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CCL17-producing cDC2s are essential in end-stage lupus nephritis and averted by a parasitic infection
Laura Amo, … , Juan Wu, Silvia Bolland
Laura Amo, … , Juan Wu, Silvia Bolland
Published June 1, 2021
Citation Information: J Clin Invest. 2021;131(11):e148000. https://doi.org/10.1172/JCI148000.
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Research Article Autoimmunity Nephrology

CCL17-producing cDC2s are essential in end-stage lupus nephritis and averted by a parasitic infection

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Abstract

Lupus nephritis is a severe organ manifestation in systemic lupus erythematosus leading to kidney failure in a subset of patients. In lupus-prone mice, controlled infection with Plasmodium parasites protects against the progression of autoimmune pathology including lethal glomerulonephritis. Here, we demonstrate that parasite-induced protection was not due to a systemic effect of infection on autoimmunity as previously assumed, but rather to specific alterations in immune cell infiltrates into kidneys and renal draining lymph nodes. Infection of lupus-prone mice with a Plasmodium parasite did not reduce the levels or specificities of autoreactive antibodies, vasculitis, immune complex–induced innate activation, or hypoxia. Instead, infection uniquely reduced kidney-infiltrating CCL17-producing bone marrow–derived type 2 inflammatory dendritic cells (iDC2s). Bone marrow reconstitution experiments revealed that infection with Plasmodium caused alterations in bone marrow cells that hindered the ability of DC2s to infiltrate the kidneys. The essential role for CCL17 in lupus nephritis was confirmed by in vivo depletion with a blocking antibody, which reduced kidney pathology and immune infiltrates, while bypassing the need for parasitic infection. Therefore, infiltration into the kidneys of iDC2s, with the potential to prime local adaptive responses, is an essential regulated event in the transition from manageable glomerulonephritis to lethal tubular injury.

Authors

Laura Amo, Hemanta K. Kole, Bethany Scott, Chen-Feng Qi, Juan Wu, Silvia Bolland

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Figure 4

Parasite infection impairs T cell and monocyte infiltration in kidney.

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Parasite infection impairs T cell and monocyte infiltration in kidney.
S...
Study of kidney-infiltrating cells in WT and FcγRIIb-KO mice 5 months after infection with Py. (A) Kidney sections were stained with anti–mouse CD45, -IBA1/Arg1, -F4/80, or -CD3 antibodies (scale bar: 200 μm). (B) Number of infiltrating (Inf) leukocytes (CD45+), myeloid cells (CD11b+), macrophages (CD11b+F4/80+), and CD4+/CD8+ T cells (TCRb+) measured by flow cytometry and gated as described in Supplemental Figure 3D and Supplemental Figure 4A. n = 6, 6, 13, and 12 for WT control, WT Py-infected, FcγRIIb-KO control, and FcγRIIb-KO Py–infected mice, respectively. Data are presented as the mean ± SD. Group comparisons were made using 1-way ANOVA. *P < 0.05 and **P < 0.01. (C) Correlation chart showing the number of kidney-infiltrating CD45 cells versus proteinuria levels in 6- to 7-month-old FcγRIIb-KO control mice (n = 56). Spearman’s r = 0.624; ****P < 0.0001.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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