T-cell receptor diversity in minimal change disease in the NEPTUNE study

• Published in: Pediatric nephrology (Berlin, West) West), 2023-04, Vol.38 (4), p.1115-1126
• Main Authors: Liu, Shiying, Bush, William S., Miskimen, Kristy, Gonzalez-Vicente, Agustin, Bailey, Jessica N. Cooke, Konidari, Ioanna, McCauley, Jacob L., Sedor, John R., O’Toole, John F., Crawford, Dana C.
• Format: Article
• Language: English
• Subjects: Antigens; Causes of; Child; Children; Demographic aspects; Edema; Glomerulonephritis, Membranous - complications; Glomerulosclerosis, Focal Segmental - complications; Health aspects; Humans; Immune system; Immunosuppressive agents; Lymphocytes T; Medicine; Medicine & Public Health; Membranous nephropathy; Nephrology; Nephropathy; Nephrosis, Lipoid - drug therapy; Nephrotic syndrome; Nephrotic Syndrome - drug therapy; Neptune; Original Article; Pathogenesis; Pediatrics; Proteinuria; Proteinuria - etiology; Receptors, Antigen, T-Cell - therapeutic use; Recurrence; Remission; Remission (Medicine); T cell receptors; T cells; Urology
• ISSN: 0931-041X; 1432-198X
• DOI: 10.1007/s00467-022-05696-x

Background Minimal change disease (MCD) is the major cause of childhood idiopathic nephrotic syndrome, which is characterized by massive proteinuria and debilitating edema. Proteinuria in MCD is typically rapidly reversible with corticosteroid therapy, but relapses are common, and children often have many adverse events from the repeated courses of immunosuppressive therapy. The pathobiology of MCD remains poorly understood. Prior clinical observations suggest that abnormal T-cell function may play a central role in MCD pathogenesis. Based on these observations, we hypothesized that T-cell responses to specific exposures or antigens lead to a clonal expansion of T-cell subsets, a restriction in the T-cell repertoire, and an elaboration of specific circulating factors that trigger disease onset and relapses. Methods To test these hypotheses, we sequenced T-cell receptors in fourteen MCD, four focal segmental glomerulosclerosis (FSGS), and four membranous nephropathy (MN) patients with clinical data and blood samples drawn during active disease and during remission collected by the Nephrotic Syndrome Study Network (NEPTUNE). We calculated several T-cell receptor diversity metrics to assess possible differences between active disease and remission states in paired samples. Results Median productive clonality did not differ between MCD active disease (0.0083; range: 0.0042, 0.0397) and remission (0.0088; range: 0.0038, 0.0369). We did not identify dominant clonotypes in MCD active disease, and few clonotypes were shared with FSGS and MN patients. Conclusions While these data do not support an obvious role of the adaptive immune system T-cells in MCD pathogenesis, further study is warranted given the limited sample size. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information .