Atomistic scattering modeling of the solution structure of human dimeric IgA1 reveals a structural and mechanistic basis for IgA nephropathy.

IgA nephropathy (IgAN) is characterized by mesangial deposition of J-chain containing dimeric IgA1 (dIgA1). Given that deposited IgA1 is mostly dIgA1, solution structure determinations of dIgA1 in phenotyped patients may be relevant to the pathogenesis of IgAN. Thus, dIgA1 from three IgAN patients and a healthy control was isolated. Biochemically, the dIgA1 structures were correlated with serum IgA-IgG immune complex levels, activated human mesangial cells interleukin-6 production, and the pattern of IgA1 N- and O-glycosylation. The degree of dIgA1 hinge O-glycosylation varied between the four subjects, being lower in IgAN subjects with an active renal biopsy Oxford score and clinically progressive IgAN. Their solution structures were investigated using analytical ultracentrifugation and small angle X-ray and neutron scattering. The increased O-glycosylation of the dIgA1 hinge was associated with larger X-ray radii of gyration Rg0 (healthy control, 8.75 ± 0.05 nm; patient A, 8.90±0.06 nm) compared to subjects with reduced O-glycosylation that showed more compact structures (patient B, 8.62±0.05 nm and patient C, 8.62±0.07 nm). Similar findings were observed by neutron scattering. Atomistic modeling of the X-ray data identified 100 best-fit structures that accounted for the scattering curves for each of the four dIgA1 samples. Analysis of these structures showed that the angle between the main axes of the two monomers in the dimeric structures for the three patients is slightly reduced compared to that of the healthy control. This difference implicates conformational change in the overall dIgA1 structure that may increase mesangial IgA deposition and ability to generate renal injury.