Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus
Amedeo Cappione III, … , Gregg Silverman, Iñaki Sanz
Amedeo Cappione III, … , Gregg Silverman, Iñaki Sanz
Published November 1, 2005
Citation Information: J Clin Invest. 2005;115(11):3205-3216. https://doi.org/10.1172/JCI24179.
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Research Article Autoimmunity

Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus

Abstract

Breach of B cell tolerance is central to the pathogenesis of systemic lupus erythematosus (SLE). However, how B cell tolerance is subverted in human SLE is poorly understood due to difficulties in identifying relevant autoreactive B cells and in obtaining lymphoid tissue. We have circumvented these limitations by using tonsil biopsies to study autoreactive B cells (9G4 B cells), whose regulation is abnormal in SLE. Here we show that 9G4 B cells are physiologically excluded during the early stages of the GC reaction before acquiring a centroblast phenotype. Furthermore, we provide evidence to indicate that an anergic response to B cell receptor stimulation may be responsible for such behavior. In contrast, in SLE, 9G4 B cells progressed unimpeded through this checkpoint, successfully participated in GC reactions, and expanded within the post-GC IgG memory and plasma cell compartments. The faulty regulation of 9G4 B cells was not shared by RA patients. To our knowledge, this work represents the first comparative analysis of the fate of a specific autoreactive human B cell population. The results identify a defective tolerance checkpoint that appears to be specific for human SLE.

Authors

Amedeo Cappione III, Jennifer H. Anolik, Aimee Pugh-Bernard, Jennifer Barnard, Paul Dutcher, Gregg Silverman, Iñaki Sanz

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Figure 4

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9G4 cells are normally censored at the GC founder stage. (A) The left do...
9G4 cells are normally censored at the GC founder stage. (A) The left dot plot is representative of normal tonsils, demonstrating a prominent GC founder population (fraction e). As shown in the dot plot on the right, even in these tonsils, 9G4 B cells fail to progress past the pre-GC compartment and are scarce among GC founders. (B) Tonsils were analyzed for the expression of developmental markers CD10, CD44, and CD27 on conventional Bm1–Bm5 subsets (fractions a, b, f, and g). Pre-GC/Bm2′ cells were further divided into 3 fractions (c–e), with e containing the putative GC founders. As shown in the corresponding histograms, CD10 (a GC marker) was progressively acquired in fractions c–f, while CD44 (a marker downregulated in GC) was progressively lost. CD27 also experienced progressive upregulation in fractions c–f. Strikingly, the highest expression of the nuclear proliferation protein Ki67 was observed in fraction e. These results are consistent with fraction e representing GC founders undergoing the initial phases of clonal expansion. Importantly, the majority of 9G4 B cells was lost during pre-GC progression, greatly underrepresented among GC founders, and failed to expand within the GC, where their frequency continued to decline. (C) The scarce 9G4 B cells present within the GC founder and GC compartments were further analyzed for intracellular Ki67 expression. Consistent with their inability to form productive GC reactions, and in contrast to total B cells within these fractions, 9G4 B cells expressed very low levels of Ki67.