Abstract
The nucleus is the target of autoantibodies in many diseases, which suggests intrinsic nuclear adjuvants that confer its high autoimmunogenicity. Nucleolin (NCL) is one abundant nucleolar autoantigen in systemic lupus erythematosus (SLE) patients and, in lupus-prone mice, it elicits autoantibodies early. With purified NCL, we observed that it was a potent alarmin that activated monocytes, macrophages and dendritic cells and it was a ligand for TLR2 and TLR4. NCL released by necrotic cells also exhibited alarmin activity. The NCL alarmin activity resides in its glycine/arginine-rich (GAR/RGG) motif and can be displayed by synthetic GAR/RGG peptides. Two more GAR/RGG-containing nucleolar proteins, fibrillarin (FBRL) and GAR1, were also confirmed to be novel alarmins. Therefore, the GAR/RGG alarmin motif predicts a family of nucleolar alarmins. The apparent prevalence of nucleolar alarmins suggests their positive contribution to tissue homeostasis by inducing self-limiting tissue inflammation with autoimmunity only occurring when surveillance is broken down.
Highlights
Despite of the central tolerance mechanisms, polyreactive B cells remain common in the naive repertoire as potential origins of pathogenic autoantibodies[1,2]
TxNE was applied to immobilized non-immune mouse IgG1 (Ms IgG1) and equivalent elution was used as a control
NCL activated macrophages and dendritic cells (DC) (Fig. 1F, G). It consistently induces more cytokines than high mobility group box 1 (HMGB1), which is a ligand for TLR2, TLR4, and TLR540,41
Summary
Despite of the central tolerance mechanisms, polyreactive B cells remain common in the naive repertoire as potential origins of pathogenic autoantibodies[1,2]. In systemic lupus erythematosus (SLE) patients, pathogenic IgG autoantibodies originate from polyreactive B cells and, in mice, polyreactive B cells induce autoreactive germinal centers to activate autoreactive B cells of broader specificity[4,5]. The nucleoli contain abundant RNPs but pro-inflammatory nucleolar RNA or proteins have not been reported[11]. Nucleolin (NCL) is an abundant nucleolar protein with multiple RNA-binding motifs[10,14,15]. It is not a known RNP component but it is a major autoantigen in a subgroup of SLE patients[16]. In lupus-prone mice, NCL-specific autoantibodies appeared early before other autoantibodies, suggesting an early pathogenic role[17]
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