Thrombospondin Type-1 Domain-Containing 7A in Idiopathic Membranous Nephropathy
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Thrombospondin Type-1 Domain-Containing 7A in Idiopathic Membranous Nephropathy. / Tomas, Nicola M; Beck, Laurence H; Meyer-Schwesinger, Catherine; Seitz-Polski, Barbara; Ma, Hong; Zahner, Gunther; Dolla, Guillaume; Hoxha, Elion; Helmchen, Udo; Dabert-Gay, Anne-Sophie; Debayle, Delphine; Merchant, Michael; Klein, Jon; Salant, David J; Stahl, Rolf A K; Lambeau, Gérard.
In: NEW ENGL J MED, Vol. 371, No. 24, 11.12.2014, p. 2277-2287.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Thrombospondin Type-1 Domain-Containing 7A in Idiopathic Membranous Nephropathy
AU - Tomas, Nicola M
AU - Beck, Laurence H
AU - Meyer-Schwesinger, Catherine
AU - Seitz-Polski, Barbara
AU - Ma, Hong
AU - Zahner, Gunther
AU - Dolla, Guillaume
AU - Hoxha, Elion
AU - Helmchen, Udo
AU - Dabert-Gay, Anne-Sophie
AU - Debayle, Delphine
AU - Merchant, Michael
AU - Klein, Jon
AU - Salant, David J
AU - Stahl, Rolf A K
AU - Lambeau, Gérard
PY - 2014/12/11
Y1 - 2014/12/11
N2 - BACKGROUND: Idiopathic membranous nephropathy is an autoimmune disease. In approximately 70% of patients, it is associated with autoantibodies against the phospholipase A2 receptor 1 (PLA2R1). Antigenic targets in the remaining patients are unknown.METHODS: Using Western blotting, we screened serum samples from patients with idiopathic membranous nephropathy, patients with other glomerular diseases, and healthy controls for antibodies against human native glomerular proteins. We partially purified a putative new antigen, identified this protein by means of mass spectrometry of digested peptides, and validated the results by analysis of recombinant protein expression, immunoprecipitation, and immunohistochemical analysis.RESULTS: Serum samples from 6 of 44 patients in a European cohort and 9 of 110 patients in a Boston cohort with anti-PLA2R1-negative idiopathic membranous nephropathy recognized a glomerular protein that was 250 kD in size. None of the serum samples from the 74 patients with idiopathic membranous nephropathy who were seropositive for anti-PLA2R1 antibodies, from the 76 patients with other glomerular diseases, and from the 44 healthy controls reacted against this antigen. Although this newly identified antigen is clearly different from PLA2R1, it shares some biochemical features, such as N-glycosylation, membranous location, and reactivity with serum only under nonreducing conditions. Mass spectrometry identified this antigen as thrombospondin type-1 domain-containing 7A (THSD7A). All reactive serum samples recognized recombinant THSD7A and immunoprecipitated THSD7A from glomerular lysates. Moreover, immunohistochemical analyses of biopsy samples from patients revealed localization of THSD7A to podocytes, and IgG eluted from one of these samples was specific for THSD7A.CONCLUSIONS: In our cohort, 15 of 154 patients with idiopathic membranous nephropathy had circulating autoantibodies to THSD7A but not to PLA2R1, a finding that suggests a distinct subgroup of patients with this condition. (Funded by the French National Center for Scientific Research and others.).
AB - BACKGROUND: Idiopathic membranous nephropathy is an autoimmune disease. In approximately 70% of patients, it is associated with autoantibodies against the phospholipase A2 receptor 1 (PLA2R1). Antigenic targets in the remaining patients are unknown.METHODS: Using Western blotting, we screened serum samples from patients with idiopathic membranous nephropathy, patients with other glomerular diseases, and healthy controls for antibodies against human native glomerular proteins. We partially purified a putative new antigen, identified this protein by means of mass spectrometry of digested peptides, and validated the results by analysis of recombinant protein expression, immunoprecipitation, and immunohistochemical analysis.RESULTS: Serum samples from 6 of 44 patients in a European cohort and 9 of 110 patients in a Boston cohort with anti-PLA2R1-negative idiopathic membranous nephropathy recognized a glomerular protein that was 250 kD in size. None of the serum samples from the 74 patients with idiopathic membranous nephropathy who were seropositive for anti-PLA2R1 antibodies, from the 76 patients with other glomerular diseases, and from the 44 healthy controls reacted against this antigen. Although this newly identified antigen is clearly different from PLA2R1, it shares some biochemical features, such as N-glycosylation, membranous location, and reactivity with serum only under nonreducing conditions. Mass spectrometry identified this antigen as thrombospondin type-1 domain-containing 7A (THSD7A). All reactive serum samples recognized recombinant THSD7A and immunoprecipitated THSD7A from glomerular lysates. Moreover, immunohistochemical analyses of biopsy samples from patients revealed localization of THSD7A to podocytes, and IgG eluted from one of these samples was specific for THSD7A.CONCLUSIONS: In our cohort, 15 of 154 patients with idiopathic membranous nephropathy had circulating autoantibodies to THSD7A but not to PLA2R1, a finding that suggests a distinct subgroup of patients with this condition. (Funded by the French National Center for Scientific Research and others.).
KW - Autoantibodies
KW - Blotting, Western
KW - Case-Control Studies
KW - Glomerulonephritis, Membranous
KW - Humans
KW - Kidney Glomerulus
KW - Receptors, Phospholipase A2
KW - Thrombospondins
U2 - 10.1056/NEJMoa1409354
DO - 10.1056/NEJMoa1409354
M3 - SCORING: Journal article
C2 - 25394321
VL - 371
SP - 2277
EP - 2287
JO - NEW ENGL J MED
JF - NEW ENGL J MED
SN - 0028-4793
IS - 24
ER -
