Kidney Tertiary Lymphoid Structures in Lupus Nephritis Develop into Large Interconnected Networks and Resemble Lymph Nodes in Gene Signature

Seyed Esmaeil Dorraji,Premasany Kanapathippillai,Aud-Malin Karlsson Hovd,Mikael Ryan Stenersrød,Kjersti Daae Horvei,Anita Ursvik,Stine Linn Figenschau,Dhivya Thiyagarajan,Christopher Graham Fenton,Hege Lynum Pedersen,Kristin Andreassen Fenton

doi:10.1016/j.ajpath.2020.07.015

Seyed Esmaeil Dorraji, Premasany Kanapathippillai + Show 9 more

Open Access

https://doi.org/10.1016/j.ajpath.2020.07.015

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Abstract

Immune aggregates organized as tertiary lymphoid structures (TLS) are observed within the kidneys of patients with systemic lupus erythematosus and lupus nephritis (LN). Renal TLS was characterized in lupus-prone New Zealand black × New Zealand white F1 mice analyzing cell composition and vessel formation. RNA sequencing was performed on transcriptomes isolated from lymph nodes, macrodissected TLS from kidneys, and total kidneys of mice at different disease stages by using a personal genome machine and RNA sequencing. Formation of TLS was found in anti-double-stranded DNA antibody-positive mice, and the structures were organized as interconnected large networks with distinct T/B cell zones with adjacent dendritic cells, macrophages, plasma cells, high endothelial venules, supporting follicular dendritic cells network, and functional germinal centers. Comparison of gene profiles of whole kidney, renal TLS, and lymph nodes revealed a similar gene signature of TLS and lymph nodes. The up-regulated genes within the kidneys of lupus-prone mice during LN development reflected TLS formation, whereas the down-regulated genes were involved in metabolic processes of the kidney cells. A comparison with human LN gene expression revealed similar up-regulated genes asobserved during the development of murine LN and TLS. In conclusion, kidney TLS have a similar cell composition, structure, and gene signature as lymph nodes and therefore may function as a kidney-specific type of lymph node.

Highlights

Gene CountFalse Discovery RateData from http://geneontology.org/docs/go-enrichment-analysis, last accessed June 25, 2020.GO, Gene Ontology.larger tertiary lymphoid structures (TLS) (Figure 2A)
Smaller TLS were detected in the cortex of kidneys from proteinuric mice (Figure 1, C and F)
To examine the structural specifications of TLS and to investigate whether the TLS developed in separate regions of the kidneys, a three-dimensional structure of serial sections of a whole kidney was made (Figure 1G)

Summary

Introduction

Data from http://geneontology.org/docs/go-enrichment-analysis, last accessed June 25, 2020. Mist and plasma cells were detected within the TLS in areas outside the dense B-cell zones and germinal centers (Figure 2C). Many small microvessels were detected ajp.amjpathol.org throughout the structure, whereas HEVs were mostly located along the pelvic wall (Figure 2D). Large lymphatic vessel endothelial hyaluronan receptor 1epositive thin vessels were identified and contained CD3þ and B220þ T. Organ Development Group 1 vs Group 2 Gene Target Description.

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