Serum levels of guanidinylated YB-1 indicate active lupus nephritis

Lupus nephritis (LN) is one of the most severe organ manifestations of systemic lupus erythematosus (SLE). Timely detection of LN is crucial to prompt early treatment and prevent kidney damage. Kidney biopsy remains the gold standard for LN diagnosis. Previous studies linked a guanidinylated form of cold-shock protein Y-box binding protein (YB)-1, denoted YB-1-2G, to SLE pathogenesis. We hypothesized that the presence of YB-1-2G associates with active LN and may serve as new biomarker candidate.

Using MALDI mass spectrometry (MS), we quantified serum YB-1-2G levels in our expanded discovery cohort (n=50) and, for the first time, associated YB-1-2G with clinical and serological markers of disease activity, as well as histological LN classes. These findings were corroborated in a second, independent SLE cohort (n=38). Furthermore, YB-1-2G was analyzed in urine samples, and a novel guanidinylated YB-1 variant with three modified lysine residues (YB-1-3G) was identified in serum. The presence of autoantibodies against YB-1-2G was assessed via peptide-based binding assays.

Serum YB-1-2G was significantly more prevalent in SLE patients with high disease activity and biopsy-proven LN, particularly in proliferative (classes III and IV) and flaring LN forms. Serum YB-1-2G exhibited a sensitivity of 85% for the presence of LN, a specificity of 70%, with strong discriminatory power indicative for kidney involvement in SLE patients (AUC=0.852). YB-1-3G was found in serum and YB-1-2G was also detectable in urine samples from LN patients, yet both were less indicative than serum YB-1-2G. Concordance rates between serum and urinary YB-1-2G were higher during flares. YB-1-2G immunogenicity was confirmed by circulating anti-YB-1-2G autoantibodies in lupus-prone mice and in LN patient sera.

We demonstrate that guanidinylated YB-1 is associated with disease flares and renal activity in SLE patients. Both, YB-1-2G and its autoantibodies exhibit key biomarker traits and warrant further evaluation in larger lupus cohorts.