Dataset Information

Deletions in VANGL1 are a novel risk factor for antibody mediated kidney disease

ABSTRACT: Kidney involvement is one of the most devastating manifestations of systemic lupus erythematosus. Approximately half of all SLE patients develop kidney involvement yet the mechanisms predisposing to nephritis are unelucidated. Genetic variance is a potent risk factor for development of SLE, yet limited evidence of the contribution to specific organ involvement exists. Using an Affymetrix SNP array and qPCR we identified a recurrent intronic copy number variation (CNV) in intron 8 of Van Gogh Like 1 (VANGL1) which associated with nephritis. To model the effect of VANGL1 deficiency we obtained Vangl1 deficient mice. Kidneys from Vangl1+/- mice were cryopreserved and sections stained for immunoglobulin. Vangl1+/- developed spontaneous IgA and IgG deposition within the glomerular mesangium with no evidence of proteinuria or inflammation. Vangl1+/- had normal lymphocyte populations by flow cytometry and were ANA negative. Serum transfer into a B cell deficient Vangl1+/- mice resulted in IgG deposition, but not in B cell deficient Vangl1+/+ mice suggesting that immunoglobulin deposition occurs in a kidney intrinsic fashion. We have identified a recurrent copy number variation in VANGL1 which associates with the development of nephritis in SLE, but not SLE in general. Examination of Vangl1 deficient mice demonstrates a kidney-intrinsic role in the development of nephritis. This represents the first known copy number variant which predisposes to the development of nephritis in SLE in a kidney-intrinsic method.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188480 | GEO | 2021/11/11

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Introduction: Pediatric systemic lupus erythematosus (pSLE) patients often initially present with more active and severe disease than adults, including a higher frequency of lupus nephritis. Specific autoantibodies, including anti-C1q, anti-DNA and anti-alpha-actinin, have been associated with kidney involvement in SLE, and DNA antibodies are capable of initiating early stage lupus nephritis in severe combined immunodeficiency (SCID) mice. Over 100 different autoantibodies have been described in SLE patients, highlighting the need for comprehensive autoantibody profiling. Knowledge of the antibodies associated with pSLE and proliferative nephritis will increase the understanding of SLE pathogenesis, and may aid in monitoring patients for renal flare. Methods: We used autoantigen microarrays composed of 140 recombinant or purified antigens to compare the serum autoantibody profiles of new-onset pSLE patients (n=45) to healthy controls (n=17). We also compared pSLE patients with biopsy-confirmed class III or IV proliferative nephritis (n=23) and without significant renal involvement (n=18). We performed ELISA with selected autoantigens to validate the microarray findings. We created a multiple logistic regression model, based on the ELISA and clinical information, to predict whether a patient had proliferative nephritis, and used a validation cohort (n=23) and longitudinal samples (88 patient visits) to test its accuracy. Results: Fifty autoantibodies were at significantly higher levels in the sera of pSLE patients compared to healthy controls, including anti-B-cell activating factor (BAFF). High levels of anti-BAFF were associated with active disease. Thirteen serum autoantibodies were present at significantly higher levels in pSLE patients with proliferative nephritis than those without, and we confirmed five autoantigens (dsDNA, C1q, collagens IV & X and aggrecan) by ELISA. Our model, based on ELISA measurements and clinical variables, correctly identified patients with proliferative nephritis with 91% accuracy. Conclusions: Autoantigen microarrays are an ideal platform for identifying autoantibodies associated with both pSLE and specific clinical manifestations of pSLE. Using multiple regression analysis to integrate autoantibody and clinical data permits accurate prediction of clinical manifestations with complex etiologies in pSLE.

Dataset Information

Deletions in VANGL1 are a novel risk factor for antibody mediated kidney disease

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure