B-cell overexpression of Bcl-2 cooperates with p21 deficiency for the induction of autoimmunity and lymphomas

Santiuste, Inés; Buelta, Luis; Iglesias, Marcos; Genre, Fernanda; Mazorra, Francisco; Izui, Shozo; Merino, Jesús; Merino, Ramón

doi:10.1016/j.jaut.2010.07.002

Cited by 8 publications

(4 citation statements)

References 37 publications

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“…Purified Treg cells from different mice were cultured in triplicate at a concentration of 10 6 /ml in complete RPMI 1640 medium containing 10% fetal calf serum. Cell viability was assessed daily by trypan blue exclusion, as previously described (25). Naive CD4+ cells were stimulated with plastic‐bound anti‐CD3 mAb for 3–5 days in the presence or absence of different concentrations of recombinant human TGFβ1.…”

Section: Methodsmentioning

confidence: 99%

p27^Kip1 inhibits systemic autoimmunity through the control of Treg cell activity and differentiation

Iglesias¹,

Postigo²,

Santiuste³

et al. 2013

Arthritis & Rheumatism

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Objective. Despite the importance of Treg cells in the maintenance of immunologic tolerance, the mechanisms that control their generation and activity are unknown. Since the cell cycle inhibitor p27 Kip1 (p27) was involved in T cell anergy, we undertook this study to explore its role in both Treg cell processes.Methods. The development of type II collageninduced arthritis (CIA) and lupus-like abnormalities was compared between transgenic mice overexpressing human Bcl-2 in T cells (BCL2-TgT mice) and nontransgenic mice that were deficient or not deficient in p27. The contribution of Treg cells to disease evolution was also explored. Finally, the in vitro activity of Treg cells and their differentiation from naive CD4؉ cells was compared between these strains of mice.Results. BCL2-TgT mice were protected against CIA by a Treg cell-dependent mechanism. In association with this protection, the overexpression of Bcl-2 in T cells enhanced the differentiation and activity of Treg cells. Both Bcl-2 effects were independent of its antiapoptotic activity but dependent on its capacity to induce the expression of p27 that augmented the strength of transforming growth factor ␤ (TGF␤) signaling in T cells. Accordingly, down-modulation of p27 expression in BCL2-TgT mice promoted CIA. In addition, p27 deficiency in aged C57BL/6 mice reduced the number and activity of Treg cells and induced the development of mild lupus-like abnormalities.Conclusion. Our results point to p27 as a critical regulator of Treg cell differentiation and function through the positive modulation of TGF␤ signaling strength in T cells.

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Section: Methodsmentioning

confidence: 99%

p27^Kip1 inhibits systemic autoimmunity through the control of Treg cell activity and differentiation

Iglesias¹,

Postigo²,

Santiuste³

et al. 2013

Arthritis & Rheumatism

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“…Furthermore, p21 -/mice developed a lethal autoimmune syndrome characterized by the production of autoantibodies with expansion of memory B and CD4 + T cells (Santiuste et al, 2010).…”

Section: And Thus Neurogenesis Which Correlates With Our Resultsmentioning

confidence: 99%

Cerebral Organoids In Primary Progressive Multiple Sclerosis Reveal Stem Cell Disruption And Failure To Produce Oligodendrocytes

Daviaud

Chen

Edwards

et al. 2022

Preprint

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Multiple sclerosis (MS) is an auto-immune inflammatory disorder affecting the central nervous system. The cause of the disease is unknown but both genetic and environmental factors are implicated in the pathogenesis. We derived cerebral organoids from induced pluripotent stem cells (iPSC) of healthy control subjects as well as from primary progressive MS (PPMS), secondary progressive MS (SPMS) and relapsing remitting MS (RRMS) patients to better understand the pathologic basis of the varied clinical phenotypic expressions of MS. In MS organoids, most notably in PPMS, we observed a decrease of proliferation marker Ki67 and a reduction of the SOX2+ stem cell pool associated with an increased expression of neuronal markers CTIP2 and TBR1. This dysregulation of the stem cell pool is associated with a decreased expression of the cell cycle inhibitor p21. Our findings show that the genetic background of a patient can directly alter stem cell function. This study also provides new insights on the innate cellular dysregulation in MS and identifies p21 pathway as a new potential target for therapeutic strategies in MS.

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“…Also, p21-deficient mice showed increased in vitro and in vivo T cell cycling and activation, leading to mild autoimmune manifestations ( Santiago-Raber et al, 2001 ). Furthermore, p21 −/− mice developed a lethal autoimmune syndrome characterized by the production of autoantibodies with expansion of memory B and CD4 + T cells ( Santiuste et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Cerebral organoids in primary progressive multiple sclerosis reveal stem cell and oligodendrocyte differentiation defect

et al. 2023

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Multiple sclerosis (MS) is an auto-immune inflammatory disorder affecting the central nervous system. The cause of the disease is unknown but both genetic and environmental factors are implicated in the pathogenesis. We derived cerebral organoids from induced pluripotent stem cells (iPSC) of healthy control subjects as well as from primary progressive MS (PPMS), secondary progressive MS (SPMS) and relapsing remitting MS (RRMS) patients to better understand the pathologic basis of the varied clinical phenotypic expressions of MS. In MS organoids, most notably in PPMS, we observed a decrease of proliferation marker Ki67 and a reduction of the SOX2+ stem cell pool associated with an increased expression of neuronal markers CTIP2 and TBR1 as well as a strong decrease of oligodendrocyte differentiation. This dysregulation of the stem cell pool is associated with a decreased expression of the cell cycle inhibitor p21. Our findings show that the genetic background of a patient can directly alter stem cell function, provides new insights on the innate cellular dysregulation in MS and identifies p21 pathway as a new potential target for therapeutic strategies in MS.

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B-cell overexpression of Bcl-2 cooperates with p21 deficiency for the induction of autoimmunity and lymphomas

Cited by 8 publications

References 37 publications

p27^Kip1 inhibits systemic autoimmunity through the control of Treg cell activity and differentiation

p27^Kip1 inhibits systemic autoimmunity through the control of Treg cell activity and differentiation

Cerebral Organoids In Primary Progressive Multiple Sclerosis Reveal Stem Cell Disruption And Failure To Produce Oligodendrocytes

Cerebral organoids in primary progressive multiple sclerosis reveal stem cell and oligodendrocyte differentiation defect

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B-cell overexpression of Bcl-2 cooperates with p21 deficiency for the induction of autoimmunity and lymphomas

Cited by 8 publications

References 37 publications

p27Kip1 inhibits systemic autoimmunity through the control of Treg cell activity and differentiation

p27Kip1 inhibits systemic autoimmunity through the control of Treg cell activity and differentiation

Cerebral Organoids In Primary Progressive Multiple Sclerosis Reveal Stem Cell Disruption And Failure To Produce Oligodendrocytes

Cerebral organoids in primary progressive multiple sclerosis reveal stem cell and oligodendrocyte differentiation defect

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p27^Kip1 inhibits systemic autoimmunity through the control of Treg cell activity and differentiation

p27^Kip1 inhibits systemic autoimmunity through the control of Treg cell activity and differentiation