Deletion of CD137 Ligand Exacerbates Renal and Cutaneous but Alleviates Cerebral Manifestations in Lupus
The CD137-CD137 ligand (CD137L) costimulatory system is a critical immune checkpoint with pathophysiological implications in autoimmunity. In this study, we investigated the role of CD137L-mediated costimulation on renal, cutaneous and cerebral manifestations in lupus and the underlying immunologica...
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Published in | Frontiers in immunology Vol. 10; p. 1411 |
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Abstract | The CD137-CD137 ligand (CD137L) costimulatory system is a critical immune checkpoint with pathophysiological implications in autoimmunity. In this study, we investigated the role of CD137L-mediated costimulation on renal, cutaneous and cerebral manifestations in lupus and the underlying immunological mechanism. Lupus-prone C57BL/6
(B6.lpr) mice were crossed to C57BL/6.CD137L
mice to obtain
deficient B6.lpr [double knock out (DKO)] mice. We investigated the extent of survival, glomerulonephritis, skin lesions, cerebral demyelination, immune deviation and long-term synaptic plasticity among the two mouse groups. Cytokine levels, frequency of splenic leukocyte subsets and phenotypes were compared between DKO, B6.lpr and B6.WT mice. A 22 month observation of 226 DKO and 137 B6.lpr mice demonstrated significantly more frequent proliferative glomerulonephritis, larger skin lesions and shorter survival in DKO than in B6.lpr mice. Conversely, microglial activation and cerebral demyelination were less pronounced while long-term synaptic plasticity, was superior in DKO mice. Splenic Th17 cells were significantly higher in DKO than in B6.lpr and B6.WT mice while Th1 and Th2 cell frequencies were comparable between DKO and B6.lpr mice. IL-10 and IL-17 expression by T cells was not affected but there were fewer IL-10-producing myeloid (CD11b
) cells, and also lower serum IL-10 levels in DKO than in B6.lpr mice. The absence of CD137L causes an immune deviation toward Th17, fewer IL-10-producing CD11b
cells and reduced serum IL-10 levels which potentially explain the more severe lupus in DKO mice while leading to reduced microglia activation, lesser cerebral damage and less severe neurological deficits. |
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AbstractList | The CD137—CD137 ligand (CD137L) costimulatory system is a critical immune checkpoint with pathophysiological implications in autoimmunity. In this study, we investigated the role of CD137L-mediated costimulation on renal, cutaneous and cerebral manifestations in lupus and the underlying immunological mechanism. Lupus-prone C57BL/6
lpr−/−
(B6.lpr) mice were crossed to C57BL/6.CD137L
−/−
mice to obtain
CD137L-
deficient B6.lpr [double knock out (DKO)] mice. We investigated the extent of survival, glomerulonephritis, skin lesions, cerebral demyelination, immune deviation and long-term synaptic plasticity among the two mouse groups. Cytokine levels, frequency of splenic leukocyte subsets and phenotypes were compared between DKO, B6.lpr and B6.WT mice. A 22 month observation of 226 DKO and 137 B6.lpr mice demonstrated significantly more frequent proliferative glomerulonephritis, larger skin lesions and shorter survival in DKO than in B6.lpr mice. Conversely, microglial activation and cerebral demyelination were less pronounced while long-term synaptic plasticity, was superior in DKO mice. Splenic Th17 cells were significantly higher in DKO than in B6.lpr and B6.WT mice while Th1 and Th2 cell frequencies were comparable between DKO and B6.lpr mice. IL-10 and IL-17 expression by T cells was not affected but there were fewer IL-10-producing myeloid (CD11b
+
) cells, and also lower serum IL-10 levels in DKO than in B6.lpr mice. The absence of CD137L causes an immune deviation toward Th17, fewer IL-10-producing CD11b
+
cells and reduced serum IL-10 levels which potentially explain the more severe lupus in DKO mice while leading to reduced microglia activation, lesser cerebral damage and less severe neurological deficits. The CD137—CD137 ligand (CD137L) costimulatory system is a critical immune checkpoint with pathophysiological implications in autoimmunity. In this study, we investigated the role of CD137L-mediated costimulation on renal, cutaneous and cerebral manifestations in lupus and the underlying immunological mechanism. Lupus-prone C57BL/6lpr−/− (B6.lpr) mice were crossed to C57BL/6.CD137L−/− mice to obtain CD137L-deficient B6.lpr [double knock out (DKO)] mice. We investigated the extent of survival, glomerulonephritis, skin lesions, cerebral demyelination, immune deviation and long-term synaptic plasticity among the two mouse groups. Cytokine levels, frequency of splenic leukocyte subsets and phenotypes were compared between DKO, B6.lpr and B6.WT mice. A 22 month observation of 226 DKO and 137 B6.lpr mice demonstrated significantly more frequent proliferative glomerulonephritis, larger skin lesions and shorter survival in DKO than in B6.lpr mice. Conversely, microglial activation and cerebral demyelination were less pronounced while long-term synaptic plasticity, was superior in DKO mice. Splenic Th17 cells were significantly higher in DKO than in B6.lpr and B6.WT mice while Th1 and Th2 cell frequencies were comparable between DKO and B6.lpr mice. IL-10 and IL-17 expression by T cells was not affected but there were fewer IL-10-producing myeloid (CD11b+) cells, and also lower serum IL-10 levels in DKO than in B6.lpr mice. The absence of CD137L causes an immune deviation toward Th17, fewer IL-10-producing CD11b+ cells and reduced serum IL-10 levels which potentially explain the more severe lupus in DKO mice while leading to reduced microglia activation, lesser cerebral damage and less severe neurological deficits. The CD137-CD137 ligand (CD137L) costimulatory system is a critical immune checkpoint with pathophysiological implications in autoimmunity. In this study, we investigated the role of CD137L-mediated costimulation on renal, cutaneous and cerebral manifestations in lupus and the underlying immunological mechanism. Lupus-prone C57BL/6 (B6.lpr) mice were crossed to C57BL/6.CD137L mice to obtain deficient B6.lpr [double knock out (DKO)] mice. We investigated the extent of survival, glomerulonephritis, skin lesions, cerebral demyelination, immune deviation and long-term synaptic plasticity among the two mouse groups. Cytokine levels, frequency of splenic leukocyte subsets and phenotypes were compared between DKO, B6.lpr and B6.WT mice. A 22 month observation of 226 DKO and 137 B6.lpr mice demonstrated significantly more frequent proliferative glomerulonephritis, larger skin lesions and shorter survival in DKO than in B6.lpr mice. Conversely, microglial activation and cerebral demyelination were less pronounced while long-term synaptic plasticity, was superior in DKO mice. Splenic Th17 cells were significantly higher in DKO than in B6.lpr and B6.WT mice while Th1 and Th2 cell frequencies were comparable between DKO and B6.lpr mice. IL-10 and IL-17 expression by T cells was not affected but there were fewer IL-10-producing myeloid (CD11b ) cells, and also lower serum IL-10 levels in DKO than in B6.lpr mice. The absence of CD137L causes an immune deviation toward Th17, fewer IL-10-producing CD11b cells and reduced serum IL-10 levels which potentially explain the more severe lupus in DKO mice while leading to reduced microglia activation, lesser cerebral damage and less severe neurological deficits. |
Author | Dharmadhikari, Bhushan Kow, Nien Yee Wong, Hiu Yi Wong, Lik Wei Sajikumar, Sreedharan Mak, Anselm Schwarz, Herbert Tang, Qianqiao Thamboo, Thomas Paulraj |
AuthorAffiliation | 5 Department of Pathology, National University of Singapore , Singapore , Singapore 2 Department of Medicine, National University of Singapore , Singapore , Singapore 3 Division of Rheumatology, University Medicine Cluster, National University Health System , Singapore , Singapore 4 Immunlogy Programme, National University of Singapore , Singapore , Singapore 1 Department of Physiology, National University of Singapore , Singapore , Singapore |
AuthorAffiliation_xml | – name: 1 Department of Physiology, National University of Singapore , Singapore , Singapore – name: 4 Immunlogy Programme, National University of Singapore , Singapore , Singapore – name: 5 Department of Pathology, National University of Singapore , Singapore , Singapore – name: 3 Division of Rheumatology, University Medicine Cluster, National University Health System , Singapore , Singapore – name: 2 Department of Medicine, National University of Singapore , Singapore , Singapore |
Author_xml | – sequence: 1 givenname: Anselm surname: Mak fullname: Mak, Anselm organization: Division of Rheumatology, University Medicine Cluster, National University Health System, Singapore, Singapore – sequence: 2 givenname: Bhushan surname: Dharmadhikari fullname: Dharmadhikari, Bhushan organization: Immunlogy Programme, National University of Singapore, Singapore, Singapore – sequence: 3 givenname: Nien Yee surname: Kow fullname: Kow, Nien Yee organization: Department of Medicine, National University of Singapore, Singapore, Singapore – sequence: 4 givenname: Thomas Paulraj surname: Thamboo fullname: Thamboo, Thomas Paulraj organization: Department of Pathology, National University of Singapore, Singapore, Singapore – sequence: 5 givenname: Qianqiao surname: Tang fullname: Tang, Qianqiao organization: Immunlogy Programme, National University of Singapore, Singapore, Singapore – sequence: 6 givenname: Lik Wei surname: Wong fullname: Wong, Lik Wei organization: Department of Physiology, National University of Singapore, Singapore, Singapore – sequence: 7 givenname: Sreedharan surname: Sajikumar fullname: Sajikumar, Sreedharan organization: Department of Physiology, National University of Singapore, Singapore, Singapore – sequence: 8 givenname: Hiu Yi surname: Wong fullname: Wong, Hiu Yi organization: Immunlogy Programme, National University of Singapore, Singapore, Singapore – sequence: 9 givenname: Herbert surname: Schwarz fullname: Schwarz, Herbert organization: Immunlogy Programme, National University of Singapore, Singapore, Singapore |
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CitedBy_id | crossref_primary_10_3390_cells10020353 crossref_primary_10_1093_rheumatology_keab511 crossref_primary_10_3390_cells8101213 crossref_primary_10_4103_1673_5374_371357 crossref_primary_10_1007_s12017_023_08764_z crossref_primary_10_3390_cells8091044 crossref_primary_10_1007_s12017_020_08623_1 crossref_primary_10_1016_j_celrep_2020_02_103 crossref_primary_10_1016_j_jaut_2020_102499 crossref_primary_10_1002_JLB_2MR1119_224R |
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ContentType | Journal Article |
Copyright | Copyright © 2019 Mak, Dharmadhikari, Kow, Thamboo, Tang, Wong, Sajikumar, Wong and Schwarz. 2019 Mak, Dharmadhikari, Kow, Thamboo, Tang, Wong, Sajikumar, Wong and Schwarz |
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Keywords | CD137 ligand skin lesions synaptic plasticity glomerulonephritis SLE Th17 |
Language | English |
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Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by: J. Michelle Kahlenberg, University of Michigan, United States These authors have contributed equally to this work Reviewed by: Joshua Daniel Ooi, Monash University, Australia; Jeremy Scott Tilstra, University of Pittsburgh, United States This article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology |
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Snippet | The CD137-CD137 ligand (CD137L) costimulatory system is a critical immune checkpoint with pathophysiological implications in autoimmunity. In this study, we... The CD137—CD137 ligand (CD137L) costimulatory system is a critical immune checkpoint with pathophysiological implications in autoimmunity. In this study, we... |
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SubjectTerms | CD137 ligand glomerulonephritis Immunology skin lesions SLE synaptic plasticity Th17 |
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Title | Deletion of CD137 Ligand Exacerbates Renal and Cutaneous but Alleviates Cerebral Manifestations in Lupus |
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