Patterns of ANA+ B cells for SLE patient stratification
Jolien Suurmond, Yemil Atisha-Fregoso, Ashley N. Barlev, Silvia A. Calderon, Meggan C. Mackay, Cynthia Aranow, Betty Diamond
Jolien Suurmond, Yemil Atisha-Fregoso, Ashley N. Barlev, Silvia A. Calderon, Meggan C. Mackay, Cynthia Aranow, Betty Diamond
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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 1

Distinct phenotypes of ANA+ B cells and PC in SLE patients.

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Distinct phenotypes of ANA+ B cells and PC in SLE patients. (A–F) Freque...
(A–F) Frequencies of ANA+ and total B cell subsets in healthy controls (n = 15) and SLE patients (n = 36). Each dot indicates an individual, and the bars represent the median. *P < 0.05; **P < 0.01, using Mann-Whitney test. (G and H) Principal component analysis of all B cell parameters analyzed (frequencies of ANA+ and total B cell and PC subsets). The percentage indicated on the axis is the percentage of variance explained by that principal component. SLE patients were separated based on whether they displayed an increase in the frequency of ANA+ IgG PCs compared with healthy controls (quartile 3 + 1.5 × interquartile range). Patients without expansion are denoted as “cluster 0.” (G) 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. (H) The coordinates of each healthy individual and SLE patient. Ellipses represent the 95% confidence interval for each group. (I) Frequency of ANA+ IgG+ memory B cells and ANA+ PCs in SLE patients with an expansion of ANA+ PCs. Each dot indicates a patient (n = 22). (J) Relative proportion of ANA+ IgG memory B cells and ANA+ IgM and IgG PCs in healthy controls and SLE patients. The median and range of SLEDAI scores is shown below each circle. Patients were defined as “cluster 1” when their ANA+ PCs were >20% of the total ANA+ antigen-experienced cells (memory B cells and PCs). Patients were defined as “cluster 2” when their ANA+ PCs were <20% of the total ANA+ antigen-experienced cells. (K) Principal component analysis as in C and D, here only showing patients from cluster 1 and 2. ANA, antinuclear antibody; HC, healthy control; PC, plasmablast/plasma cell; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index.