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Loss of an IgG plasma cell checkpoint in patients with lupus.

ABSTRACT: BACKGROUND:IgG antinuclear antibodies (ANAs) are a feature of several autoimmune diseases. These antibodies arise through defects in central or peripheral tolerance checkpoints. The specific checkpoints breached in patients with autoimmune disease are not fully understood. OBJECTIVES:We sought to study whether autoreactive plasma cells in lupus models and patients with systemic lupus erythematosus (SLE) arise as a consequence of defective antigen-specific selection or a global enhancement of IgG plasma cell differentiation. METHODS:We optimized and validated a novel technique to detect naturally occurring ANA+ B cells and plasma cells. RESULTS:We observed a major checkpoint for generation of ANA+ IgG+ plasma cells in both nonautoimmune mice and healthy human subjects. Interestingly, we observed increased numbers of ANA+ IgG+ plasma cells despite normal tolerance checkpoints in immature and naive B cells of lupus-prone MRL/lpr and NZB/W mice, as well as patients with SLE. This increase was due to increased numbers of total IgG+ plasma cells rather than lack of selection against ANA+ plasma cells. CONCLUSION:Using a method that permits quick and accurate quantification of autoreactive B cells and plasma cells in vivo within a native B-cell repertoire in mice and human subjects, we demonstrate the importance of a checkpoint that restricts the generation of IgG plasma cells and protects against IgG ANAs. Our observations suggest a fundamentally revised understanding of SLE: that it is a disease of aberrant B-cell differentiation rather than a defect in antigen-specific B-cell tolerance.

SUBMITTER: Suurmond J

PROVIDER: S-EPMC6451885 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Loss of an IgG plasma cell checkpoint in patients with lupus.

Suurmond Jolien J Atisha-Fregoso Yemil Y Marasco Emiliano E Barlev Ashley N AN Ahmed Naveed N Calderon Silvia A SA Wong Mei Yin MY Mackay Meggan C MC Aranow Cynthia C Diamond Betty B

The Journal of allergy and clinical immunology 20181113 4

<h4>Background</h4>IgG antinuclear antibodies (ANAs) are a feature of several autoimmune diseases. These antibodies arise through defects in central or peripheral tolerance checkpoints. The specific checkpoints breached in patients with autoimmune disease are not fully understood.<h4>Objectives</h4>We sought to study whether autoreactive plasma cells in lupus models and patients with systemic lupus erythematosus (SLE) arise as a consequence of defective antigen-specific selection or a global enh ...[more]

PMID: 30439406

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Project description:ObjectivePlasma thermograms (thermal stability profiles of blood plasma) are being utilized as a new diagnostic approach for clinical assessment. In this study, we investigated the ability of plasma thermograms to classify systemic lupus erythematosus (SLE) patients versus non SLE controls using a sample of 300 SLE and 300 control subjects from the Lupus Family Registry and Repository. Additionally, we evaluated the heterogeneity of thermograms along age, sex, ethnicity, concurrent health conditions and SLE diagnostic criteria.MethodsThermograms were visualized graphically for important differences between covariates and summarized using various measures. A modified linear discriminant analysis was used to segregate SLE versus control subjects on the basis of the thermograms. Classification accuracy was measured based on multiple training/test splits of the data and compared to classification based on SLE serological markers.ResultsMedian sensitivity, specificity, and overall accuracy based on classification using plasma thermograms was 86%, 83%, and 84% compared to 78%, 95%, and 86% based on a combination of five antibody tests. Combining thermogram and serology information together improved sensitivity from 78% to 86% and overall accuracy from 86% to 89% relative to serology alone. Predictive accuracy of thermograms for distinguishing SLE and osteoarthritis / rheumatoid arthritis patients was comparable. Both gender and anemia significantly interacted with disease status for plasma thermograms (p<0.001), with greater separation between SLE and control thermograms for females relative to males and for patients with anemia relative to patients without anemia.ConclusionPlasma thermograms constitute an additional biomarker which may help improve diagnosis of SLE patients, particularly when coupled with standard diagnostic testing. Differences in thermograms according to patient sex, ethnicity, clinical and environmental factors are important considerations for application of thermograms in a clinical setting.

Dataset Information

Loss of an IgG plasma cell checkpoint in patients with lupus.

Publications

Loss of an IgG plasma cell checkpoint in patients with lupus.

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