NELL1 is a target antigen in malignancy-associated membranous nephropathy
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Tiffany N Caza1, Samar I Hassen1, Zeljko Dvanajscak1
1Arkana Laboratories, Little Rock, Arkansas, USA.
Abstract:
Patients with membranous nephropathy have an increased risk of malignancy compared to the general population, but the target antigen for malignancy-associated membranous nephropathy is unknown. To explore this, we utilized mass spectrometry for antigen discovery in malignancy-associated membranous nephropathy examining immune complexes eluted from frozen kidney biopsy tissue using protein G bead immunoglobulin capture. Antigen discovery was performed comparing cases of membranous nephropathy of unknown and known type. Mass spectrophotometric analysis revealed that nerve epidermal growth factor-like 1 (NELL1) immune complexes were uniquely present within the biopsy tissue in membranous nephropathy. Additional NELL1-positive cases were subsequently identified by immunofluorescence. In a consecutive series, 3.8% of PLA2R- and THSD7A-negative cases were NELL1-positive. These NELL1-positive cases had segmental to incomplete IgG capillary loop staining (93.4%) and dominant or co-dominant IgG1-subclass staining (95.5%). The mean age of patients with NELL1-positive membranous nephropathy was 66.8 years, with a slight male predominance (58.2%) and 33% had concurrent malignancy. Compared with PLA2R- and THSD7A-positive cases of membranous nephropathy, there was a greater proportion of cases with malignancies in the NELL1-associated group. Thus, NELL1-associated membranous nephropathy has a unique histopathology characterized by incomplete capillary loop staining, IgG1-predominance, and is more often associated with malignancy than other known types of membranous nephropathy.
Insights
Researchers identified nerve epidermal growth factor-like 1 (NELL1) as a novel antigen in malignancy-associated membranous nephropathy. NELL1-positive cases show distinct histopathology and a higher prevalence of concurrent cancers.
Area of Science:
- Nephrology
- Oncology
- Immunopathology
Background:
- Membranous nephropathy (MN) is linked to an elevated risk of malignancy.
- The specific antigens driving malignancy-associated MN remain largely unidentified.
- Existing research lacks clarity on the pathological characteristics of malignancy-associated MN.
Purpose of the Study:
- To identify novel antigens associated with malignancy-induced membranous nephropathy.
- To characterize the distinct histopathological features of NELL1-associated MN.
- To investigate the association between NELL1-positive MN and concurrent malignancies.
Main Methods:
- Mass spectrometry was employed to analyze immune complexes from kidney biopsy tissues.
- Protein G bead immunoglobulin capture technique was used for antigen discovery.
- Immunofluorescence staining confirmed the presence of NELL1 in additional cases.
Main Results:
- Nerve epidermal growth factor-like 1 (NELL1) immune complexes were uniquely identified in MN kidney biopsies.
- NELL1-positive MN cases exhibited segmental to incomplete IgG capillary loop staining and IgG1-subclass predominance.
- A significant proportion (33%) of NELL1-positive MN patients had concurrent malignancies, higher than PLA2R/THSD7A-positive MN.
Conclusions:
- NELL1 is a novel target antigen in a subset of membranous nephropathy, particularly associated with malignancy.
- NELL1-associated MN presents unique histopathological findings, including incomplete capillary loop staining and IgG1 predominance.
- This discovery aids in identifying patients with a higher risk of underlying cancer among MN cases negative for other known antigens.
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