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PHILADELPHIA -- Researchers may have found another autoantigen involved in idiopathic membranous nephropathy, they reported here.
In a study of 154 patients who did not have antibodies to PLA2R1 -- the antibody implicated in 70% of idiopathic membranous nephropathy -- about 2.5% to 5% had autoantibodies against THSD7A, Gerard Lambeau, PhD, of the Institute de Pharmacologie Moleculaire in France, and colleagues reported online in the and here at .
That corresponds to about 8% to 14% of all patients who are seronegative for anti-PLA2R1 antibodies, the researchers said.
Idiopathic membranous nephropathy, an autoimmune disease, is associated with autoantibodies against the phospholipase A2 receptor (PLA2R1) in 70% of patients.
In the remaining 30%, it is thought that other endogenous glomerular antigens may be involved -- but there have been no other antigenic targets thus far.
Lambeau and colleagues screened serum samples from patients with idiopathic membranous nephropathy, other glomerular diseases, and healthy controls for antibodies against human native glomerular proteins.
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.
On mass spectrometry, this antigen was recognized as thrombospondin type-1 domain-containing 7A (TSHD7A).
None of the other groups -- the 74 patients with idiopathic membranous nephropathy who were sero-positive for anti-PLA2R1 antibodies, the 76 patients with other glomerular diseases, and the 44 healthy controls -- reacted against TSHD7A, they reported.
TSHD7A shares some biochemical features with PLA2R1, such as N-glycosylation, membranous location, and reactivity with serum only under nonreducing conditions, Lambeau and colleagues reported.
They added that all reactive serum samples recognized recombinant TSHD7A and immunoprecipitated TSHD7A from glomerular lysates, and that these antibodies appear to be associated with the IgG4 subclass.
They concluded that their finding that 15 of 154 patients with idiopathic membranous nephropathy had circulating autoantibodies to TSHD7A but not to PLA2R1 suggests a distinct subgroup of patients with this condition.
"The finding not only furthers our understanding of the pathophysiological basis of membranous nephropathy, but also allows for the potential identification and monitoring of patients who are positive for anti-THSD7A autoantibodies, by both serologic testing and histologic staining for the antigen," they wrote.
Taken together, Lambeau and colleagues expect that THSD7A and PLA2R1-associated membranous nephropathy may now account for approximately 75% to 85% of cases, which "further helps to distinguish idiopathic from secondary membranous nephropathy."
The remaining 15% to 25% of cases, they added, may involve some as-yet unidentified autoantigens that are distinct from THSD7A and PLA2R1, or may have been wrongly classified as idiopathic owing to an undetected secondary cause of the disease.
Disclosures
The study was supported by the French National Center for Scientific Research.
The researchers reported relationships with Questcor and Pfizer, and having patents on diagnostics and monitoring kits for membranous nephropathy.
Primary Source
New England Journal of Medicine
Tomas NM, et al "Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy" N Engl J Med 2014; DOI: 10.1056/NEJMoa1409354.