Specific in situ inflammatory states associate with progression to renal failure in lupus nephritis
Rebecca Abraham, … , Maryellen L. Giger, Marcus R. Clark
Rebecca Abraham, … , Maryellen L. Giger, Marcus R. Clark
Published May 24, 2022
Citation Information: J Clin Invest. 2022;132(13):e155350. https://doi.org/10.1172/JCI155350.
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Clinical Research and Public Health Autoimmunity

Specific in situ inflammatory states associate with progression to renal failure in lupus nephritis

Abstract

BACKGROUND In human lupus nephritis (LN), tubulointerstitial inflammation (TII) on biopsy predicts progression to end-stage renal disease (ESRD). However, only about half of patients with moderate-to-severe TII develop ESRD. We hypothesized that this heterogeneity in outcome reflects different underlying inflammatory states. Therefore, we interrogated renal biopsies from LN longitudinal and cross-sectional cohorts.METHODS Data were acquired using conventional and highly multiplexed confocal microscopy. To accurately segment cells across whole biopsies, and to understand their spatial relationships, we developed computational pipelines by training and implementing several deep-learning models and other computer vision techniques.RESULTS High B cell densities were associated with protection from ESRD. In contrast, high densities of CD8+, γδ, and other CD4–CD8– T cells were associated with both acute renal failure and progression to ESRD. B cells were often organized into large periglomerular neighborhoods with Tfh cells, while CD4– T cells formed small neighborhoods in the tubulointerstitium, with frequency that predicted progression to ESRD.CONCLUSION These data reveal that specific in situ inflammatory states are associated with refractory and progressive renal disease.FUNDING This study was funded by the NIH Autoimmunity Centers of Excellence (AI082724), Department of Defense (LRI180083), Alliance for Lupus Research, and NIH awards (S10-OD025081, S10-RR021039, and P30-CA14599).

Authors

Rebecca Abraham, Madeleine S. Durkee, Junting Ai, Margaret Veselits, Gabriel Casella, Yuta Asano, Anthony Chang, Kichul Ko, Charles Oshinsky, Emily Peninger, Maryellen L. Giger, Marcus R. Clark

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Figure 4

Specific cellular neighborhoods associated with renal failure.

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Specific cellular neighborhoods associated with renal failure. Proportio...
Proportions of cells that have (A) CD20+ B cells and (B) CD4– T cells as nearest neighbors in ESRD+ and ESRD– patients (χ2 test for independence with Bonferroni’s correction for multiple comparisons). (C) Neighborhoods of automatically detected cells were detected by DBSCAN. Automatic cell segmentations and representative neighborhoods (highlighted in E) are shown for images taken at 63x magnification with a zoom factor of 1.7. (D) Heatmap showing test statistics for each feature from leave-one-out t tests used to define 6 types of cell neighborhoods, colored by the magnitude of the test statistic. (E) Representative neighborhoods from each defined class. (F and G) The abundance of neighborhoods between the patient cohorts, normalized by the number of ROIs per patient, was compared by Mann-Whitney U test with a Bonferroni’s correction for (F) all cell neighborhoods and (G) CD4– T cell neighborhoods. A 3-group comparison for CD4– neighborhoods, splitting the ESRD+ population into ESRD+ and ESRD current patients is shown in H. Significant P values after correcting for multiple comparisons are noted. The data set analyzed in this figure is the same as the data set introduced in Figure 2. For all box plots, the population mean is represented by a white diamond, and quartile ranges are defined by the whisker boundaries and upper and lower box boundaries. Outliers are represented as open circles.