Tweetorial on 'Antigens in Primary Membranous Nephropathy & Epitope Spreading' ..inspired by excellent clinicians @GlassockJ & @NephRodby whose daily case discussions on @ASNCommunities have been like a virtual fellowship @RenalFellowNtwk @NSMCInternship @kidney_boy
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💥Primary MN
⚡️one of the commonest causes of nephrotic syndrome
⚡️reflects histological change of GBM thickening with little or no proliferation or infiltration
⚡️many antigens identified recently, starting with PLA2R
⚡️15 to 20% of MN remain negative for any known antigens
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⚡️one of the commonest causes of nephrotic syndrome
⚡️reflects histological change of GBM thickening with little or no proliferation or infiltration
⚡️many antigens identified recently, starting with PLA2R
⚡️15 to 20% of MN remain negative for any known antigens
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💥Animal Model
⚡️Rat model of Heyman Nephritis which resembles human MN clinically and histologically
⚡️Circulating antibody targets antigen megalin on podocytes--> subepithelial immune deposits --> activates complements--> C5-9 MAC--> podocyte injury---> nephrotic syndrome 👇
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⚡️Rat model of Heyman Nephritis which resembles human MN clinically and histologically
⚡️Circulating antibody targets antigen megalin on podocytes--> subepithelial immune deposits --> activates complements--> C5-9 MAC--> podocyte injury---> nephrotic syndrome 👇
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💥Antigens in Primary MN
⚡️Phospholipase A2 receptor (PLA2R)- present in about 70% of primary MN
⚡️Thrombospondin type I domain 7A (THSD7A): represents up to 3 to 5%
⚡️NELL-1: up to 16% of PLA2R negative primary MN
⚡️SEMA-3B: recently identified; mostly present in children
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⚡️Phospholipase A2 receptor (PLA2R)- present in about 70% of primary MN
⚡️Thrombospondin type I domain 7A (THSD7A): represents up to 3 to 5%
⚡️NELL-1: up to 16% of PLA2R negative primary MN
⚡️SEMA-3B: recently identified; mostly present in children
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💥PLA2R
⚡️major antigen in human primary MN; first of the antigens to be identified
⚡️70% of all pts with Primary MN had anti-PLA2R Ab in a seminal study by Beck LH, Salant DJ et al
⚡️since then, 50 to 84% of pts with Primary MN in various studies had similar results
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⚡️major antigen in human primary MN; first of the antigens to be identified
⚡️70% of all pts with Primary MN had anti-PLA2R Ab in a seminal study by Beck LH, Salant DJ et al
⚡️since then, 50 to 84% of pts with Primary MN in various studies had similar results
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💥Phospholipase A2 Receptor (PLA2R)
⚡️180kD, transmembrane receptor protein
⚡️highly expressed in podocytes
⚡️large extracellular region with total 10 domains
⚡️immunodominant epitopes lie within CysR, FNII, CTLD-1, CTLD-7 regions as depicted👇
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⚡️180kD, transmembrane receptor protein
⚡️highly expressed in podocytes
⚡️large extracellular region with total 10 domains
⚡️immunodominant epitopes lie within CysR, FNII, CTLD-1, CTLD-7 regions as depicted👇
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💥Tissue staining of PLA2R
⚡️PLA2R staining in biopsy by immunoflorescence or immunohistochemistry identifies primary MN
⚡️it may identify pts with PLA2R primary MN & Neg serum antibody test
⚡️highly specific but has been detected in deposits of some pts with secondary MN
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⚡️PLA2R staining in biopsy by immunoflorescence or immunohistochemistry identifies primary MN
⚡️it may identify pts with PLA2R primary MN & Neg serum antibody test
⚡️highly specific but has been detected in deposits of some pts with secondary MN
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💥NELL-1
⚡️second most common antigen after PLA2R
⚡️present in 16% of PLA2R neg primary MN
⚡️associated with anti-NELL-1 antibodies; which is predominantly IgG1 type
⚡️a distinct form of primary MN
⚡️clinically noted to be..older patients; and no sex predilection
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⚡️second most common antigen after PLA2R
⚡️present in 16% of PLA2R neg primary MN
⚡️associated with anti-NELL-1 antibodies; which is predominantly IgG1 type
⚡️a distinct form of primary MN
⚡️clinically noted to be..older patients; and no sex predilection
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💥Nell-1
⚡️Neural Epidermal Growth Factor-like 1
⚡️homologous to a gene NELL
⚡️encodes a 90kD secreted protein containingsecretory signal peptide, N-terminal thromobosponding -1 like (TSPN) moleculte, coiled-coil domain, 4 vW-type domains; and 6 EGF-like repeats as depcited 👇
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⚡️Neural Epidermal Growth Factor-like 1
⚡️homologous to a gene NELL
⚡️encodes a 90kD secreted protein containingsecretory signal peptide, N-terminal thromobosponding -1 like (TSPN) moleculte, coiled-coil domain, 4 vW-type domains; and 6 EGF-like repeats as depcited 👇
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💥THSD7A Antigen
⚡️Thrombospondin type-1 domain containing 7A
⚡️3 to 5% of all Primary MN
⚡️about 10% of PLA2R neg Primary MN
⚡️up to 5 to 20% associated with malignancy
⚡️rare cases of dual positivity with PLA2R
⚡️molecular architecture is depicted in👇
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⚡️Thrombospondin type-1 domain containing 7A
⚡️3 to 5% of all Primary MN
⚡️about 10% of PLA2R neg Primary MN
⚡️up to 5 to 20% associated with malignancy
⚡️rare cases of dual positivity with PLA2R
⚡️molecular architecture is depicted in👇
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💥Semaphorin-3B
⚡️SEMA-3B: a recently identified antigen
⚡️A group of secreted & transmembrane protein with SEMA domain
⚡️Expressed diversely in different organ systems
⚡️Its exact function and mechanism of SEMA associated diseases unknown
⚡️Molecular structure is as 👇
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⚡️SEMA-3B: a recently identified antigen
⚡️A group of secreted & transmembrane protein with SEMA domain
⚡️Expressed diversely in different organ systems
⚡️Its exact function and mechanism of SEMA associated diseases unknown
⚡️Molecular structure is as 👇
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💥SEMA cont..
⚡️unique antigen which is involved mainly in children & young adults
⚡️associated with ciruclating anti-SEMA-3B antibodies
⚡️8 of 118 cases of diff cohorts of PLA2R neg MN were SEMA +
⚡️finding of Anti-Sema-3B in children with nephrotic syndrome may indicate MN
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⚡️unique antigen which is involved mainly in children & young adults
⚡️associated with ciruclating anti-SEMA-3B antibodies
⚡️8 of 118 cases of diff cohorts of PLA2R neg MN were SEMA +
⚡️finding of Anti-Sema-3B in children with nephrotic syndrome may indicate MN
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💥Epitope Spreading
⚡️phenomenon by which one or more epitopes are recognized by T or B cells over time
⚡️critical steps in linked immune response
⚡️alters the clinical picture
⚡️schematic representation of epitope spreading is as below 👇
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⚡️phenomenon by which one or more epitopes are recognized by T or B cells over time
⚡️critical steps in linked immune response
⚡️alters the clinical picture
⚡️schematic representation of epitope spreading is as below 👇
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💥For examples....
⚡️in MCTD, epitope spreading can occur within 2 yrs of diagnosis; results in lower skin sclerosis, higher lung disease and lower arthritic manifestations
⚡️epitope spreading in autoimmune encephalomyelitis, RA, MS can lead to worsening of clinical picture
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⚡️in MCTD, epitope spreading can occur within 2 yrs of diagnosis; results in lower skin sclerosis, higher lung disease and lower arthritic manifestations
⚡️epitope spreading in autoimmune encephalomyelitis, RA, MS can lead to worsening of clinical picture
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💥..in Primary MN
⚡️Seitz-Polski et al showed that epitope spreading from CystR to CTLD1/CTLD7 leads to worse prognosis
⚡️Reinhard et al argued-- it is total antibody titres not epitope spreading that determines outcomes
⚡️Assays not availabe commercially/ areas of research
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⚡️Seitz-Polski et al showed that epitope spreading from CystR to CTLD1/CTLD7 leads to worse prognosis
⚡️Reinhard et al argued-- it is total antibody titres not epitope spreading that determines outcomes
⚡️Assays not availabe commercially/ areas of research
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For additional tweetorial on Membranous GN, excellent work by @caioqualunque on @RenalFellowNtwk at following link.. @GlomCon
Thank you. 🙏
Thank you. 🙏
