The spectrum of apoptotic defects and clinical manifestations, including systemic lupus erythematosus, in humans with CD95 (Fas/APO-1) mutations

Vaishnaw, Akshay; Toubi, Elias; Ohsako, Satomi; Drappa, Jörn; Buys, Saundra S.; Estrada, Jaime; Sitarz, Anneliese L.; Zemel, Larry; Chu, Jia Li; Elkon, Keith B.

doi:10.1002/1529-0131(199909)42:9<1833::aid-anr7>3.0.co;2-q

Cited by 86 publications

(32 citation statements)

References 33 publications

(32 reference statements)

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“…35). However, hereditary defects in complement (36) or apoptosis (37,38) account for only a minority of humans with SLE. Thus, the exact role of altered apoptosis in lupus pathogenesis has been controversial.…”

Section: Discussionmentioning

confidence: 99%

Apoptotic Splenocytes Drive the Autoimmune Response to Poly(ADP-ribose) Polymerase 1 in a Murine Model of Lupus

Grader‐Beck¹,

Casciola‐Rosen²,

Lang

et al. 2007

The Journal of Immunology

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Although defects in apoptosis have been linked to both human and murine lupus, the exact mechanisms remain unknown. Moreover, it is not clear whether such defects are primary or secondary events in disease pathogenesis. To address these issues, we used an induced model of murine lupus, the parent-into-F1 model of chronic graft-versus-host disease (cGVHD) in which a lupus-like phenotype highly similar to human systemic lupus erythematosus is reliably induced in normal F1 mice. We addressed the role of nuclear Ags modified by caspases during apoptosis as potential targets of the autoantibody response and our results identify poly(ADP-ribose) polymerase 1 (PARP-1) as a frequently targeted autoantigen. Additional proteins cleaved during apoptosis were also targeted by the immune response. Importantly, female mice exhibited significantly greater numbers of apoptotic cells in germinal centers and higher serum anti-PARP-1 Ab levels compared with male cGVHD mice. Serum anti-PARP-1 levels in male cGVHD mice could be elevated to levels comparable to those of female cGVHD mice by the injection of apoptotic syngeneic F1 splenocytes early in the disease course. These results provide a mechanism by which lupus autoantibodies target apoptotic molecules. Specifically, T cell-driven polyclonal B cell activation characteristic of systemic lupus erythematosus is sufficient to saturate otherwise normal apoptotic clearance mechanisms, permitting apoptotic material to accumulate, serve as autoantigens, and drive autoantibody production.

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Section: Discussionmentioning

confidence: 99%

Apoptotic Splenocytes Drive the Autoimmune Response to Poly(ADP-ribose) Polymerase 1 in a Murine Model of Lupus

Grader‐Beck¹,

Casciola‐Rosen²,

Lang

et al. 2007

The Journal of Immunology

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“…[15][16][17][18] Abnormal expression of FasL on lymphocytes and apoptosis triggering has been demonstrated in SLE patients. [19][20][21][22] Anti-FasL antibody, which inhibits Fas/FasL-mediated apoptosis, can be detected in SLE patients. 23 The enhanced serum levels of soluble Fas demonstrated that the intriguing effect of the Fas/FasL pathway on cell death was related to disease activity.…”

Section: Introductionmentioning

confidence: 99%

The −844C/T polymorphism in the Fas ligand promoter associates with Taiwanese SLE

Chen¹,

Wang²,

Chi³

et al. 2005

Genes Immun

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FasL expression is critical in T-cell activation-induced apoptosis, which is involved in lupus pathogenesis. This study identified two SNPs in the FasL promoter regions from -1145 to -45 by genomic DNA sequencing. The -844C/T polymorphism was previously described by its location in and affect on the CCAAT/enhancer-binding protein b (C/EBPB b)-binding site and the other (-1094A/C, a novel polymorphism) was located at the NF-kB transcription-binding site. FasL gene promoter polymorphisms were genotyped in 260 systemic lupus erythematosus (SLE) patients and 280 healthy controls using MassArray matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry. The distribution of FasL promoter -844C/C genotype, predominant in Taiwanese, was skewed in Taiwanese SLE patients (odds ratio: 1.53; P-value ¼ 0.014). FasL promoter À844C/T polymorphism genotype distributions of Taiwanese, African Americans, and Caucasians differed. Moreover, no particular clinical association of À844C/T and À1094A/C polymorphisms with SLE was found in patients in Taiwan. This study confirmed that À844C/C genotype is associated with lupus susceptibility. The -1094A/C polymorphism is not significantly associated with lupus disease susceptibility, albeit the role of NF-kB pathway in FasL promoter activation remains unclear. Fas/FasL pathway may contribute to SLE polygenic disease entity.

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“…At least partly, this may be related to the fact that the majority of the genetic manipulations in lupus-prone mice used the MRL-lpr/lpr strain, which lacks functional activity of the CD95 (Fas) apoptosis gene, an important regulator of activated T and B lymphocytes. Consequently, extrapolation of conclusions derived from these mice to human SLE in general must bear in mind that the vast majority of SLE patients possess functionally intact CD95 (2) and CD95 ligand (3). Therefore, we postulate that greater correlation to human SLE can be obtained by performing such experiments in non-lpr strains.…”

mentioning

confidence: 99%

Pivotal Role of Stat4 and Stat6 in the Pathogenesis of the Lupus-Like Disease in the New Zealand Mixed 2328 Mice

Jacob¹,

Zang²,

Li³

et al. 2003

The Journal of Immunology

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We have developed novel genetically lupus-prone (NZB × NZW)F1-derived congenic New Zealand mixed (NZM) 2328 lines, which are either Stat4- or Stat6-deficient. Our studies show that the deficiency of Stat4 and Stat6 significantly alters the phenotype of the lupus-like disease in NZM 2328 congenic mice. Specifically, Stat4-deficient NZM mice develop accelerated nephritis and increased mortality in the absence of high levels of autoantibodies including anti-dsDNA Abs, and in the presence of relatively reduced levels of IFN-γ. In contrast, Stat6-deficient NZM mice display a significant reduction in incidence of kidney disease, with a dramatic increase in survival, despite the presence of high levels of anti-dsDNA Abs. The lack of correlation between levels of these autoantibodies and kidney disease raises the question of the direct cause-effect relationships between the presence of autoantibodies and kidney disease. Furthermore, these results also question the apparent equation of the effect of Stat deficiency with loss of secretion or response to particular cytokines.

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The spectrum of apoptotic defects and clinical manifestations, including systemic lupus erythematosus, in humans with CD95 (Fas/APO-1) mutations

Abstract: CD95 mutations are associated with loss of regulation of B lymphocytes, which predisposes to systemic autoimmunity including SLE. The P4 family provides a model of the complex genetic and functional interactions that are required for the development of a lupus-like syndrome.

Cited by 86 publications

References 33 publications

Apoptotic Splenocytes Drive the Autoimmune Response to Poly(ADP-ribose) Polymerase 1 in a Murine Model of Lupus

Apoptotic Splenocytes Drive the Autoimmune Response to Poly(ADP-ribose) Polymerase 1 in a Murine Model of Lupus

The −844C/T polymorphism in the Fas ligand promoter associates with Taiwanese SLE

Pivotal Role of Stat4 and Stat6 in the Pathogenesis of the Lupus-Like Disease in the New Zealand Mixed 2328 Mice

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