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Epitope Spreading of Autoantibody Response to PLA2R Associates with Poor
Prognosis in Membranous Nephropathy
#MMPMID26567246
Seitz-Polski B
; Dolla G
; Payré C
; Girard CA
; Polidori J
; Zorzi K
; Birgy-Barelli E
; Jullien P
; Courivaud C
; Krummel T
; Benzaken S
; Bernard G
; Burtey S
; Mariat C
; Esnault VL
; Lambeau G
J Am Soc Nephrol
2016[May]; 27
(5
): 1517-33
PMID26567246
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The phospholipase A2 receptor (PLA2R1) is the major autoantigen in idiopathic
membranous nephropathy. However, the value of anti-PLA2R1 antibody titers in
predicting patient outcomes is unknown. Here, we screened serum samples from 50
patients positive for PLA2R1 for immunoreactivity against a series of PLA2R1
deletion mutants covering the extracellular domains. We identified reactive
epitopes in the cysteine-rich (CysR), C-type lectin domain 1 (CTLD1), and C-type
lectin domain 7 (CTLD7) domains and confirmed the reactivity with soluble forms
of each domain. We then used ELISAs to stratify 69 patients positive for PLA2R1
by serum reactivity to one or more of these domains: CysR (n=23), CysRC1 (n=14),
and CysRC1C7 (n=32). Median ELISA titers measured using the full-length PLA2R1
antigens were not statistically different between subgroups. Patients with
anti-CysR-restricted activity were younger (P=0.008), had less nephrotic range
proteinuria (P=0.02), and exhibited a higher rate of spontaneous remission
(P=0.03) and lower rates of renal failure progression (P=0.002) and ESRD (P=0.01)
during follow-up. Overall, 31 of 69 patients had poor renal prognosis (urinary
protein/creatinine ratio >4 g/g or eGFR<45 ml/min per 1.73 m(2) at end of
follow-up). High anti-PLA2R1 activity and epitope spreading beyond the CysR
epitope were independent risk factors of poor renal prognosis in multivariable
Cox regression analysis. Epitope spreading during follow-up associated with
disease worsening (n=3), whereas reverse spreading from a CysRC1C7 profile back
to a CysR profile associated with favorable outcome (n=1). We conclude that
analysis of the PLA2R1 epitope profile and spreading is a powerful tool for
monitoring disease severity and stratifying patients by renal prognosis.
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