression of BAFF receptor, BR3, on monocytes correlates with B cell activation and clinical features of patients with primary Sjögren’s syndrome

et al. 2020

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“…Recently, rituximab therapy failed to show a benefit in two clinical trials despite the compelling evidence supporting the key roles of B-cells in disease pathogenesis, such as the high prevalence of autoantibodies and hypergammaglobulinemia, the presence of germinal center–like structures in salivary gland biopsies, the increased risk of non-Hodgkin’s B-cell lymphoma, and genetic studies linking the risk for pSS with polymorphisms in genes critical for B-cell development 7, 8 . The optimism for targeting B-cells was fueled by promising results in early pilot studies of rituximab in pSS 9– 11 .…”

Section: Clinical Trials In Primary Sjögren’s Syndrome: Coming Up Drymentioning

confidence: 99%

“…Despite the failure of rituximab therapy to show a benefit in the TEARS and TRACTISS trials, B-cells remain a focus of interest in the treatment of pSS. A host of studies has demonstrated alterations in peripheral and tissue-resident B-cell subsets, genetic and epigenetic modifications in B-cells, and B-cell microRNA expression profiles 8 . BAFF may promote B-cell over-activation and loss of tolerance in pSS.…”

Section: Identifying Mechanistically Based Therapeutic Targetsmentioning

confidence: 99%

“…Another potential strategy for reducing B-cell activity in pSS is inhibition of PI3Kδ, an intracellular lipid kinase that plays a critical role in B-cell receptor signal transduction 8 . A selective inhibitor of PI3Kδ, called leniolisib, was recently approved for the treatment of chronic lymphocytic leukemia and non-Hodgkin’s lymphoma.…”

Section: Identifying Mechanistically Based Therapeutic Targetsmentioning

confidence: 99%

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Recent advances in the search for a targeted immunomodulatory therapy for primary Sjögren’s syndrome

Leverenz

Clair

2019

F1000Res

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Primary Sjögren’s syndrome is a chronic autoimmune disease characterized by salivary and lacrimal gland dysfunction, leading to substantial morbidity and reduced quality of life. Many patients with primary Sjögren’s syndrome also have extraglandular systemic complications, some of which can be organ- or life-threatening. Over the last decade, numerous targeted immunomodulatory therapies for primary Sjögren’s syndrome have failed to show a benefit in clinical trials, and as yet no disease-modifying therapy has been approved for this disease. Herein, we provide an updated review of the clinical trial landscape for primary Sjögren’s syndrome and the numerous efforts to move the field forward, including the development of new classification criteria and outcome measures, the results of recent clinical trials in this field, the challenges faced in the search for effective therapies, and the expanding pipeline of novel therapies under development.

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“…Importantly, these autoantibodies have been shown to play a pathogenic role (4,7). Besides the occurrence of these autoantibodies, SjS patients are characterized by deep alterations in the frequency of several B lymphocyte populations, both in the blood and in the infiltrated exocrine glands (8)(9)(10). Another hallmark of the disease is the B cell hyperreactivity due to chronic antigenic stimulation, which is initially polyclonal but can progress to monoclonal B cell lymphoproliferation.…”

Section: Introductionmentioning

confidence: 99%

Autoimmune B Cell Repertoire in a Mouse Model of Sjögren’s Syndrome

et al. 2021

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In genetically prone individuals, chronic immune activation may lead to expansion of autoreactive lymphocyte clones that can induce organ damage developing autoimmune disorders. Sjögren’s Syndrome (SjS) is a systemic chronic autoimmune disease that primarily affects exocrine glands. Despite the accumulated evidences of profound B-cell alterations of humoral immunity, the repertoire and development of B-cell autoreactivity in SjS remains to be determined. We hypothesize that SjS mice will have an increased frequency of self-reactive B cells with a progressive evolution to antigen-driven oligoclonality. Here, we study the B cell repertoire of NOD.H-2h4 mice, a mouse model of spontaneous autoimmunity mimicking SjS without developing diabetes. A library of 168 hybridomas from NOD.H-2h4 mice and 186 C57BL/6J splenocytes at different ages was created. The presence of mono or polyreactive autoantibodies to several antigens was evaluated by ELISA, and their staining patterns and cellular reactivity were tested by IFA and FACS. We observed a higher frequency of autoreactivity among B-cell clones from NOD.H-2h4 mice as compared to wild-type mice. The presence of polyreactive and autoreactive IgG clones increased with mice age. Strikingly, all anti-Ro52 autoantibodies were polyreactive. No loss of polyreactivity was observed upon antibody class switching to IgG. There was a progression to oligoclonality in IgG B cells with mice aging. Our results indicate that in the NOD.H-2h4 mouse model of SjS, IgG+ B cells are mainly polyreactive and might expand following an unknown antigen-driven positive selection process.

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B cells in Sjögren’s syndrome: from pathophysiology to therapeutic target

Cited by 30 publications

References 146 publications

Elevated expression of BAFF receptor, BR3, on monocytes correlates with B cell activation and clinical features of patients with primary Sjögren’s syndrome

Elevated expression of BAFF receptor, BR3, on monocytes correlates with B cell activation and clinical features of patients with primary Sjögren’s syndrome

Recent advances in the search for a targeted immunomodulatory therapy for primary Sjögren’s syndrome

Autoimmune B Cell Repertoire in a Mouse Model of Sjögren’s Syndrome

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