Patterns of ANA+ B cells for SLE patient stratification
Jolien Suurmond, … , Cynthia Aranow, Betty Diamond
Jolien Suurmond, … , Cynthia Aranow, Betty Diamond
Published May 2, 2019
Citation Information: JCI Insight. 2019;4(9):e127885. https://doi.org/10.1172/jci.insight.127885.
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Research Article Immunology

Patterns of ANA+ B cells for SLE patient stratification

Abstract

IgG antinuclear antibodies (ANAs) are a dominant feature of several autoimmune diseases. We previously showed that systemic lupus erythematosus (SLE) is characterized by increased ANA+ IgG plasmablasts/plasma cells (PCs) through aberrant IgG PC differentiation rather than an antigen-specific tolerance defect. Here, we aimed to understand the differentiation pathways resulting in ANA+ IgG PCs in SLE patients. We demonstrate distinct profiles of ANA+ antigen-experienced B cells in SLE patients, characterized by either a high frequency of PCs or a high frequency of IgG+ memory B cells. This classification of SLE patients was unrelated to disease activity and remained stable over time in almost all patients, suggesting minimal influence of disease activity. A similar classification applies to antigen-specific B cell subsets in mice following primary immunization with T-independent and T-dependent antigens as well as in lupus-prone mouse models (MRL/lpr and NZB/W). We further show that, in both lupus-prone mice and SLE patients, the classification correlates with the serum autoantibody profile. In this study, we identified B cell phenotypes that we propose reflect an extrafollicular pathway for PC differentiation or a germinal center pathway, respectively. The classification we propose can be used to stratify patients for longitudinal studies and clinical trials.

Authors

Jolien Suurmond, Yemil Atisha-Fregoso, Ashley N. Barlev, Silvia A. Calderon, Meggan C. Mackay, Cynthia Aranow, Betty Diamond

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Figure 6

Characteristics of serum autoantibodies in SLE patients.

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Characteristics of serum autoantibodies in SLE patients. (A and B) Profi...
(A and B) Profiles of recognition of nuclear antigens by serum IgG. Patients are separated based on classification, as described in Figure 1, into cluster 1 and cluster 2. (A) Heatmap, including hierarchical clustering based on the profile of antigen recognition. Blocks that show 2 colors represent the patients in which the classification changed over time (Figure 2), in which case the top left triangle represents the classification in the first measurement and the lower right represents the classification in the second measurement. (B) The number of nuclear antigens recognized. Each dot indicates an individual patient, and the bars represent the median. (C) Total ANA-IgG was determined by ELISA. (D and E) Relative affinity of anti-dsDNA IgG was measured in serum of SLE patients by inhibition ELISA. (D) Relative OD (average ± SEM) of each group is shown. (E) IC50 values for each individual patient. (F and G) Principal component analysis of all parameters analyzed (frequencies of ANA+ and total B cell and PC subsets as well as ELISA recognition of nuclear antigens). The percentage indicated on the axis is the percentage of variance explained by that principal component. A selection of the vectors for direction of parameters is shown here. The parameters omitted here (ANA+ and total transitional and naive B cells) are shown in Figure 1G. Their directionality remained the same. SLE patients were clustered as described in Figure 1. (F) The variables contributing to each dimension in principal component analysis. The length and direction of each arrow shows the strength of their contribution to each PC. (G) The coordinates of each SLE patient. Ellipses represent the 95% confidence interval for each group. *P < 0.05, using Mann Whitney U test. ANA, antinuclear antibody; PC, plasmablast/plasma cell; SS-A/B, anti–Sjögren’s syndrome–related antigen; Sm, Smith antigen; SLE, systemic lupus erythematosus.