RANTES: a genetic risk marker for multiple sclerosis

Gade-Andavolu, Radhika; Comings, David E.; MacMurray, James P.; Vuthoori, Ravi; Tourtellotte, Wallace W.; Nagra, Rashed M.; Cone, Lawrence A.

doi:10.1191/1352458504ms1080oa

Cited by 39 publications

(25 citation statements)

References 23 publications

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“…[5][6][7][8][9][10][11][12] Therefore, RANTES could be considered a gene generally predisposing to autoimmune disease. To test this hypothesis, we investigated RANTES SNPs rs2306630, rs2280788 and rs2107538 in a group of 310 CD patients.…”

Section: Discussionmentioning

confidence: 99%

“…This gene has not yet been investigated in the context of T1D, although it has been shown to be associated with other autoimmune diseases, such as atopic dermatitis, asthma, sarcoidosis, rheumatoid arthritis and multiple sclerosis. [5][6][7][8][9][10][11][12] RANTES belongs to the family of CC chemokines, which are involved in immunoregulatory and inflammatory processes owing to their ability to recruit, activate and co-stimulate T cells and monocytes. 13,14 In addition to the trafficking effect, RANTES, like other CC chemokines, plays an important role in co-stimulation of T-cell proliferation 15,16 and activation of the T cells localized in the inflammatory lesion.…”

Section: Introductionmentioning

confidence: 99%

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Genetic variants of RANTES are associated with serum RANTES level and protection for type 1 diabetes

et al. 2006

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RANTES (regulated on activation, normal T-cell expressed and secreted) is a T-helper type 1 (Th1) chemokine that promotes T-cell activation and proliferation. RANTES is genetically associated with asthma, sarcoidosis and multiple sclerosis. The concentration of RANTES is increased at inflammation sites in different autoimmune diseases. Type 1 diabetes (T1D) is a Th1-mediated disease with complex genetic predisposition. We tested RANTES as a candidate gene for association with T1D using three single-nucleotide polymorphism (SNP) variants (rs4251719, rs2306630 and rs2107538) to capture haplotype information. The minor alleles of all SNPs were transmitted less frequently to T1D offspring (transmission rates 37.3% (P ¼ 0.002), 38.7% (P ¼ 0.007) and 41.0% (P ¼ 0.01)) and were less frequently present in patients compared to controls (P ¼ 0.009, 0.03 and 0.04, respectively). A similar protective effect was observed for the haplotype carrying three minor alleles (transmission disequilibrium test (TDT): P ¼ 0.003; odds ratio (OR) ¼ 0.55; confidence interval (CI): 0.37-0.83; case/control: P ¼ 0.03; OR ¼ 0.74; CI: 0.55-0.98). Both patients and controls carrying the protective haplotype express significantly lower serum levels of RANTES compared to non-carriers. Subsequently, we tested a cohort of 310 celiac disease patients, but failed to detect association. RANTES SNPs are significantly associated with RANTES serum concentration and development of T1D. The rs4251719*A-rs2306630*A-rs2107538*A haplotype associated with low RANTES production confers protection from T1D. Our data imply that RANTES is associated with T1D both genetically and functionally, and contributes to diabetesprone Th1 cytokine profile.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic variants of RANTES are associated with serum RANTES level and protection for type 1 diabetes

et al. 2006

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“…A mean of 22% (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) of the input CD3+ T-cells expressed CCR5. There was no change in the total numbers of CD3+CCR5+ T-cells in either the basal IVBBB or aIVBBB assays, comparing the mean number of input CD3+CCR5+ T cells with the mean total numbers of non-migrating and migrating CD3+CCR5+ T-cells in the absence of CCL5 (Table 2a).…”

Section: Regulation Of Ccr5 On Migrating Cd3+ T Cells In the Absence mentioning

confidence: 99%

“…It remains uncertain what role CCR5 and its ligands might play in MS, based on genetic studies of the Δ32 polymorphism and animal models of MS [17][18][19]. However, data exist implicating CCR5 and a commonly expressed ligand, CCL5, in pathogenic neuroinflammation as well as host defense against WNVE [4,[20][21][22][23]. As a consequence, it would be important to decipher if CCR5 is necessary for the migration of certain leukocytes across the BBB (as seen with CCR2) [24] or is a marker for mononuclear cells capable of undergoing transmigration, as seen with CXCR3 [25].…”

Section: Introductionmentioning

confidence: 99%

CCR5 expression on monocytes and T cells: Modulation by transmigration across the blood–brain barrier in vitro

Ubogu

Callahan

Tucky

et al. 2006

Cellular Immunology

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Observational studies in multiple sclerosis (MS) demonstrated altered expression of chemokine receptors (CkRs) on comparable populations of mononuclear cells (e.g. CD4 + /CD45RO + T-cells) in brain sections compared with blood. These findings raised questions about the regulation of CkRs on trafficking cells. Regulatory processes for CkRs are complex: examples include down-regulation following ligand engagement during migration and either up-or down-regulation following activation. Additionally, CkRs that mediate transmigration without being down-regulated will be selectively enriched on migrating cells in the inflammatory site. Finally, CkRs may act as functionally neutral markers of activated cells capable of undergoing transmigration. Clarifying CkR regulation may aid in the selection and application of antagonists for treating neuroinflammation. Mechanisms of receptor regulation during transmigration cannot be studied by descriptive methods. We evaluated CCR5 expression on CD14+ monocytes and CD3+ T-cells following CCL5-driven transmigration through an in vitro blood-brain barrier (IVBBB), as both T-cells and monocytes in MS lesions express CCR5. CCR5 expression was augmented on non-migrating CD14+ but not CD3+ cells, suggesting selective activation of monocytes by incubation in contact with endothelial cells. As proposed from observational studies, CCR5 was enriched on monocytes that migrated spontaneously in the absence of exogenous chemokine. Addition of the CCR5 ligand CCL5 to the lower chamber led to enhanced CD3+ T-cell migration. Interestingly, CCR5 was down-regulated on both CD14+ monocytes and CD3+ T cells during CCL5-driven migration. These results are distinct from those obtained in comparable studies of CCR2 and CXCR3, suggesting that the specifics for CkR expression should be studied for individual receptors on each leukocyte subpopulation during the design of strategies for pharmacological blockade in neuroinflammation.

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“…Respiratory syncytial virus mediated post-trascriptional regulation of RANTES in airway epithelial cells in dependent on both p38 MAPK and Erk [51], suggesting that Mnk kinases may also be involved in the post-transcriptional regulation of RANTES mRNA. It should be noted that RANTES knockout mice are characterized by impaired T cell proliferation and an attenuated expression of IL-2 and IFNγ [52], while RANTES overexpression has been associated with various auto-immune diseases such as asthma [53], rheumatoid arthritis [54] and multiple sclerosis [55]. Although RANTES can promote immune responses against malignant cells, it also appears to play an important role in tumor progression and metastasis [56].…”

Section: Rantesmentioning

confidence: 99%

Mnk kinases in cytokine signaling and regulation of cytokine responses

Joshi¹,

Platanias²

2012

Biomolecular Concepts

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The kinases Mnk1 and Mnk2 are activated downstream of the p38 MAPK and MEK/ERK signaling pathways. Extensive work over the years has shown that these kinases control phosphorylation of the eukaryotic initiation factor 4E (eIF4E) and regulate engagement of other effector elements, including hnRNPA1 and PSF. Mnk kinases are ubiquitously expressed and play critical roles in signaling for various cytokine receptors, while there is emerging evidence that they have important functions as mediators of pro-inflammatory cytokine production. In this review the mechanisms of activation of MNK pathways by cytokine receptors are addressed and their roles in diverse cytokine-dependent biological processes are reviewed. The clinical-translational implications of such work and the relevance of future development of specific MNK inhibitors for the treatment of malignancies and auto-immune disorders are discussed.

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RANTES: a genetic risk marker for multiple sclerosis

Abstract: There is a significant but complex association of the RANTES gene with MS.

Cited by 39 publications

References 23 publications

Genetic variants of RANTES are associated with serum RANTES level and protection for type 1 diabetes

Genetic variants of RANTES are associated with serum RANTES level and protection for type 1 diabetes

CCR5 expression on monocytes and T cells: Modulation by transmigration across the blood–brain barrier in vitro

Mnk kinases in cytokine signaling and regulation of cytokine responses

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