A Comprehensive Phenotypic and Functional Immune Analysis Unravels Circulating Anti-Phospholipase A2 Receptor Antibody Secreting Cells in Membranous Nephropathy Patients

被引：37

作者：

Cantarelli, Chiara ^{[1
,2
]}

Jarque, Marta ^{[3
]}

Angeletti, Andrea ^{[4
]}

Manrique, Joaquin ^{[5
]}

Hartzell, Susan ^{[1
]}

O'Donnell, Timothy ^{[6
]}

Merritt, Elliot ^{[6
]}

Laserson, Uri ^{[6
]}

Perin, Laura ^{[7
]}

Donadei, Chiara ^{[4
]}

Anderson, Lisa ^{[1
]}

Fischman, Clara ^{[1
]}

Chan, Emilie ^{[1
]}

Draibe, Juliana ^{[3
]}

Fulladosa, Xavier ^{[3
]}

Torras, Joan ^{[3
]}

Riella, Leonardo, V ^{[8
,9
]}

La Manna, Gaetano ^{[4
]}

Fiaccadori, Enrico ^{[2
]}

Maggiore, Umberto ^{[2
]}

Bestard, Oriol ^{[3
]}

Cravedi, Paolo ^{[1
]}

机构：

[1] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA

[2] Univ Parma, Dipartimento Med & Chirurg, Unita Operat Nefrol, Azienda Osped Univ Parma, Parma, Italy

[3] Barcelona Univ, Bellvitge Univ Hosp, Nephrol Dept, Kidney Transplant Unit,Biomed Res Inst Bellvitge, Barcelona, Spain

[4] Policlin St Orsola Malpighi, Dipartimento Med Specialist Diagnost & Sperimenta, Bologna, Italy

[5] Complejo Hosp Navarra, Nephrol Serv, Pamplona, Spain

[6] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[7] Univ Southern Calif, Keck Sch Med, Dept Urol, Los Angeles, CA 90007 USA

[8] Harvard Med Sch, Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02115 USA

[9] Massachusetts Gen Hosp, Dept Surg, Ctr Transplantat Sci, Boston, MA 02114 USA

来源：

KIDNEY INTERNATIONAL REPORTS | 2020年 / 5卷 / 10期

基金：

美国国家卫生研究院;

关键词：

membranous nephropathy; phospholipase A2 receptor; plasma cells; regulatory B cells; regulatory T cells; NECROSIS-FACTOR-ALPHA; NEPHROTIC SYNDROME; DISEASE-ACTIVITY; PLASMA-CELLS; RITUXIMAB; COMPLEMENT; EXPRESSION; BORTEZOMIB; THERAPY;

D O I：

10.1016/j.ekir.2020.07.028

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

1002 ; 100201 ;

摘要：

Introduction: Primary membranous nephropathy (MN) is characterized by the presence of antipodocyte antibodies, but studies describing phenotypic and functional abnormalities in circulating lymphocytes are limited. Methods: We analyzed 68 different B- and T-cell subsets using flow cytometry in 30 MN patients (before initiating immunosuppression) compared with 31 patients with non-immune-mediated chronic kidney disease (CKD) and 12 healthy individuals. We also measured 19 serum cytokines in MN patients and in healthy controls. Lastly, we quantified the ex vivo production of phospholipase A2 receptor (PLA2R)-specific IgG by plasmablasts (measuring antibodies in culture supernatants and by the newly developed FluoroSpot assay [AutoImmun Diagnostika, Strasberg, Germany]) and assessed the circulating antibody repertoire by phage immunoprecipitation sequencing (PhIP-Seq). Results: After adjusting for multiple testing, plasma cells and regulatory B cells (BREG) were significantly higher (P < 0.05) in MN patients compared with both control groups. The percentages of circulating plasma cells correlated with serum anti-PLA2R antibody levels (P = 0.042) and were associated with disease activity. Ex vivo-expanded PLA2R-specific IgG-producing plasmablasts generated from circulating PLA2R-specific memory B cells (mBCs) correlated with serum anti-PLA2R IgG antibodies (P < 0.001) in MN patients. Tumor necrosis factor-alpha (TNF-alpha) was the only significantly increased cytokine in MN patients (P < 0.05), whereas there was no significant difference across study groups in the autoantibody and antiviral antibody repertoire. Conclusion: This extensive phenotypic and functional immune characterization shows that autoreactive plasma cells are present in the circulation of MN patients, providing a new therapeutic target and a candidate biomarker of disease activity.

引用

页码：1764 / 1776

页数：13

共 57 条

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