Can the Use of the Serum Anti-PLA2R Antibody Negate the Need for a Renal Biopsy in Primary Membranous Nephropathy?

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Background:
The complement pathway is an innate immune defense mechanism, and uncontrolled activation can cause damage to host tissues including the kidney.C3GN is characterized by deposits in the glomerulus made up entirely of complement C3 protein without the presence of immunoglobulins.
Methods: The activity of the alternative complement pathway (ACP) was determined in serum derived from C3GN patients, IgA Nephropathy (IgAN) and Polycystic Kidney Disease (PKD) and heathy controls (HC) by measuring the lysis of rabbit red blood cells (rRBC).Complement factor H (CFH) was added to the serum of C3GN patients to establish if CFH is capable of inhibiting the ACP in C3GN.
Results: Analysis of the ACP using the serum of C3GN, IgAN, PKD patients and healthy controls can be calculated by the lysis of rRBC.The percent lysis at specified time points (5, 10 and 15 minutes) was calculated using the maximal lysis for each sample.Serum from C3GN patients result in more significant lysis (one way ANOVA P < 0.01) at 5 and 10 minutes (22.9% ± 11% and 42.7% ± 12%, respectively) compared to HC (7.1% ± 3% and 21.7% ± 6%, respectively), IgAN (10.9% ± 7% and 27.3% ± 15%, respectively) and PKD (8.6% ± 6% and 24.4% ± 12%, respectively).However, at 15 minutes, there were no significant differences in the lysis of the rRBC between these groups, suggesting that the ACP is more rapidly activated in C3GN patients, leading to faster depletion of C3.Addition of CFH to the serum of C3GN patients reduced the ACP activity to control levels in 6 out of 14 patients.We did not detect CFH specific antibodies in the serum of patients who did not respond to CFH, indicating additional mechanisms are involved with the rapid activation of the ACP in C3GN.
Conclusions: The ACP is rapidly activated by the serum of C3GN patients compared to other kidney diseases and HC.Although the addition of CFH to the serum reduced the ACP activation comparable to controls in 42% of C3GN patients, not all the serum samples responded to CFH.Future work may elucidate additional mechanisms of the continued ACP activation in C3GN patients and have implications for therapy of these patients.Background: Pathogenic autoantibodies (autoAb) promote severe glomerulonephritis in ANCA vasculitis and lupus.Genetic susceptibility and environmental exposures, particularly inhalation of silica (Si) dust, are implicated in dysregulated autoimmunity and are targets for therapeutic intervention.Using a mouse reporter system expressing a regulated nephrotropic autoAb transgene (Tg) targeting basement membrane (BM) and instilling Si by oropharyngeal aspiration (OPA), we demonstrated that central B cell tolerance and anergy to BM are preserved in multiple lupus strains despite induction of lung inflammation and ectopic lymphoid tissue.Nonetheless, Si exposure increased local and systemic anti-DNA Ig levels in wildtype (WT) B6 and lupus mice, suggesting subversion of alternative regulatory checkpoints.Herein we leverage the aberrant M7 anti-BM Tg lineage that demonstrates partial escape from tolerance and evidence of glomerular Ig deposition to study the interaction of Si exposure with preexisting defects in autoreactive cell regulation.

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Methods: M7 Tg mice (WT at Ig light chain, or LC, locus) were exposed to Si or vehicle (V) by OPA, organs harvested at 5-6 weeks, and cells cultured ±Toll-like receptor ligand (TLR-L).To restrict Ig specificity, a subset of mice (Tg/KI) was bred to heterozygosity for the Vk8/Jk5 V8R Ig LC knock-in.Tg autoAb were measured by ELISA; mean OD±SD.
Conclusions: An autoAb reporter system reveals that anti-BM autoreactive lymphocytes that escape tolerance can be recruited to the lung after exposure to inhaled silica dust.Anti-BM cell activation by superimposed stimuli, such as TLR-L, can lead to secretion of nephrotropic autoAb.