1/ A tweetorial on antigens and antibodies seen in primary membranous nephropathy @NSMCInternship
What’s the latest so far?
2/ Let's start with a poll: which of the following antigens are not associated with primary membranous nephropathy:
3/ Primary MN
⚡️20-30% of nephrotic syndrome in Caucasian adults
⚡️MN reflects GBM thickening with little/no cellular proliferation/infiltration on LM
⚡️Several antigens discovered: PLA2R, THSD7A, NELL-1, Semaphorin 3B
⚡️No antigens identifiable in 15-20% cases
4/ Rat Model - MN
⚡️Heymann nephritis resembles human disease clinically & histologically
⚡️Circulating Ab against megalin on podocytes → subepithelial immune deposits → (+) complements → C5b-9:MAC → podocyte injury → proteinuria
⚡️Megalin not expressed in human glomerulus
5/ Let’s discuss different antigens in Primary MN
M-type Phospholipase A2 receptor (PLA2R)
⚡️Seen in ~ 70-80% of Primary MN
⚡️Circulating anti-PLA2R antibodies predominantly IgG4
nejm.org/doi/full/10.10…
6/ PLA2R antigen
⚡️180kD transmembrane receptor protein
⚡️High expression in podocytes
⚡️Immunological epitopes lie in CysR, FNII, CTLD1, CTLD7 regions
⚡️Epitope spreading associated with lower spontaneous remission rate, higher CKD risk, lower response to Rituximab
7/ Serum anti-PLA2R Ab
⚡️Detected by IFA & ELISA
⚡️IFA: ↑ sensitivity, semi-quantitative, not clinically used
⚡️ELISA: Quantifies Ab levels [(-) <14; borderline 14-19; (+) ≥20 RU/mL]
⚡️↑ titers: ↑ relapse, ↓ Rx response, ↑ time to remission, ↓ kidney function
8/ PLA2R - tissue (kidney) staining
⚡️Detected by immunofluorescence or immunohistochemistry
⚡️Overlapping granular IgG (esp. IgG4) deposits
⚡️Can identify PLA2R associated primary MN with (-) serum PLA2R Ab
⚡️Highly specific; seen in some cases of secondary MN
9/ (B) Thrombospondin type-1 domain-containing 7A (THSD7A) antigen
⚡️250kD transmembrane receptor protein expressed on podocytes
⚡️Found in 3-5% of primary MN; 10% of PLA2R (-) primary MN
⚡️IgG4 (+) immune response
⚡️Rare dual (+) with PLA2R
⚡️6-20% associated with malignancy
10/ (C) Neural epidermal growth factor-like 1 (NELL-1) antigen
⚡️Present in ~10-15% of PLA2R (-) primary MN
⚡️Circulating anti-NELL-1 antibodies predominantly IgG1 type
⚡️Accumulation & co-localization of NELL-1 & IgG along GBM
⚡️Incomplete capillary loop staining
11/ (D) Semaphorin 3B (Sema3B)
⚡️A unique form of PLA2R (-) primary MN
⚡️Mainly involves children & young adults
⚡️Associated with circulating anti-Sema3B Ab
⚡️Anti-Sema3B Ab in children with nephrotic syndrome may indicate MN
12/ Neutral endopeptidase (NEP)
⚡️Expressed on podocytes
⚡️Rare antenatal form of MN
⚡️Transplacental anti-NEP Ab causing MN with subepithelial deposits in neonates
⚡️IgG4 (+) immune response
⚡️Resolution of nephrotic syndrome & deposits upon clearance of maternal Ab over time
13/ Antigens in secondary MN
⚡️Exostosin 1 & 2 (EXT1/EXT2) immunostaining seen in MN associated with autoimmune disorders incl. Class V lupus nephritis & Sjogren’s d/e
⚡️Origin unclear
⚡️♀ > ♂
⚡️EM - subepithelial, subendothelial, mesangial deposits
jasn.asnjournals.org/content/30/6/1…
14/ Summary
⚡️Primary MN responsible for ~ 70% MN cases
⚡️PLA2R associated with 70-80% of primary MN; tissue staining and serum Ab levels helpful
⚡️THSD7A associated with3-5% of primary MN; ↑ in malignancy
⚡NELL1, Semaphorin 3b associated with < 10% of primary MN
15/ Let’s end where we started with the poll: which of the following antigens are not associated with primary membranous nephropathy:
16/ Thank you for scrolling through. Hope you found this helpful. Stay tuned for more tweetorials on glomerular diseases in the future. Appreciate #NSMC mentors for their guidance! #Nephforward

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