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Fat1 is atarget antigen in de novo allograft membranous nephropoathy associated with antibody mediated rejection.

ABSTRACT: Membranous nephropathy (MN) occurs either as recurrent or de novo MN in the kidney allograft. Recurrent MN is most often associated with antibodies to the target antigen M-type phospholipase A2 receptor (PLA2R). 1-3 Most cases of de novo MN are PLA2R-negative and the target antigen in unknown.2 We have previously used the laser microdissection and mass spectrometry (LMD/MS) to search for target antigens in PLA2R-negative MN. In this study, we used LMD/MS to search for the target antigen(s) in de novo MN. Our studies identified target antigen FAT1 in de novo MN when it is associated with concurrent antibody mediated rejection.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney

SUBMITTER: Benjamin Madden

LAB HEAD: Sanjeev Sethi M.D. Ph.D.

PROVIDER: PXD055559 | Pride | 2024-10-22

REPOSITORIES: Pride

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			Action	DRS
	Case_01.mgf	Mgf
	Case_01.raw	Raw
	Case_02.mgf	Mgf
	Case_02.raw	Raw
	Case_03.mgf	Mgf

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Publications

FAT1 is a target antigen in a subset of de novo allograft membranous nephropathy associated with antibody mediated rejection.

Sethi Sanjeev S Madden Benjamin B Casal Moura Marta M Nasr Samih H SH Alexander Mariam P MP Debiec Hanna H Torrel Nate N Gross LouAnn L Negron Vivian V Specks Ulrich U Fervenza Fernando C FC Haas Mark M Ronco Pierre P Batal Ibrahim I

Kidney international 20240823 5

PMID: 39181399

Similar Datasets

Minor Antigens in Membranous Nephropathy Identified by Mass Spectrometry

Project description:Background: Multiple autoantigens have been identified in membranous nephropathy (MN) by tissue-based proteomics. However, the antigenic targets of disease are unknown for >10% of MN and >50% of membranous lupus nephritis (MLN) cases. We identified multiple new targets in PLA2R-/THSD7A-/EXT-/NELL1-quadruple negative MN biopsies through mass spectrometry (MS) of immune complexes recovered from biopsy tissue of patients with MN. Methods: MN cases negative for PLA2R, THSD7A, EXT1/2, and NELL1 were identified from a biopsy database. Protein G immunoprecipitation was used to recover immune complexes from frozen biopsy tissue, followed by interrogation by mass spectrometry (MS). Potential antigens were confirmed through paraffin immunofluorescence of protein targets, followed by co-localization with IgG within immune deposits. Consecutive series of 165 cases of PLA2R-negative MN biopsies and 95 MLN biopsies was screened to determine the frequency for each potential antigen. Results: Seven protein targets were discovered within immune complexes from MN biopsies including FCN3, CD206, EEA1, SEZ6L2, NPR3, MST1, and VASN. Peptides from these proteins on MS were not enriched in PLA2R (n=86), THSD7A (n=64), NELL1 (n=64), or EXT1/2 (n=60) controls. Between 3-30 unique peptides were detected for each target. Frequencies of each antigen, determined by staining consecutive case series, were SEZ6L2 (1/165 idiopathic; 0/95 MLN), VASN (8/165 idiopathic; 2/95 MLN), EEA1 (6/165 idiopathic; 7/95 MLN), MST1 (6/165 idiopathic; 2/95 MLN), and FCN3 (0/165 idiopathic, 6/95 MLN), NPR3 and CD206 were positive in index cases. All cases showed co-localization of IgG within immune deposits. Conclusion: Seven novel protein targets were identified in MN and MLN.

2023-04-06 | PXD035853 | Pride

Identification of novel target antigens in Membranous Nephorphathy

Project description:Membranous nephropathy (MN) is an autoimmune kidney disease with the clinical hallmark of causing high level proteinuria. MN is caused by circulating antibodies binding to targeting antigens on the surface of podocytes â€“ specialized endothelial cells contributing to the formation of the glomerular filtration barrier. Histomorphologically MN is characterized by a deposition of IgG along the glomerular basement membrane (GBM) â€“ predominantly IgG4 in primary MN â€“ as well as an accumulation of the respective target antigen, thickening of the GBM and effacement of podocyte foot processes. The predominant MN target antigen in 70-80% of MN patients is the phospholipase A2 receptor 1. Additional target antigens, which occur with lower frequencies, have recently been described. The aim of the study was the identification of a novel MN target antigen, which fulfills the typical criteria of MN target antigen: being a podocytic membrane protein, which is recognized by IgG4 subclass specific autoantibodies. Performing a mass spectrometry analysis based on a TMT-based relative quantification approach of immunoprecipitated samples resulted in the identification of Netrin G1 (NTNG1) as a novel MN target antigen. The results were validated using immunohistochemistry, Western Blot and ELISA. The molecular characterization of patients with MN will allow a better diagnosis and clinical management of these patients in the future.

2022-08-03 | PXD032713 | Pride

Estimating the Contribution of Proteasomal Spliced Peptides to the HLA-I Ligandome

Project description:Spliced peptides are short protein fragments spliced together in the proteasome by peptide bond formation. True estimation of the contribution of proteasome-spliced peptides (PSPs) to the global Human Leukocyte Antigen (HLA) ligandome is critical. A recent study suggested that PSPs contribute up to 30% of the HLA ligandome. We performed a thorough reanalysis of the reported results using multiple computational tools and various validation steps and concluded that only a fraction of the proposed PSPs passes the quality filters. To better estimate the actual number of PSPs, we present an alternative workflow. We performed de-novo sequencing of the HLA-peptide spectra and discarded all de-novo sequences found in the UniProt database. We checked whether the remaining de-novo sequences could match spliced peptides from human proteins. The spliced sequences were appended to the UniProt fasta file, which was searched by two search tools at a FDR of 1%. We find that 2-6% of the HLA ligandome could be explained as spliced protein fragments. The majority of these potential PSPs have good peptide-spectrum match properties and are predicted to bind the respective HLA molecules. However, it remains to be shown how many of these potential PSPs actually originate from proteasomal splicing events.

2018-09-03 | PXD010793 | Pride

Integrated genomic analyses of de novo pathways underlying atypical meningiomas [ChIP-Seq]

Project description:Meningiomas are mostly benign brain tumors, with a potential for becoming atypical or malignant. Based on comprehensive genomic, transcriptomic and epigenomic analyses of meningiomas, we compared benign tumors to atypical ones. We show that the vast majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent mutations in SMARCB1. These tumors harbor increased H3K27me3 repressive signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells (hESCs), thereby phenocopying a more primitive cellular state. Consistent with this observation, and based on differential gene expression analysis as well as correlation of mRNA:miRNA regulatory networks, atypical meningiomas exhibit up-regulation of EZH2, the catalytic subunit of the PRC2 complex, well as the E2F2 and FOXM1 transcriptional networks that promote proliferation through activation of the cell cycle pathways. In addition, based on H3K27ac ChIP-seq analysis, we show atypical tumors to display an activated super-enhancer near the meningeal identity transcription factor ZIC1, leading to its transcriptional upregulation. The H3k27ac ChIP-seq data for 15 benign meningiomas and 2 dura samples listed below were created by Dr. Justin Cotney in Dr. James Noonan’s lab at Yale and previously published in a paper by our group with Drs. Cotney and Noonan as co-authors (Clark et al. Science, 2013). Sample IDs: MN-297, MN-288, MN-292, MN-163, MN-1037, MN-105, MN-201, MN-249, MN-191, MN-1066, MN-169, MN-291, MN-24, MN-79, MN-1044, CONTROL1, CONTROL2. In this study, we used these benign meningioma H3k27ac ChIP-seq data as controls and compared them to the newly created ChIP-seq data. Sample IDs: MN-54, MN-97 and MN-171. This GEO entry contains ChIP-seq results for both data sets.

2016-12-20 | GSE91372 | GEO

De novo assembly of siRNA immunity in wild plants

Project description:We describe an application of deep sequencing and de novo assembly of short RNA reads to investigate small interfering (si)RNAs mediated immunity in leaf samples from eight tree taxa naturally occurring in Wytham Woods, Oxfordshire, UK. BLAST search for homologues of contigs in the GenBank identified siRNA populations against a number of RNA viruses and a Ty1-copia retrotransposons in these tree species. Small RNA sequencing and de novo assembly

2012-06-01 | E-GEOD-22079 | biostudies-arrayexpress

Mass spectrometry spatial-omics on a single conductive slide

Project description:Mass spectrometry imaging (MSI) can analyze the spatial distribution of hundreds of different molecules directly from tis-sue sections usually placed on conductive glass slides to provide conductivity on the sample surface. Additional experiments are often required for molecular identification using consecutive sections on membrane slides compatible with laser capture microdissection (LMD). In this work, we demonstrate for the first time the use of a single conductive slide for both matrix assisted laser desorption ionization (MALDI)-MSI and direct proteomics. In this workflow, regions of interest can be directly ablated with LMD while preserving protein integrity. These results offer an alternative for MSI based multimodal spatial-omics.

2021-09-09 | PXD023196 | Pride

Application of de novo sequencing to large-scale complex proteomics datasets

Project description:Dependent on concise, pre-defined protein sequence databases, traditional search algorithms perform poorly when analyzing mass spectra derived from wholly uncharacterized protein products. Conversely, de novo peptide sequencing algorithms can interpret mass spectra without relying on reference databases. However, such algorithms have been difficult to apply to complex protein mixtures, in part due to a lack of methods for automatically validating de novo sequencing results. Here, we present novel metrics for benchmarking de novo sequencing algorithm performance on large scale proteomics datasets, and present a method for accurately calibrating false discovery rates on de novo results. We also present a novel algorithm (LADS) which leverages experimentally disambiguated fragmentation spectra to boost sequencing accuracy and sensitivity. LADS improves sequencing accuracy on longer peptides relative to other algorithms and improves discriminability of correct and incorrect sequences. Using these advancements, we demonstrate accurate de novo identification of peptide sequences not identifiable using database search-based approaches.

2016-01-12 | PXD003317 | Pride

Proteogenomic analysis unveils the HLA Class I presented immunopeptidome in melanoma and EGFR mutant lung adenocarcinoma

Project description:Immune checkpoint inhibitor and adoptive lymphocyte transfer-based therapies have shown great therapeutic potential for cancers with high tumor mutation burden (TMB). Here, we employed mass spectrometry (MS)-based proteogenomic large-scale profiling to identify potential immunogenic human leukocyte antigen (HLA) Class ǀ-presented peptides in both melanoma, a “hot tumor” with high TMB, and EGFR mutant lung adenocarcinoma, a “cold tumor” with low TMB. We used cell line and patient-specific databases constructed using variants identified from whole-exome sequencing, as well as a de novo search algorithm from the PEAKS search algorithm to interrogate the mass spectrometry data of the Class I immunopeptidome. We identified 12 mutant neoantigens. Several classes of tumor-associated antigen-derived peptides were also identified. We constructed a cancer germline (CG) antigen database with 285 antigens and identified 42 Class I-presented CG antigens. We identified more than 1000 post-translationally modified (PTM) peptides representing 58 different PTMs. Our results suggest that PTMs play a critical role impacting HLA-binding affinity dramatically. Finally, leveraging de novo search and an annotated lncRNA database, we developed a novel non-canonical peptide discovery pipeline to identify 44 lncRNA-derived peptides that are presented by Class I. We validated MS/MS spectra of select peptides using synthetic peptides and performed HLA Class I binding assays to demonstrate binding of select neo-peptides and lncRNA-derived peptides to Class I proteins. In summary, we provide direct evidence of HLA Class I presentation of a large number of mutant and tumor-associated peptides for potential use as vaccine or adoptive cell therapy in melanoma and EGFR mutant lung cancer.

2021-08-23 | PXD022949 | Pride

Dissecting the Functional Consequences of de Novo DNA Methylation Dynamics in Human Motor Neuron Differentiation and Physiology

Project description:DNA methylation is a well studied, yet still incompletely understood component of the multi-layered epigenome. The somatic DNA methylation landscape is established early in development, but remains highly dynamic within focal regions that tend to overlap with gene regulatory elements. The functional significance of these dynamic changes remains unresolved. Here we utilized a powerful human ESC differentiation model for the generation of motor neurons (MNs) in combination with genetic mutations in the de novo DNA methylation machinery to dissect the role of DNA methylation in directing somatic cell fate. We quantitatively and in high-resolution measure the molecular and functional consequences of epigenetic perturbation. We find defects in neuralization and MN development. We also observe decreased dendritic arborization and altered electrophysiological properties in DNMT3A KO MNs. Our work provides a specific list of epigenetically deregulated targets and a mechanistic link between de novo DNA methylation, cellular differentiation and human MN function.

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2021-10-21 | E-MTAB-11014 | biostudies-arrayexpress

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