Serine Protease HTRA1 as a Novel Target Antigen in Primary Membranous Nephropathy.
| Title: | Serine Protease HTRA1 as a Novel Target Antigen in Primary Membranous Nephropathy. |
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| Authors: | Al-Rabadi LF; Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah Health, Salt Lake City, Utah.; Caza T; Arkana Laboratories, Little Rock, Arkansas.; Trivin-Avillach C; Section of Nephrology, Department of Medicine, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts.; Rodan AR; Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah Health, Salt Lake City, Utah.; Molecular Medicine Program, University of Utah Health, Salt Lake City, Utah.; Department of Human Genetics, University of Utah Health, Salt Lake City, Utah.; Medical Service, Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah.; Andeen N; Department of Pathology, Oregon Health and Science University, Portland, Oregon.; Hayashi N; Section of Nephrology, Department of Medicine, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts.; Kanazawa Medical University, Ishikawa, Japan.; Williams B; Moran Eye Center, University of Utah Health, Salt Lake City, Utah.; Revelo MP; Department of Pathology, University of Utah Health, Salt Lake City, Utah.; Clayton F; Department of Pathology, University of Utah Health, Salt Lake City, Utah.; Abraham J; Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah Health, Salt Lake City, Utah.; Lin E; Department of Human Genetics, University of Utah Health, Salt Lake City, Utah.; Liou W; Department of Pathology, University of Utah Health, Salt Lake City, Utah.; Zou CJ; Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah Health, Salt Lake City, Utah.; Ramkumar N; Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah Health, Salt Lake City, Utah.; Cummins T; Clinical Proteomics Laboratory, Division of Nephrology and Hypertension, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky.; Wilkey DW; Clinical Proteomics Laboratory, Division of Nephrology and Hypertension, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky.; Kawalit I; International Renal Care Association, Amman, Jordan.; Herzog C; Nephrology Division, Internal Medicine Department, University of Arkansas for Medical Science, Little Rock, Arkansas.; Storey A; Nephrology Division, Internal Medicine Department, University of Arkansas for Medical Science, Little Rock, Arkansas.; Edmondson R; Nephrology Division, Internal Medicine Department, University of Arkansas for Medical Science, Little Rock, Arkansas.; Sjoberg R; Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden.; Yang T; Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah Health, Salt Lake City, Utah.; Medical Service, Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah.; Chien J; Department of Biochemistry and Molecular Medicine, University of California Davis Health, Davis, California.; Merchant M; Clinical Proteomics Laboratory, Division of Nephrology and Hypertension, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky.; Arthur J; Nephrology Division, Internal Medicine Department, University of Arkansas for Medical Science, Little Rock, Arkansas.; Klein J; Clinical Proteomics Laboratory, Division of Nephrology and Hypertension, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky.; Robley Rex Veterans Administration Medical Center, Louisville, Kentucky.; Larsen C; Arkana Laboratories, Little Rock, Arkansas.; Beck LH Jr; Section of Nephrology, Department of Medicine, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts. |
| Source: | Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2021 Jul; Vol. 32 (7), pp. 1666-1681. Date of Electronic Publication: 2021 May 05. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Wolters Kluwer Health, on behalf of the American Society of Nephrology Country of Publication: United States NLM ID: 9013836 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1533-3450 (Electronic) Linking ISSN: 10466673 NLM ISO Abbreviation: J Am Soc Nephrol Subsets: MEDLINE; PubMed not MEDLINE |
| Imprint Name(s): | Publication: 2023- : Hagerstown, MD : Wolters Kluwer Health, on behalf of the American Society of Nephrology; Original Publication: Baltimore, MD : Williams & Wilkins, c1990- |
| Abstract: | Background: Identification of target antigens PLA2R, THSD7A, NELL1, or Semaphorin-3B can explain the majority of cases of primary membranous nephropathy (MN). However, target antigens remain unidentified in 15%-20% of patients.; Methods: A multipronged approach, using traditional and modern technologies, converged on a novel target antigen, and capitalized on the temporal variation in autoantibody titer for biomarker discovery. Immunoblotting of human glomerular proteins followed by differential immunoprecipitation and mass spectrometric analysis was complemented by laser-capture microdissection followed by mass spectrometry, elution of immune complexes from renal biopsy specimen tissue, and autoimmune profiling on a protein fragment microarray.; Results: These approaches identified serine protease HTRA1 as a novel podocyte antigen in a subset of patients with primary MN. Sera from two patients reacted by immunoblotting with a 51-kD protein within glomerular extract and with recombinant human HTRA1, under reducing and nonreducing conditions. Longitudinal serum samples from these patients seemed to correlate with clinical disease activity. As in PLA2R- and THSD7A- associated MN, anti-HTRA1 antibodies were predominantly IgG4, suggesting a primary etiology. Analysis of sera collected during active disease versus remission on protein fragment microarrays detected significantly higher titers of anti-HTRA1 antibody in active disease. HTRA1 was specifically detected within immune deposits of HTRA1-associated MN in 14 patients identified among three cohorts. Screening of 118 "quadruple-negative" (PLA2R-, THSD7A-, NELL1-, EXT2-negative) patients in a large repository of MN biopsy specimens revealed a prevalence of 4.2%.; Conclusions: Conventional and more modern techniques converged to identify serine protease HTRA1 as a target antigen in MN.; (Copyright © 2021 by the American Society of Nephrology.) |
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| Grant Information: | P30 ES030283 United States ES NIEHS NIH HHS; P20 GM113226 United States GM NIGMS NIH HHS; P50 AA024337 United States AA NIAAA NIH HHS; UL1 TR002538 United States TR NCATS NIH HHS; R01 DK110358 United States DK NIDDK NIH HHS |
| Contributed Indexing: | Keywords: membranous nephropathy; nephrotic syndrome; podocyte |
| Entry Date(s): | Date Created: 20210506 Latest Revision: 20230808 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC8425645 |
| DOI: | 10.1681/ASN.2020101395 |
| PMID: | 33952630 |
| Database: | MEDLINE |
Journal Article