👤 Jerome Jean-Gilles

The pathologic features of membranous lupus nephritis (MLN) are occasionally encountered in secondary membranous nephropathy (sMN) without overt clinical evidence of systemic lupus erythematosus. Moreover, some sMN with lupus-like features (lupus-like membranous nephropathy [LL-MN]) have a clinical presentation more typical of primary membranous nephropathy (pMN). Based on the confounding clinical and pathologic presentation, it is unclear how to categorize and treat these patients. We performed immunohistochemical staining for recently discovered target antigens associated with MN -NELL-1, THSD7A, and EXT1/2 and compared the clinicopathologic presentation of patients with LL-MN to those with pMN and MLN. From 2015 to 2020, there were 21 patients with MLN and 99 with MN, of which 59% were diagnosed pMN and 41% sMN. 44% of sMN patients showed lupus-like features (LL-fx). All LL-MN patients were negative for PLA2R and NELL1, but 12% were positive for EXT1/2. 50% of LL-MN patients had an identifiable systemic disease, of which 56% were autoimmune disease (AD) and 44% infection. Compared to pMN, LL-MN had a higher incidence of underlying AD (p = 0.02). Within pMN, 24% also had LL-fx (LL-pMN), and all but 1 were PLA2R- (78%) or NELL1-positive (15%). Only 5% of pMN patients had an AD, 66% of which showed LL-fx. Most idiopathic LL-MN were treated and behaved clinically similarly to pMN. There were no differences in outcome in terms of progression toward end-stage renal disease or mortality between LL-MN versus pMN and MLN. LL-MN appears to have a significant association with underlying AD and has a subset showing EXT1/2 positivity, whereas most LL-pMN and idiopathic LL-MN likely represent an atypical pathologic presentation of pMN. Show less

Evidence suggests that β-secretase (BACE1), which cleaves Amyloid Precursor Protein (APP) to form sAPPβ and amyloid-β, is elevated in Alzheimer's disease (AD) brains and biofluids and, thus, BACE1 is a therapeutic target for this devastating disease. The direct product of BACE1 cleavage of APP, sAPPβ, serves as a surrogate marker of BACE1 activity in the central nervous system. This biomarker could be utilized to better understand normal APP processing, aberrant processing in the disease setting, and modulations to processing during therapeutic intervention. In this paper, we present a method for measuring the metabolism of sAPPβ and another APP proteolytic product, sAPPα, in vivo in humans using stable isotope labeling kinetics, paired with immunoprecipitation and liquid chromatography/tandem mass spectrometry. The method presented herein is robust, reproducible, and precise, and allows for the study of these analytes by taking into account their full dynamic potential as opposed to the traditional methods of absolute concentration quantitation that only provide a static view of a dynamic system. A study of in vivo cerebrospinal fluid sAPPβ and sAPPα kinetics using these methods could reveal novel insights into pathophysiological mechanisms of AD, such as increased BACE1 processing of APP. Show less