Neuronal Proteins as Antigenic Targets in Membranous Nephropathy.

CONTEXT: The discovery of new target antigens in membranous nephropathy (MN) has revealed new disease phenotypes and, in some cases, has suggested mechanisms of disease shared by two concurrent autoimmune diseases. Subject of Review: Several recent reports and an accompanying editorial describe the association of anti-contactin-1 (CNTN1) autoantibodies of the IgG4 subclass with a novel subtype of MN that co-occurs with a form of chronic inflammatory demyelinating polyradiculoneuropathy caused by anti-CNTN1 antibodies. CNTN1, the cellular source of which is still undetermined, is identified as the target antigen in the kidney since it is present within glomerular subepithelial deposits and anti-CNTN1 IgG4 antibodies can be eluted from the corresponding kidney biopsy tissue. Second Opinion: These new reports reinforce recent findings that many proteins targeted in several other types of primary and secondary MN are proteins whose expression is shared by podocytes and neurons. While complement-mediated podocyte damage represents a well-established paradigm in the pathogenesis of MN, interference with the normal functions of these shared proteins by autoantibodies should be considered as another potential mechanism of glomerular injury to be explored in future research.

Serine Protease HTRA1 as a Novel Target Antigen in Primary Membranous Nephropathy.

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.