Possible mechanisms for the production of anti-β2-spectrin IgA antibodies in IgA nephropathy

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Possible mechanisms for the production of anti-β2-spectrin IgA antibodies in IgA nephropathy

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Co-author 1

Yoshihito Nihei y-nihei@juntendo.ac.jp Juntendo University Department of Nephrology Tokyo Japan *

Co-author 2

Sho Hamaguchi s-hamaguchi@juntendo.ac.jp Juntendo University Department of Nephrology Tokyo Japan -

Co-author 3

Kei Ogiwara k-ogiwara@juntendo.ac.jp Juntendo University Department of Nephrology Tokyo Japan -

Co-author 4

Nozumi Kadota n.kadota.tn@juntendo.ac.jp Juntendo University Department of Nephrology Tokyo Japan -

Co-author 5

Kazuaki Mori kz-mori@juntendo.ac.jp Juntendo University Department of Nephrology Tokyo Japan -

Co-author 6

Eriko Kosuge e.kosuge.ak@juntendo.ac.jp Juntendo University Department of Nephrology Tokyo Japan -

Co-author 7

Wataru Suda wataru.suda@riken.jp RIKEN Center for Integrative Medical Sciences Laboratory for Symbiotic Microbiome Sciences Kanagawa Japan -

Co-author 8

Hitoshi Suzuki shitoshi@juntendo.ac.jp Juntendo University Urayasu hospital Department of Nephrology Chiba Japan -

Co-author 9

Yusuke Suzuki yusuke@juntendo.ac.jp Juntendo University Department of Nephrology Tokyo Japan -

Co-author 10

Co-author 11

Co-author 12

Co-author 13

Co-author 14

Co-author 15

Introduction

IgA nephropathy (IgAN) is mediated by immune complexes containing galactose-deficient IgA (Gd-IgA1), but antigen specificity of Gd-IgA1 had been unclear in the pathogenesis of IgAN. We recently reported the presence of IgA autoantibodies specific to β2-spectrin, selectively expressed on the mesangial cell surface, in the sera of patients with IgAN (Sci. Adv. 2023.). Serum anti-β2-spectrin IgA antibodies were specifically detected in patients with IgAN and found to be enriched for galactose-deficient IgA1 (Kidney Int. Rep. 2025.). Thus, we expanded the etiologic concept of IgAN as an autoimmune glomerulonephritis associated with tissue-specific autoantibodies. (Int. Immunol. 2025.). In this study, we aimed to elucidate the mechanism of production of anti-β2-spectrin IgA antibodies. Since nephritogenic IgA production in IgAN is thought to be driven by mucosal bacterial stimuli, we hypothesized that anti-β2-spectrin IgA autoantibodies are generated by mucosal bacteria through a mechanism of molecular mimicry.

Methods

We sorted approximately 1000 IgA+ plasma cells from the tonsils of patients with chronic tonsillitis (CT) and IgAN, and the genes encoding the variable regions of the heavy and light chains in each plasma cell were sequenced. Based on these unbiased and paired B cell receptor repertoire sequencing analysis, we generated panels of IgAN- and CT-tonsil derived recombinant antibodies (trAbs), and then evaluated the binding of the trAbs to mesangial autoantigens and oral bacteria. BALB/c mice were subcutaneously immunized with heat-killed bacteria and CFA.

Results

The binding of the trAbs to human mesangial cells (HMCs) were evaluated by ELISA, Western blot, and immunofluorescence staining. Four clones from IgAN patients recognized HMCs whereas the trAbs from patients with CT did not. Among these four clones, trAb#9 strongly recognized β2-spectrin. Bacterial FCM revealed that trAb#9 bound to the oral bacterial strain isolated from patients with IgAN (C#31-3-3: tentatively named by its colony number), suggesting the structural similarity between β2-spectrin and this bacterium. The BALB/c mice immunized with C#31-3-3 showed an increased level of serum autoantibodies against β2-spectrin, and immunoglobulin deposits in glomeruli.

Conclusion

We identified the oral bacteria responsible for generating anti-β2-spectrin IgA antibodies. Molecular mimicry between mesangial autoantigen and mucosal bacteria may be involved in pathogenesis of IgAN.

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