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Membranous Nephropathy in Syphilis is Associated with Neuron-Derived Neurotrophic Factor
Sanjeev Sethi1, Benjamin Madden2, Marta Casal Moura3
1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
Significance Statement:
Syphilis is a common worldwide sexually transmitted infection. Proteinuria may occur in patients with syphilis. Membranous nephropathy (MN) is the most common cause of proteinuria in syphilis. The target antigen of MN in syphilis is unknown. This study shows that MN in syphilis is associated with a novel target antigen called neuron-derived neurotrophic factor (NDNF). NDNF-associated MN has distinctive clinical and pathologic manifestations and NDNF appears to be the target antigen in syphilis-associated MN.
Background:
Syphilis is a common sexually transmitted infection. Membranous nephropathy (MN) is a common cause of proteinuria in syphilis. The target antigen is not known in most cases of syphilis-associated MN.
Methods:
We performed laser microdissection of glomeruli and mass spectrometry (MS/MS) in 250 cases (discovery cohort) of phospholipase A2 receptor-negative MN to identify novel target antigens. This was followed by immunohistochemistry/confocal microscopy to localize the target antigen along the glomerular basement membrane (GBM). Western blot analyses using IgG eluted from frozen biopsy tissue were performed to detect binding to target antigen.
Results:
MS/MS studies of the discovery cohort revealed high total spectral counts of a novel protein, neuron-derived neurotrophic factor (NDNF), in three patients: one each with syphilis and hepatitis B, HIV (syphilis status not known), and lung tumor. Next, MS/MS studies of five cases of syphilis-MN (validation cohort) confirmed high total spectral counts of NDNF (average 45±20.4) in all (100%) cases. MS/MS of 14 cases of hepatitis B were negative for NDNF. All eight cases of NDNF-associated MN were negative for known MN antigens. Electron microscopy showed stage I MN in all cases, with superficial and hump-like deposits without GBM reaction. IgG1 was the dominant IgG subtype on MS/MS and immunofluorescence microscopy. Immunohistochemistry/confocal microscopy showed granular staining and colocalization of NDNF and IgG along GBM. Western blot analyses using eluate IgG of NDNF-MN showed binding to both nonreduced and reduced NDNF, while IgG eluate from phospholipase A2 receptor-MN showed no binding.
Conclusion:
NDNF is a novel antigenic target in syphilis-associated MN.
Insights
Syphilis-associated membranous nephropathy (MN) is linked to a newly identified target antigen, neuron-derived neurotrophic factor (NDNF). This discovery clarifies the cause of proteinuria in syphilis patients with MN.
Area of Science:
- Nephrology
- Immunology
- Infectious Diseases
Background:
- Syphilis is a prevalent sexually transmitted infection globally.
- Proteinuria is a common complication in syphilis patients.
- Membranous nephropathy (MN) is the primary cause of proteinuria in syphilis, but its target antigen remains largely unknown.
Purpose of the Study:
- To identify the unknown target antigen in syphilis-associated MN.
- To characterize the clinical and pathological features of MN associated with the novel antigen.
Main Methods:
- Laser microdissection of glomeruli and mass spectrometry (MS/MS) were used to identify novel antigens in phospholipase A2 receptor-negative MN.
- Immunohistochemistry, confocal microscopy, and Western blot analyses were performed to localize and confirm antigen binding.
Main Results:
- Neuron-derived neurotrophic factor (NDNF) was identified as a novel protein with high spectral counts in syphilis-MN cases.
- NDNF was localized to the glomerular basement membrane (GBM) and co-localized with IgG deposits.
- NDNF-associated MN showed distinct clinical and pathological features, with IgG1 as the dominant subtype.
Conclusions:
- Neuron-derived neurotrophic factor (NDNF) is a novel antigenic target in syphilis-associated MN.
- Understanding NDNF's role provides insights into the pathogenesis of syphilis-related kidney disease.
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