Protective Role of Myeloid Cells Expressing a G-CSF Receptor Polymorphism in an Induced Model of Lupus

Sivakumar, Ramya; Abboud, Georges; Mathews, Clayton E.; Atkinson, Mark A.; Morel, Laurence

doi:10.3389/fimmu.2018.01053

Cited by 4 publications

(2 citation statements)

References 71 publications

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“…Given that the transferred bm12-CD4 + T cells were CD38 sufficient and the allo-reactive donor bm12 CD4 + T cells activated by host MHC II provide cognate help for host B cells to initiate lupus (36), these data support the role for Ag-presenting, B-cell-intrinsic CD38 in the induction of autoreactive immune responses. Alternatively, another antigen-presenting cell such as CD8a + DCs, known for its tolerogenic phenotype, may act in the early phases of the allo-immune response (57).…”

Section: Discussionmentioning

confidence: 99%

CD38 Deficiency Ameliorates Chronic Graft-Versus-Host Disease Murine Lupus via a B-Cell-Dependent Mechanism

et al. 2021

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The absence of the mouse cell surface receptor CD38 in Cd38−/− mice suggests that this receptor acts as a positive regulator of inflammatory and autoimmune responses. Here, we report that, in the context of the chronic graft-versus-host disease (cGVHD) lupus inducible model, the transfer of B6.C-H2bm12/KhEg(bm12) spleen cells into co-isogenic Cd38−/− B6 mice causes milder lupus-like autoimmunity with lower levels of anti-ssDNA autoantibodies than the transfer of bm12 spleen cells into WT B6 mice. In addition, significantly lower percentages of Tfh cells, as well as GC B cells, plasma cells, and T-bet+CD11chi B cells, were observed in Cd38−/− mice than in WT mice, while the expansion of Treg cells and Tfr cells was normal, suggesting that the ability of Cd38−/− B cells to respond to allogeneic help from bm12 CD4+ T cells is greatly diminished. The frequencies of T-bet+CD11chi B cells, which are considered the precursors of the autoantibody-secreting cells, correlate with anti-ssDNA autoantibody serum levels, IL-27, and sCD40L. Proteomics profiling of the spleens from WT cGVHD mice reflects a STAT1-driven type I IFN signature, which is absent in Cd38−/− cGVHD mice. Kidney, spleen, and liver inflammation was mild and resolved faster in Cd38−/− cGVHD mice than in WT cGVHD mice. We conclude that CD38 in B cells functions as a modulator receptor that controls autoimmune responses.

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Section: Discussionmentioning

confidence: 99%

CD38 Deficiency Ameliorates Chronic Graft-Versus-Host Disease Murine Lupus via a B-Cell-Dependent Mechanism

et al. 2021

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“…We identified a hypomorph allele of Cdkn2c as responsible for the Sle2c B1a cell expansion (9, 10). Sle2c contains a suppressive Sle2c2 sublocus (11) that we have mapped to a missense mutation in the Csf3r gene encoding for the GCSF receptor and regulates the development of CD8a + dendritic cells (11–13). In addition, we mapped the pathological phenotype synergizing with lpr to the centromeric portion of Sle2c , the Sle2c1 sublocus (7).…”

Section: Introductionmentioning

confidence: 99%

A Variant of the Histone-Binding Protein sNASP Contributes to Mouse Lupus

Zhu

et al. 2019

Front. Immunol.

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The Sle2c1rec1c ( rec1c ) sublocus is derived from the mouse lupus susceptibility 2 ( Sle2 ) locus identified in the NZM2410 model. Our current study dissected the functional characters and the genetic basis of the rec1c locus relative to lupus when co-expressed with the Fas lpr mutation, an established inducer of autoimmunity. The rec1c.lpr mice exhibited mild expansion of lymph nodes and had a normal T cell cellularity, but developed significantly kidney and lung inflammation, indicating that the rec1c amplifies lpr -induced autoimmune pathogenesis. A variant of somatic nuclear autoantigenic sperm protein (sNASP) was identified from the rec1c interval as a substitution of two consecutive amino acid residues in the histone-binding domain, resulting in an increased binding affinity to histone H4 and H3.1/H4 tetramer. To determine the role of the sNASP rec1c allele in mouse lupus, a novel strain was generated by introducing the rec1c mutations into the B6 genome. In this transgenic model, the sNASP allele synergized with the lpr mutation leading to moderate autoimmune phenotypes and aggravating inflammatory pathology alterations in kidney and lung that were similar to those observed in the rec1c.lpr mice. These results establish that the sNASP allele is a pathogenic genetic element in the rec1c sublocus, which not only promotes autoimmunity, but also exacerbates the inflammation reaction of end organs in mouse lupus pathogenesis. It also shows the complexity of the Sle2c locus, initially mapped as the major locus associated with B1a cell expansion. In addition to Cdkn2c , which regulates this expansion, we have now identified in the same locus a protective allele of Csf3r , a variant of Skint6 associated with T cell activation, and now a variant of sNASP that amplifies autoimmunity and tissue damage.

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Immunomodulatory effects of G-CSF in cancer: Therapeutic implications

Mouchemore

Anderson

2021

Seminars in Immunology

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Protective Role of Myeloid Cells Expressing a G-CSF Receptor Polymorphism in an Induced Model of Lupus

Cited by 4 publications

References 71 publications

CD38 Deficiency Ameliorates Chronic Graft-Versus-Host Disease Murine Lupus via a B-Cell-Dependent Mechanism

CD38 Deficiency Ameliorates Chronic Graft-Versus-Host Disease Murine Lupus via a B-Cell-Dependent Mechanism

A Variant of the Histone-Binding Protein sNASP Contributes to Mouse Lupus

Immunomodulatory effects of G-CSF in cancer: Therapeutic implications

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