Blog entry by Meguid El Nahas

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by Meguid El Nahas - Monday, 15 December 2014, 4:03 PM
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N Engl J Med. 2014 Dec 11;371(24):2277-2287. Epub 2014 Nov 13.

Thrombospondin Type-1 Domain-Containing 7A in Idiopathic Membranous Nephropathy.

Abstract

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.).

COMMENTS:

More and more autoantibodies are being identified in patients with idiopathic membranous nephropathy:

anti-PLA2R1

Anti-SOD

Anti-Aldose Reductase (AR)

Anti-Enolase

Anti-NEP

http://www.ncbi.nlm.nih.gov/pubmed/22773590

http://www.ncbi.nlm.nih.gov/pubmed/23643301

and now 

Anti-Thrombospondin Type1 D7A (abstract above)

These anti-Podocytes antibodies, mostly IgG4, are most likely to represent, in my opinion, a paraphenomenon of podocyte injury with subsequent damage of the podocyte and exposure or enhanced antigenecity of these cytoplasmic and cell surface proteins and enzymes with a secondary auto-immune response.

It would be most unlikely that all these, overlapping and often correlating auto-antibodies are the primary auto-immune event in IMN. This would be the first disease, toi my knowledge, that is triggered simultaneously by 4 or 5 auto-immune antibody...the hypothesis that I put forward that these are events secondary to a primary podocytic insult/injury with subsequent injurious amplification loop is more plausible.

Unless, as suggested by the author of the publication above, there are different and distinctive subgroup of patients with IMN initiated by different auto-antibodies...seems less likely to me!

 

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