Fas/Fas Ligand Deficiency Results in Altered Localization of Anti-Double-Stranded DNA B Cells and Dendritic Cells

Fields, Michele L.; Sokol, Caroline L.; Eaton-Bassiri, Ashlyn; Seo, Su-jean; Madaio, Michael P.; Erikson, Jan

doi:10.4049/jimmunol.167.4.2370

Cited by 59 publications

(54 citation statements)

References 83 publications

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“…S1A). Moreover, the relevance of the exacerbated phenotype observed in lpr/ lpr/Sparc −/− mice on a BALB/c background was strengthened, as the severity of autoimmunity related to Fas lpr mutation is strain-dependent and reduced in BALB/c mice compared with the original MRL background ( 23 ). anti-dsDNA antibody levels in lpr/lpr/Sparc +/+ , lpr/lpr/Sparc −/− , and control Sparc +/+ and Sparc −/− mice.…”

Section: Exacerbated Autoimmunity and Lymphoproliferation In Fas -Mutmentioning

confidence: 99%

Defective Stromal Remodeling and Neutrophil Extracellular Traps in Lymphoid Tissues Favor the Transition from Autoimmunity to Lymphoma

et al. 2014

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Altered expression of matricellular proteins can become pathogenic in the presence of persistent perturbations in tissue homeostasis. Here, we show that autoimmunity associated with Fas mutation was exacerbated and transitioned to lymphomagenesis in the absence of SPARC (secreted protein acidic rich in cysteine). The absence of SPARC resulted in defective collagen assembly, with uneven compartmentalization of lymphoid and myeloid populations within secondary lymphoid organs (SLO), and faulty delivery of inhibitory signals from the extracellular matrix. These conditions promoted aberrant interactions between neutrophil extracellular traps and CD5 + B cells, which underwent malignant transformation due to defective apoptosis under the pressure of neutrophil-derived trophic factors and NF-κB activation. Furthermore, this model of defective stromal remodeling during lymphomagenesis correlates with human lymphomas arising in a SPARC-defective environment, which is prototypical of CD5 + B-cell chronic lymphocytic leukemia (CLL). SIGNIFICANCE:These results reveal the importance of stromal remodeling in SLO to accommodate autoimmune lymphoproliferation while preventing lymphomagenesis. Our fi ndings reveal a link between SPARC, collagen deposition, and the engagement of the immune-inhibitory receptor LAIR-1 on neutrophils, neutrophil cell death via NETosis, and the stimulation of CD5 + B-cell proliferation. Moreover, we show that SPARC defi ciency promotes CD5 + B-cell lymphomagenesis and is correlated with CLL in humans. Cancer Discov; 4(1);

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Section: Exacerbated Autoimmunity and Lymphoproliferation In Fas -Mutmentioning

confidence: 99%

Defective Stromal Remodeling and Neutrophil Extracellular Traps in Lymphoid Tissues Favor the Transition from Autoimmunity to Lymphoma

et al. 2014

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“…The number of circulating plasmacytoid DCs (pDCs) is reduced in lupus patients (19,20), and the number of total DCs is increased in the lymphoid organs of lupus-prone mice (21)(22)(23)(24). Abnormal costimulatory profiles have also been reported in lupus patients (25)(26)(27) and in BWF 1 or NZM2410 mice (28).…”

Section: Il-6 Produced By Dendritic Cells From Lupus-prone Micementioning

confidence: 99%

IL-6 Produced by Dendritic Cells from Lupus-Prone Mice Inhibits CD4+CD25+ T Cell Regulatory Functions

Wan

Xia

Morel

2007

The Journal of Immunology

185

178

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The B6.Sle1.Sle2.Sle3 triple congenic mouse (B6.TC) is a model of lupus coexpressing the three major NZM2410-derived susceptibility loci on a C57BL/6 background. B6.TC mice produce high titers of antinuclear nephrogenic autoantibodies and a highly penetrant glomerulonephritis. Previous studies have shown the Sle1 locus is associated with a reduced number of regulatory T cells (Treg) and that Sle3 results in intrinsic defects of myeloid cells that hyperactivate T cells. In this report, we show that B6.TC dendritic cells (DCs) accumulate in lymphoid organs and present a defective maturation process, in which bone marrow-derived, plasmacytoid, and myeloid DCs express a significantly lower level of CD80, CD86, and MHC class II. B6.TC DCs also induce a higher level of proliferation in CD4+ T cells than B6 DCs, and B6.TC DCs block the suppressive activity of Treg. B6.TC DCs overproduce IL-6, which is necessary for the blockade of Treg activity, as shown by the effect of anti-IL-6 neutralizing Ab in the suppression assays. The overproduction of IL-6 by DCs and the blockade of Treg activity maps to Sle1, which therefore not only confers a reduced number of Treg but also blocks their ability to regulate autoreactive T cells. Taken together, these results provide a genetic and mechanistic evidence for systemic autoimmunity resulting from an impaired regulatory T cell compartment in both number and function and for Sle1-expressing DCs playing a major role in the latter defect though their production of IL-6.

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“…ANA assays were performed using neat supernatants from hybridoma cultures as described (48). Briefly, ANA slides with fixed, permeabilized HEp-2 cells (Antibodies Incorporated) were incubated with neat hybridoma supernatants and binding was detected using anti-IgM-FITC plus antiIgG-FITC Abs (Southern Biotechnology Associates).…”

Section: Anti-nuclear Ab (Ana) Assaymentioning

confidence: 99%

Exogenous and Endogenous TLR Ligands Activate Anti-Chromatin and Polyreactive B Cells

Fields

Metzgar

Hondowicz

et al. 2006

The Journal of Immunology

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Autoreactive B cells may become activated in a T-independent manner via synergistic engagement of the BCR and TLRs. Using the VH3H9 Ig H chain transgene to track anti-chromatin B cells, we demonstrate that VH3H9/Vλ1 anti-chromatin B cells proliferate in response to stimulatory oligodeoxynucleotides containing CpG motifs, suggesting that these autoreactive B cells are responsive to TLR9 signaling. Strikingly, some VH3H9 B cells, but not the well-characterized VH3H9/Vλ1 B cells, proliferate spontaneously in culture medium. This proliferation is blocked by inhibitory CpG oligodeoxynucleotides, implicating the TLR9 (or possibly TLR7) pathway. Most hybridomas generated from the proliferating cells are polyreactive, and one exhibits binding to nuclear Ags but not to the other Ags tested. Thus, B cells carrying autoreactive and/or polyreactive specificities may be susceptible to T cell-independent activation via dual engagement of the BCR and TLRs.

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Fas/Fas Ligand Deficiency Results in Altered Localization of Anti-Double-Stranded DNA B Cells and Dendritic Cells

Cited by 59 publications

References 83 publications

Defective Stromal Remodeling and Neutrophil Extracellular Traps in Lymphoid Tissues Favor the Transition from Autoimmunity to Lymphoma

Defective Stromal Remodeling and Neutrophil Extracellular Traps in Lymphoid Tissues Favor the Transition from Autoimmunity to Lymphoma

IL-6 Produced by Dendritic Cells from Lupus-Prone Mice Inhibits CD4+CD25+ T Cell Regulatory Functions

Exogenous and Endogenous TLR Ligands Activate Anti-Chromatin and Polyreactive B Cells

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