<i>FOXP3, CBLB</i>and<i>ITCH</i>gene expression and cytotoxic T lymphocyte antigen 4 expression on CD4+CD25high T cells in multiple sclerosis

Sellebjerg, Finn; Krakauer, Martin; Khademi, Mohsen; Olsson, Tomas; Sørensen, P. Soelberg

doi:10.1111/j.1365-2249.2012.04654.x

Cited by 37 publications

(27 citation statements)

References 49 publications

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“…A major transcription factor in the IL-6 signaling pathway is C/EBPb (50), for which we found differential binding to the CBLB MS-associated rs12487066 risk allele. Supporting our hypothesis, a recent report shows that CBLB RNA expression is significantly lowered in regulatory T cells of RR-MS patients and that IFN-b treatment was not able to reconstitute CBLB RNA expression in this patient cohort, for whom no genotyping information is available (51). Therefore, our experiments indicate that genetic variants of CBLB are relevant in controlling T cell-mediated immune mechanisms.…”

Section: Discussionsupporting

confidence: 80%

A Multiple Sclerosis–Associated Variant of CBLB Links Genetic Risk with Type I IFN Function

Stürner

Borgmeyer

Schulze

et al. 2014

The Journal of Immunology

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Multiple sclerosis (MS) is an autoimmune disease of the CNS, and autoreactive CD4+ T cells are considered important for its pathogenesis. The etiology of MS involves a complex genetic trait and environmental triggers that include viral infections, particularly the EBV. Among the risk alleles that have repeatedly been identified by genome-wide association studies, three are located near the Casitas B-lineage lymphoma proto-oncogene b gene (CBLB). The CBLB protein (CBL-B) is a key regulator of peripheral immune tolerance by limiting T cell activation and expansion and hence T cell–mediated autoimmunity through its ubiquitin E3-ligase activity. In this study, we show that CBL-B expression is reduced in CD4+ T cells from relapsing-remitting MS (RR-MS) patients during relapse. The MS risk-related single nucleotide polymorphism of CBLB rs12487066 is associated with diminished CBL-B expression levels and alters the effects of type I IFNs on human CD4+ T cell proliferation. Mechanistically, the CBLB rs12487066 risk allele mediates increased binding of the transcription factor C/EBPβ and reduced CBL-B expression in human CD4+ T cells. Our data suggest a role of the CBLB rs12487066 variant in the interactions of a genetic risk factor and IFN function during viral infections in MS.

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Section: Discussionsupporting

confidence: 80%

A Multiple Sclerosis–Associated Variant of CBLB Links Genetic Risk with Type I IFN Function

Stürner

Borgmeyer

Schulze

et al. 2014

The Journal of Immunology

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“…Beyond that, quantitative or functional Treg impairment has been described in a number of autoimmune diseases, including systemic lupus erythematosus (6,7,28,29), rheumatoid arthritis (8,30,31), and type I diabetes (9,10,32). In MS, Tregs were reported to possess diminished suppressive potential (11,33,34) and decreased expression of Foxp3 and immunosuppressive cytotoxic T lymphocyte antigen 4 (CTLA-4) (12,(35)(36)(37).…”

mentioning

confidence: 99%

Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy

Engler

Kursawe

Solano

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

123

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Pregnancy is one of the strongest inducers of immunological tolerance. Disease activity of many autoimmune diseases including multiple sclerosis (MS) is temporarily suppressed by pregnancy, but little is known about the underlying molecular mechanisms. Here, we investigated the endocrine regulation of conventional and regulatory T cells (Tregs) during reproduction. In vitro, we found the pregnancy hormone progesterone to robustly increase Treg frequencies via promiscuous binding to the glucocorticoid receptor (GR) in T cells. In vivo, T-cell-specific GR deletion in pregnant animals undergoing experimental autoimmune encephalomyelitis (EAE), the animal model of MS, resulted in a reduced Treg increase and a selective loss of pregnancy-induced protection, whereas reproductive success was unaffected. Our data imply that steroid hormones can shift the immunological balance in favor of Tregs via differential engagement of the GR in T cells. This newly defined mechanism confers protection from autoimmunity during pregnancy and represents a potential target for future therapy.multiple sclerosis | autoimmunity | pregnancy | Treg | steroid hormones R eproduction is fundamental to the maintenance and evolution of species. To ensure successful pregnancy, mothers have to establish robust immunological tolerance toward the semiallogeneic conceptus providing a secure niche for fetal development. Multiple mechanisms have evolved to prevent fetus-directed immune responses and alloreactive infiltration of the fetomaternal interface (1). These include creating a privileged local microenvironment that hampers T-cell priming and infiltration (2-4) but also imply global modulation of the immune system by pregnancy hormones and the shedding of fetal antigen into the mothers circulation (5).Intriguingly, pregnancy is also well known to suppress the inflammatory activity of a number of cell-mediated autoimmune diseases, including rheumatoid arthritis (6, 7), autoimmune hepatitis (8), and multiple sclerosis (MS) (9, 10). However, this beneficial effect is limited to the period of gestation and usually followed by a rebound of disease activity postpartum. In the case of MS, third trimester pregnancy leads to a remarkable reduction of the MS relapse rate (11), which exceeds the effects of most currently available disease-modifying drugs. Similarly, pregnancy as well as treatment with pregnancy hormones protect rodents from experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS (12) in both SJL/J and C57BL/6 mice (13-16), underpinning an interaction between pregnancy-related immune and endocrine adaptations and central nervous system (CNS) autoimmunity (17).The sensitive balance between conventional effector T cells (Tcons) and regulatory T cells (Tregs) has transpired as a common theme that connects reproductive biology and autoimmunity on a mechanistic level (18)(19)(20)(21). Tregs are characterized by the transcription factor forkhead box P3 (Foxp3) and effectively control effector responses mounted by Tcons in...

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“…A deubiquitinating enzyme, USP18 also found to be associated with the pathogenesis of MS (Malhotra et al 2013). Transcripts of Cbl-b and ITCH encoding E3 ligases are significantly decreased in the brain of MS patients but elevated upon treatment with IFNs, suggesting that Cbl-b and ITCH might be the pathogens of MS (Sellebjerg et al 2012). All these observations support that UPS might be a critical network associated with the development of MS in many ways.…”

Section: Multiple Sclerosismentioning

confidence: 79%

Ubiquitin proteasome system networks in the neurological disorders

Anuppalle¹,

Maddirevula²,

Huh³

et al. 2013

Animal Cells and Systems

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Human neurological disorders are associated with brain-enriched proteins in a major way. Homeostasis of such proteins is a critical event in brain functioning and development. Neuropathological studies of most common neurological disorders clearly show that accumulated, misfolded, mutant proteins are the preliminary causes for such disorders. Studies in the past few decades suggest that the ubiquitin proteasome system (UPS) network is a critical regulator of protein levels mammalian cells. To date, various proteins and substrates in UPS associated with neurological disorders have been identified, but molecular mechanisms and how they are associated with pathogenesis of neurological disorders are poorly understood. Understanding UPS network may set a new window to understand the pathogenesis of neurological disorders. Here we are reporting the current studies of UPS components in major neurological disorders, such as Parkinson's, Alzheimer's, autistic spectrum disorders, Huntington's, and multiple sclerosis.

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FOXP3, CBLBandITCHgene expression and cytotoxic T lymphocyte antigen 4 expression on CD4+CD25high T cells in multiple sclerosis

Cited by 37 publications

References 49 publications

A Multiple Sclerosis–Associated Variant of CBLB Links Genetic Risk with Type I IFN Function

A Multiple Sclerosis–Associated Variant of CBLB Links Genetic Risk with Type I IFN Function

Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy

Ubiquitin proteasome system networks in the neurological disorders

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