Animal Models of Molecular Pathology

Sang, Allison; Yin, Yiming; Zheng, Ying-Yi; Morel, Laurence

doi:10.1016/b978-0-12-394596-9.00010-x

Cited by 31 publications

(22 citation statements)

References 320 publications

(329 reference statements)

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“…Furthermore, DCs from SLE patients fail to yield a tolerizing phenotype under experimental conditions (50) and produce high levels of proinflammatory IL-6, which is known to inhibit CD4 + CD25 + regulatory T-cells (51). These findings are recapitulated in DCs from mice with SLE-like disease in which the number of DCs is increased as is their secretion of pro-inflammatory cytokines (IL-12 and IL-6), cell-surface activation and maturation markers, induction of T-cell effector responses, and reduction of regulatory T-cell function compared to control DCs (52). While these results support an important role for the expansion and activation of DCs in both human and murine models of SLE, the underlying mechanisms driving these changes are unknown.…”

Section: Discussionmentioning

confidence: 84%

Caspase-8 Acts as a Molecular Rheostat To Limit RIPK1- and MyD88-Mediated Dendritic Cell Activation

Cuda

Misharin

Gierut

et al. 2014

The Journal of Immunology

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Caspase-8, an executioner enzyme in the death receptor pathway, has previously been shown to initiate apoptosis and suppress necroptosis. Here, we identify a novel, cell death-independent role for caspase-8 in dendritic cells (DCs); namely, DC-specific expression of caspase-8 prevents the onset of systemic autoimmunity. Failure to express caspase-8 has no effect on the life-span of DCs but instead leads to an enhanced intrinsic activation and subsequently more mature and autoreactive lymphocytes. Uncontrolled toll-like receptor activation in a RIPK1-dependent manner is responsible for the enhanced functionality of caspase-8-deficient DCs, as deletion of TLR signaling mediator, MyD88, ameliorates systemic autoimmunity induced by caspase-8 deficiency. Taken together, these data demonstrate that caspase-8 functions in a cell-type-specific manner and acts uniquely in DCs to maintain tolerance.

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Section: Discussionmentioning

confidence: 84%

Caspase-8 Acts as a Molecular Rheostat To Limit RIPK1- and MyD88-Mediated Dendritic Cell Activation

Cuda

Misharin

Gierut

et al. 2014

The Journal of Immunology

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“…Native DNA is well known to be a poor immunogen, although in SLE anti-DNA autoantibodies are considered to be a hallmark of the disease. [23] But it is still unclear how DNA becomes immunogenic in SLE. Oxidative DNA damage has been implicated in SLE and experimentally induced antibodies against oxidatively modified DNA exhibit polyspecificity, [24] recognizing B-, A, and allied conformations of DNA.…”

Section: Discussionmentioning

confidence: 99%

Preferential Recognition of Peroxynitrite Damaged Thymidine-Monophosphate by Anti-DNA Autoantibodies in Systemic Lupus Erythematosus

Rasheed

Al‐Shobaili

Robaee

et al. 2012

Nucleosides, Nucleotides and Nucleic Acids

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This study was undertaken to investigate the role of peroxynitrite (ONOO(-)) modified thymine-5'-monophosphate (TMP) in the generation of anti-DNA autoantibodies in patients with systemic lupus erythematosus (SLE). TMP was exposed to ONOO(-) in vitro and challenged in vivo. TMP and ONOO(-)-modified-TMP were found to be nonimmunogenic in rabbits. TMP-linked-BSA and ONOO(-)-modified-TMP-BSA induced high titer antibodies. Induced antibodies against ONOO(-)-TMP-BSA show crossreactions with nucleic acids conformers. A high degree of specific binding by SLE autoantibodies with ONOO(-)-TMP-BSA was observed. Our novel results provide an important insight into the immunological basis of anti-DNA autoantibodies generation in SLE.

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“…[6][7][8] MRL-lpr/lpr mice as an animal model of SLE/SS MRL-lpr/lpr mice resemble human SLE in several ways, and therefore, is a widely used animal model. [9][10][11][12][13][14][15][16][17][18] MRL-lpr/ lpr mouse has a single-gene mutation (lpr) of the fas apoptosis gene on mouse chromosome 19, and therefore, a defect in apoptotic death of lymphocytes. There is massive accumulation of CD4 − CD8 − T lymphocytes and development of a disease similar to human SLE.…”

Section: Key Messagesmentioning

confidence: 99%

Significantly reduced lymphadenopathy, salivary gland infiltrates and proteinuria in MRL-lpr/lprmice treated with ultrasoluble curcumin/turmeric: increased survival with curcumin treatment

et al. 2015

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ObjectivesCommercial curcumin (CU), derived from food spice turmeric (TU), has been widely studied as a potential therapeutic for a variety of oncological and inflammatory conditions. Lack of solubility/bioavailability has hindered curcumin's therapeutic efficacy in human diseases. We have solubilised curcumin in water applying heat/pressure, obtaining up to 35-fold increase in solubility (ultrasoluble curcumin (UsC)). We hypothesised that UsC or ultrasoluble turmeric (UsT) will ameliorate systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS)-like disease in MRL-lpr/lpr mice.MethodsEighteen female MRL-lpr/lpr (6 weeks old) and 18 female MRL-MpJ mice (6 weeks old) were used. Female MRL-lpr/lpr mice develop lupus-like disease at the 10th week and die at an average age of 17 weeks. MRL-MpJ mice develop lupus-like disease around 47 weeks and typically die at 73 weeks. Six mice of each strain received autoclaved water only (lpr-water or MpJ-water group), UsC (lpr-CU or MpJ-CU group) or UsT (lpr-TU or MpJ-TU group) in the water bottle.ResultsUsC or UsT ameliorates SLE in the MRL-lpr/lpr mice by significantly reducing lymphoproliferation, proteinuria, lesions (tail) and autoantibodies. lpr-CU group had a 20% survival advantage over lpr-water group. However, lpr-TU group lived an average of 16 days shorter than lpr-water group due to complications unrelated to lupus-like illness. CU/TU treatment inhibited lymphadenopathy significantly compared with lpr-water group (p=0.03 and p=0.02, respectively) by induction of apoptosis. Average lymph node weights were 2606±1147, 742±331 and 385±68 mg, respectively, for lpr-water, lpr-CU and lpr-TU mice. Transferase dUTP nick end labelling assay showed that lymphocytes in lymph nodes of lpr-CU and lpr-TU mice underwent apoptosis. Significantly reduced cellular infiltration of the salivary glands in the lpr-TU group compared with the lpr-water group, and a trend towards reduced kidney damage was observed in the lpr-CU and lpr-TU groups.ConclusionsThese studies show that UsC/UsT could prove useful as a therapeutic intervention in SLE/SS.

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Animal Models of Molecular Pathology

Cited by 31 publications

References 320 publications

Caspase-8 Acts as a Molecular Rheostat To Limit RIPK1- and MyD88-Mediated Dendritic Cell Activation

Caspase-8 Acts as a Molecular Rheostat To Limit RIPK1- and MyD88-Mediated Dendritic Cell Activation

Preferential Recognition of Peroxynitrite Damaged Thymidine-Monophosphate by Anti-DNA Autoantibodies in Systemic Lupus Erythematosus

Significantly reduced lymphadenopathy, salivary gland infiltrates and proteinuria in MRL-lpr/lprmice treated with ultrasoluble curcumin/turmeric: increased survival with curcumin treatment

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