Proteogenomic analysis of the autoreactive B cell repertoire in blood and tissues of patients with Sjögren’s syndrome

Broeren, Mathijs G A; Wang, Jing J.; Balzaretti, G; Groenen, Patricia J.T.A.; Schaik, Barbera D. C. van; Chataway, Tim; Kaffa, Charlotte; Bervoets, Sander; Hebeda, Konnie M.; Bounova, Gergana; Pruijn, Ger J. M.; Gordon, Thomas P.; Vries, Niek de; Thurlings, Rogier M.

doi:10.1136/annrheumdis-2021-221604

Cited by 19 publications

(28 citation statements)

References 35 publications

(84 reference statements)

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“…Intraclonal diversification is limited in the peripheral blood compared to the intraclonal diversification in the eMZL clonotype in the diagnostic biopsy and SHM levels are variable in the peripheral blood over time to diagnosis Intraclonal diversification as a consequence of high levels of somatic hypermutation is a well described feature of eMZL lymphomas in pSS (6). In the diagnostic tissue biopsies we indeed observed extensive intraclonal diversification (Figures 4B, D).…”

Section: Abundant and Persistent Clonotypes With Rf-like Features May...mentioning

confidence: 60%

“…Intraclonal diversification as a consequence of high levels of somatic hypermutation is a well described feature of eMZL lymphomas in pSS ( 6 ). In the diagnostic tissue biopsies we indeed observed extensive intraclonal diversification ( Figures 4B, D ).…”

Section: Resultsmentioning

confidence: 99%

“…Strikingly, parotid eMZL in pSS frequently express antibodies with RF activity, suggesting autoreactivity is an early driver during lymphoma development (6,7). RF clones were previously shown to be enriched in inflamed tissues, particularly during pSS-related eMZL development (6). Therefore, a putative model for parotid eMZL lymphomagenesis has been proposed where RF clones organize in ectopic germinal center-like structures in a salivary gland, stimulating somatic hypermutation, proliferation and accumulation of driver mutations (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

“…Lymphoma is the main cause of a decreased survival in pSS ( 5 ). Strikingly, parotid eMZL in pSS frequently express antibodies with RF activity, suggesting autoreactivity is an early driver during lymphoma development ( 6 , 7 ). RF clones were previously shown to be enriched in inflamed tissues, particularly during pSS-related eMZL development ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

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Extranodal marginal zone lymphoma clonotypes are detectable prior to eMZL diagnosis in tissue biopsies and peripheral blood of Sjögren’s syndrome patients through immunogenetics

et al. 2023

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IntroductionActivated B cells play a key role in the pathogenesis of primary Sjögren’s syndrome (pSS) through the production of autoantibodies and the development of ectopic germinal centers in the salivary glands and other affected sites. Around 5-10% of pSS patients develop B-cell lymphoma, usually extranodal marginal zone lymphomas (eMZL) of the mucosa-associated lymphoid tissue (MALT). The aim of the current study is to investigate if the eMZL clonotype is detectable in prediagnostic blood and tissue biopsies of pSS patients.Methods/ResultsWe studied prediagnostic tissue biopsies of three pSS patients diagnosed with eMZL and four pSS controls through immunoglobulin (IG) gene repertoire sequencing. In all three cases, we observed the eMZL clonotype in prediagnostic tissue biopsies. Among controls, we observed transient elevation of clonotypes in two pSS patients. To evaluate if eMZL clonotypes may also be detected in the circulation, we sequenced a peripheral blood mononuclear cell (PBMC) sample drawn at eMZL diagnosis and two years prior to eMZL relapse in two pSS patients. The eMZL clonotype was detected in the peripheral blood prior to diagnosis in both cases. Next, we selected three pSS patients who developed eMZL lymphoma and five additional pSS patients who remained lymphoma-free. We sequenced the IG heavy chain (IGH) gene repertoire in PBMC samples taken a median of three years before eMZL diagnosis. In two out of three eMZL patients, the dominant clonotype in the prediagnostic PBMC samples matched the eMZL clonotype in the diagnostic biopsy. The eMZL clonotypes observed consisted of stereotypic IGHV gene combinations (IGHV1-69/IGHJ4 and IGHV4-59/IGHJ5) associated with rheumatoid factor activity, a previously reported feature of eMZL in pSS.DiscussionIn conclusion, our results indicate that eMZL clonotypes in pSS patients are detectable prior to overt eMZL diagnosis in both tissue biopsies and peripheral blood through immunogenetic sequencing, paving the way for the development of improved methods of early detection of eMZL.

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Section: Abundant and Persistent Clonotypes With Rf-like Features May...mentioning

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Extranodal marginal zone lymphoma clonotypes are detectable prior to eMZL diagnosis in tissue biopsies and peripheral blood of Sjögren’s syndrome patients through immunogenetics

et al. 2023

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“…This gives insight in the composition of the infiltrate and enables quantification of large numbers of IG clonotypes, including usage of V and J genes. Mainly high-affinity stereotypic rheumatoid factor producing B-cells from the autoreactive, often oligoclonal to polyclonal environment, show clonal evolution to BCL ( 42 – 44 ). Early detection and monitoring of these clones in the background of inflammation, by NGS-based clonality testing, is expected to be useful in the management of Sjs patients at high risk of lymphoma development.…”

Section: Potential Clinical Applicationsmentioning

confidence: 99%

Read the clonotype: Next-generation sequencing-based lymphocyte clonality analysis and perspectives for application in pathology

Groenen

Brand²,

Kroeze³

et al. 2023

Front. Oncol.

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Clonality assessment using the unique rearrangements of immunoglobulin (IG) and T-cell receptor (TR) genes in lymphocytes is a widely applied supplementary test for the diagnosis of B-cell and T-cell lymphoma. To enable a more sensitive detection and a more precise comparison of clones compared with conventional clonality analysis based on fragment analysis, the EuroClonality NGS Working Group developed and validated a next-generation sequencing (NGS)-based clonality assay for detection of the IG heavy and kappa light chain and TR gene rearrangements for formalin-fixed and paraffin-embedded tissues. We outline the features and advantages of NGS-based clonality detection and discuss potential applications for NGS-based clonality testing in pathology, including site specific lymphoproliferations, immunodeficiency and autoimmune disease and primary and relapsed lymphomas. Also, we briefly discuss the role of T-cell repertoire of reactive lymphocytic infiltrations in solid tumors and B-lymphoma.

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Phases and Natural History of Sjögren's Disease: A New Model for an Old Disease?

Lee

Wang

Gordon

et al. 2023

Arthritis Care & Research

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Sjögren's disease (SjD) is an archetypal and heterogenous autoimmune disorder that is characterized by exocrine glandular dysfunction. A proportion of patients develop severe extraglandular manifestations, such as cryoglobulinemia, and have an increased risk of lymphoma, both of which can adversely affect quality of life and occasionally mortality. As with most autoimmune disorders, the pathogenesis is poorly understood and difficult to predict, and, frustratingly, there is a lack of targeted therapies to cure this disease. We review the disease manifestations of SjD and propose a staged model for understanding the evolution of pathology. In longitudinal studies, most patients remain relatively stable in terms of their laboratory and clinical parameters. However, in the setting of various risk factors, a proportion of patients develop severe symptoms and/or lymphoma. We discuss potential underlying mechanisms for disease progression and the strengths and limitations of using a staged model to correlate the pathogenesis and spectrum of manifestations in SjD. Ultimately, understanding how and why some patients remain relatively stable, whereas others progress and develop florid systemic disease and a fraction develop lymphoma, is key to developing preventative and therapeutic treatments.

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Proteogenomic analysis of the autoreactive B cell repertoire in blood and tissues of patients with Sjögren’s syndrome

Cited by 19 publications

References 35 publications

Extranodal marginal zone lymphoma clonotypes are detectable prior to eMZL diagnosis in tissue biopsies and peripheral blood of Sjögren’s syndrome patients through immunogenetics

Extranodal marginal zone lymphoma clonotypes are detectable prior to eMZL diagnosis in tissue biopsies and peripheral blood of Sjögren’s syndrome patients through immunogenetics

Read the clonotype: Next-generation sequencing-based lymphocyte clonality analysis and perspectives for application in pathology

Phases and Natural History of Sjögren's Disease: A New Model for an Old Disease?

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