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In IgA nephropathy (IgAN), the detailed characteristics of nephritogenic IgA are still unclear. Recently, we have identified novel IgA type autoantibodies against mesangial autoantigen, βII-spectrin, in serum from patients with IgAN (Science Advances, 2023). Serum anti-βII-spectrin IgA (anti-SPTBN1 IgA) can bind to β2 Spectrin expressed on cell surface of mesangial cells; thus, we provided the novel pathogenesis of IgAN as a tissue-specific autoimmune disease rather than an immune-complex disease. Anti-SPTBN1 IgA was positive in the sera of 60% or 30% of patients with IgAN, analyzed by Western blot or enzyme-linked immuno sorbent assay (ELISA) respectively, but scarcely in the serum from healthy individuals. However, the clinical characteristics of anti-SPTBN1 IgA remains undetermined.
To evaluate the specificity of anti-SPTBN1 IgA, serum anti-SPTBN1 IgA were measured by ELISA in patients with IgAN or other kidney diseases (disease control: DC) from a Japanese cohort and those from a United Kingdom (UK) cohort. Clinicopathological characteristics were analyzed in patients with IgAN who were positive for anti-SPTBN1 IgA and those who were negative. We measured the titers of anti-SPTBN1 IgA before and after treatment in IgAN patients with positive for anti-SPTBN1 IgA.
In a Japanese cohort, 15 of 70 IgAN patients had anti-SPTBN1 IgA while no DC patients were positive for anti-FL-SPTBN1 IgA, based on a cutoff value of the 99% confidence intervals (CI: mean +2.58 SD of DC). In a UK cohort, 15 of 49 IgAN patients possessed anti-SPTBN1 IgA in serum while one of the patients with membranous nephropathy and two of the patients with ANCA-related vasculitis tested positive. Overall, 3 of 51 DC and 30 of 119 patients with IgAN were positive for anti-SPTBN1 IgA. There are no differences in eGFR, proteinuria, or histopathological findings between IgAN patients with positive and negative for serum anti-SPTBN1 IgA at the time of renal biopsy. Titer of serum anti-SPTBN1 IgA in patients with IgAN decreased after the treatment with amelioration of hematuria and proteinuria.
We found that anti-SPTBN1 IgA were detected in patients with IgAN with high specificity across races and decreased by treatment with improvement in hematuria and proteinuria. Our findings provide the clinical evidence that anti-SPTBN1 IgA is involved in the pathogenesis of IgAN. Such IgA autoantibody against mesangial cells can be a novel therapeutic target of IgAN.