The Role of Host CD4 T Cells in the Pathogenesis of the Chronic Graft-versus-Host Model of Systemic Lupus Erythematosus

Choudhury, Arpita; Maldonado, Michael A.; Cohen, Philip L.; Eisenberg, Robert A.

doi:10.4049/jimmunol.174.12.7600

Cited by 21 publications

(30 citation statements)

References 49 publications

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“…The latter mechanism would be parallel to what we have found in CD4 Ϫ/Ϫ mice, in which the development of B cells in the absence of the CD4 T cell subset results in their inability to respond in the cGVH (19,21). In addition, several groups have reported a failure to detect Mer on lymphocytes (7,10).…”

Section: B Cells Up-regulate Surface Expression Of Mer After Cgvhmentioning

confidence: 50%

“…Donor B cells disappear shortly after transfer and are not stimulated by the host T cells. Recipient B cells undergo polyclonal activation, accompanied by B cell phenotypic changes and increases in total serum levels of Igs (IgM and IgG), followed by the appearance of specific autoantibodies (19). We had predicted that Mer Ϫ/Ϫ mice would develop more rapid or robust cGVH, given their susceptibility to the spontaneous loss of tolerance presumably because of defective clearance of apoptotic cells (9).…”

Section: Discussionmentioning

confidence: 99%

“…Our previous studies have shown that host B cells from mice undergoing cGVH show phenotypic changes indicative of diffuse activation (19). We questioned whether Mer Ϫ/Ϫ host B cells, although unable to produce autoantibodies under these conditions, might nevertheless show evidence of activation.…”

Section: B Cells From Mer ϫ/ϫ Mice Do Not Have An Activated Phenotypementioning

confidence: 99%

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The Mer Receptor Tyrosine Kinase Is Required for the Loss of B Cell Tolerance in the Chronic Graft-versus-Host Disease Model of Systemic Lupus Erythematosus

Shao

Eisenberg

Cohen

2008

The Journal of Immunology

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The Mer receptor tyrosine kinase mediates apoptotic cell phagocytosis and modulates macrophage cytokine production. Mer−/− mice have defective clearance of apoptotic debris and develop a systemic lupus erythematosus-like autoimmune syndrome. It was surprising then that B6-Mer−/− recipients of bm12 spleen cells failed to develop anti-dsDNA and anti-chromatin autoantibodies, whereas B6 hosts produced the expected autoimmune chronic graft-vs-host (cGVH) reaction. The lack of autoantibody formation in cGVH was not due to the failure of Mer-deficient hosts to provoke alloreactivity, because Mer−/− spleen cells were recognized by bm12 T cells in MLR. Cell transfer experiments in Rag-knockout mice indicated that the lack of autoantibody production in Mer−/− cGVH disease hosts was due to an intrinsic B cell defect. This defect did not cause a global inability to produce autoantibodies, because in vivo exposure to LPS stimulated production of autoantibodies in both B6 and Mer−/− mice. We further observed that wild-type B6 B cells up-regulated Mer upon activation in cGVH, and that B cells from mice lacking Mer showed a decreased up-regulation of activation-associated cell surface markers. These findings indicate that Mer serves an important role in the activation of self-reactive B cells in systemic autoimmunity.

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Section: B Cells Up-regulate Surface Expression Of Mer After Cgvhmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Section: B Cells From Mer ϫ/ϫ Mice Do Not Have An Activated Phenotypementioning

confidence: 99%

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The Mer Receptor Tyrosine Kinase Is Required for the Loss of B Cell Tolerance in the Chronic Graft-versus-Host Disease Model of Systemic Lupus Erythematosus

Shao

Eisenberg

Cohen

2008

The Journal of Immunology

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“…cGVH was induced as previously described (21). In brief, disease was induced in 6-wk-old recipient mice by an intraperitoneal injection of a single cell suspension in HBSS of 10 8 donor spleen cells, prepared by pressing spleens through a wire mesh screen.…”

Section: Induction Of Cgvhmentioning

confidence: 99%

TWEAK/Fn14 Interactions Are Instrumental in the Pathogenesis of Nephritis in the Chronic Graft-versus-Host Model of Systemic Lupus erythematosus

Zhao

Burkly

Campbell

et al. 2007

The Journal of Immunology

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143

144

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TNF-like weak inducer of apoptosis (TWEAK), a member of the TNF superfamily, is a prominent inducer of proinflammatory cytokines in vitro and in vivo. We previously found that kidney cells display the TWEAK receptor Fn14, and that TWEAK stimulation of mesangial cells and podocytes induces a potent proinflammatory response. Several of the cytokines up-regulated in the kidney in response to TWEAK are instrumental in Lupus nephritis; we therefore hypothesized that TWEAK/Fn14 interactions may be important in the cascade(s) leading to renal damage in systemic Lupus erythematosus. In this study, we analyzed the effects of Fn14 deficiency in the chronic graft-vs-host model of SLE, and the benefits of treatment with an anti-TWEAK mAb in this mouse model. We found that anti-nuclear Ab titers were no different between C57BL/6 Fn14 wild-type and deficient mice injected with alloreactive bm12 splenocytes. However, kidney disease was significantly less severe in Fn14 knockout mice. Furthermore, kidney IgG deposition, IL-6, MCP-1, RANTES, and IP-10, as well as macrophage infiltration, were significantly decreased in Fn14-deficient mice with induced lupus. Similarly, mice with induced Lupus treated with an anti-TWEAK neutralizing mAb had significantly diminished kidney expression of IL-6, MCP-1, IL-10, as well as proteinuria, but similar autoantibody titers, as compared with control-treated mice. We conclude that TWEAK is an important mediator of kidney damage that acts by promoting local inflammatory events, but without impacting adaptive immunity in this experimental LN model. Thus, TWEAK blockade may be a novel therapeutic approach to reduce renal damage in SLE.

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“…The plates were read at various time points with an automated ELISA reader (Molecular Devices, Sunnyvale, CA). Autoantibody results from individual ELISAs were standardized against a reference serum [19].…”

Section: Detection Of Total Igg Anti-dsdna and Anti-chromatinmentioning

confidence: 99%

Accelerated atherosclerosis in ApoE deficient lupus mouse models

Choudhury

Kang

et al. 2008

Clinical Immunology

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The accelerated development of atherosclerosis with increased risk of cardiovascular disease in systemic lupus erythematosus (SLE) patients is not well understood. An appropriate mouse model would greatly help to understand the mechanisms of this association. We have therefore combined the ApoE -/-model of atherosclerosis with three different murine models of SLE. We found that induction of cGVH in B6.ApoE -/-mice, breeding a Fas null gene onto these B6/lpr.ApoE -/-mice, and breeding the ApoE -/-defect onto MRL/lpr mice all caused a modest increase of atherosclerosis at 24 weeks of age compared to B6.ApoE -/-controls. B cells in B6.ApoE -/-mice had certain phenotypic differences compared to congenic C57BL/6 mice, as indicated by high expression of MHC II, Fas, CD86, and by increased number of cells bearing marginal-zone phenotype. Furthermore, B6ApoE -/-mice had significant titers of anti-oxLDL and anti-cardiolipin autoantibodies compared to their B6 counterparts. Our studies also indicate that, following induction of cGVH, marginal zone B cells in B6.ApoE -/-are depleted, and there is considerable increase in anti-oxLDL and anticardiolipin abs along with secretion of lupus-specific autoantibodies, such as anti-dsDNA and antichromatin abs. Histological sections showed that cGVH and/or Fas deficiency could exacerbate atherosclerosis. The production of anti-oxLDL and anti-cardiolipin in ApoE -/-mice was also increased. These observations define a connection between induction of lupus-like symptoms and development of severe atherosclerosis in apoE deficient lupus mouse models.

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The Role of Host CD4 T Cells in the Pathogenesis of the Chronic Graft-versus-Host Model of Systemic Lupus Erythematosus

Cited by 21 publications

References 49 publications

The Mer Receptor Tyrosine Kinase Is Required for the Loss of B Cell Tolerance in the Chronic Graft-versus-Host Disease Model of Systemic Lupus Erythematosus

The Mer Receptor Tyrosine Kinase Is Required for the Loss of B Cell Tolerance in the Chronic Graft-versus-Host Disease Model of Systemic Lupus Erythematosus

TWEAK/Fn14 Interactions Are Instrumental in the Pathogenesis of Nephritis in the Chronic Graft-versus-Host Model of Systemic Lupus erythematosus

Accelerated atherosclerosis in ApoE deficient lupus mouse models

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