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

Abstract

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. A higher resolution version of the Graphical abstract is available as Supplementary information.

Keywords: Adaptive immunity; Immunosequencing; Minimal change disease; NEPTUNE study; T-cell receptor.

Fig. 1.. Productive Simpson clonality for minimal change disease patients during active disease and during remission (n = 14)

Fig. 1. a The box plot of productive Simpson clonality visualizes the comparison of the mean TCR diversity between the samples drawn from MCD patients during active disease and those during complete remission. Fig. 1. b The line plot of productive Simpson clonality shows changes of the TCR diversity between the sample drawn from MCD patients during active disease and the corresponding sample during complete remission from the same patient. Each dot represents a sample and the line links the samples from the same individual. A dotted line denotes an increase in productive Simpson clonality from active disease to remission for the paired sample, while a solid line denotes a decrease in productive Simpson clonality from active disease to remission for the paired sample.

Fig. 1.. Productive Simpson clonality for minimal change disease patients during active disease and during remission (n = 14)

Fig. 1. a The box plot of productive Simpson clonality visualizes the comparison of the mean TCR diversity between the samples drawn from MCD patients during active disease and those during complete remission. Fig. 1. b The line plot of productive Simpson clonality shows changes of the TCR diversity between the sample drawn from MCD patients during active disease and the corresponding sample during complete remission from the same patient. Each dot represents a sample and the line links the samples from the same individual. A dotted line denotes an increase in productive Simpson clonality from active disease to remission for the paired sample, while a solid line denotes a decrease in productive Simpson clonality from active disease to remission for the paired sample.

Fig. 2.. Hierarchical clustering of Morisita-Horn index for the MCD, FSGS, and MN patients both during active disease and during remission

The dendrogram is constructed of the Morisita-Horn index, a metric to quantify the pairwise TCR similarity, for the 14 minimal change disease (MCD) patients, four focal segmental glomerulosclerosis (FSGS) patients, and four membranous nephropathy (MN) patients during active disease and during remission. Morisita-Horn index takes a value between 0 and 1, with the higher value indicating a more similar TCR repertoire.