MDC/CCL22 intrathecal levels in patients with multiple sclerosis

Galimberti, Daniela; Fenoglio, Chiara; Comi, Cristoforo; Scalabrini, D.; Riz, Milena De; Leone, Maurizio; Venturelli, Eliana; Cortini, Francesca; Piola, Mirko; Monaco, Francesco; Bresolin, Nereo; Scarpini, Elio

doi:10.1177/1352458507084268

Cited by 26 publications

(21 citation statements)

References 11 publications

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“…Three of the five novel loci we identified have known immune functions, and have been previously associated with autoimmune disease. CCL22 is a cytokine associated with RA (15) and MS (13). ATG16L2 is involved in apoptosis and physically interacts with SLE locus ATG5.…”

Section: Discussionmentioning

confidence: 99%

“…MYNN, CCL22 and ATG16L2 have previous reported association with AD. SNP rs10936599 (MYNN) has been reportedly associated with celiac disease (30) and chronic lymphocytic leukemia (31), while CCL22 has been related to MS (13) and RA (15). ATG16L2 was recently linked to SLE (8) through a correlated SNP (rs11235667) located between FCHSD2 and P2RY2, and also associated with MS (9) and Crohn's disease (10) (Supplementary Material, Table S3).…”

Section: à6mentioning

confidence: 99%

“…ATG16L2 is an autophagy-related gene recently proposed as an SLE risk locus (8), and is associated with multiple sclerosis (MS) (9) and Crohn's disease (10). CCL22 is a pro-inflammatory chemokine (11) secreted by macrophages and dendritic cells, and previously reported as a risk factor in ischemic heart disease (12) and MS (13). CCL22 binds to its receptor CCR4, found on dendritic cells in patients with liver inflammation (14).…”

Section: Introductionmentioning

confidence: 99%

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Confirmation of five novel susceptibility loci for Systemic Lupus Erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci

et al. 2017

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We recently identified ten novel SLE susceptibility loci in Asians and uncovered several additional suggestive loci requiring further validation. This study aimed to replicate five of these suggestive loci in a Han Chinese cohort from Hong Kong, followed by meta-analysis (11,656 cases and 23,968 controls) on previously reported Asian and European populations, and to perform bioinformatic analyses on all 82 reported SLE loci to identify shared regulatory signatures. We performed a battery of analyses for these five loci, as well as joint analyses on all 82 SLE loci. All five loci passed genome-wide significance: MYNN Received: September 7, 2016. Revised: January 12, 2017. Accepted: January 13, 2017 ) of cis-genes. Transcription factor binding sites for p53, MEF2A and E2F1 were significantly (P < 0.05) over-represented in SLE loci, consistent with apoptosis playing a critical role in SLE. Enrichment analysis revealed common pathways, gene ontology, protein domains, and cell type-specific expression. In summary, we provide evidence of five novel SLE susceptibility loci. Integrated bioinformatics using all 82 loci revealed that SLE susceptibility loci share many gene regulatory features, suggestive of conserved mechanisms of SLE etiopathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: à6mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Confirmation of five novel susceptibility loci for Systemic Lupus Erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci

et al. 2017

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“…23 In line with these results, cerebrospinal fluid (CSF) MDC/CCL22 levels were increased in female patients compared with female controls, but not in male sample. 24 Recently, progranulin levels were determined in CSF from 55 MS patients when compared with 35 subjects with noninflammatory neurological diseases, 7 individuals with other inflammatory neurological diseases and 8 controls. No significant differences were found in patients compared with either noninflammatory neurological diseases, other inflammatory neurological diseases or controls even when stratifying according to the disease subtype or gender.…”

Section: Progranulin Gene Variability In Ppms C Fenoglio Et Almentioning

confidence: 99%

Progranulin gene variability increases the risk for primary progressive multiple sclerosis in males

et al. 2010

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Progranulin (GRN) gene variability has been analyzed in a sample of 354 patients with multiple sclerosis (MS) compared with 343 controls. No significant differences were observed, but by stratifying according to MS subtypes, a significant increased frequency of the rs2879096 TT genotype was found in primary progressive MS (PPMS) patients versus controls (16.0 vs 3.5%, P ¼ 0.023, odds ratio (OR) 5.2, 95% confidence interval (CI) 1.2-21.4). In addition, in PPMS, an association with the C allele of rs4792938 was observed (55.3 vs 33.5%, P ¼ 0.011, OR 2.4, 95% CI 1.2-4.7). An independent population was studied as replication, failing to confirm results previously obtained. Stratifying according to gender, an association with rs4792938 C allele was found in male PPMS patients compared with controls (40.7 vs 26.9%, P ¼ 0.002, OR 1.87, 95% CI 1.2-2.8). An association with the rs2879096T allele was observed (29.2 in patients compared with 18.9% in controls, P ¼ 0.012, OR 1.77, 95% CI 1.1-2.8). Haplotype analysis showed that TC haplotype frequency is increased in PPMS male patients compared with male controls (25.7 vs 16.6%; P ¼ 0.02, OR 1.69, 95% CI 1.1-2.7), whereas the respective GC haplotype seems to exert a protective effect, as its frequency is decreased in patients compared with controls (55.8% vs 70.9%; P ¼ 0.001, OR 0.52, 95% CI 0.4-0.8). Therefore, GRN haplotypes likely influence the risk of developing PPMS in males.

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“…DCs are important cellular sources for CCL17 and, in concert with macrophages, produce CCL22 during both homeostasis and inflammation (16,17). Different studies have suggested a critical role for CCR4 in the pathogenesis of EAE and MS. For example, elevated levels of the CCR4 ligands CCL17 or CCL22 have been found in the cerebrospinal fluid of MS patients (18)(19)(20). CCL22 protein has been identified in CNS-infiltrating leukocytes and microglia of EAE-induced mice, and CCR4 is expressed by invading leukocyte subsets (21,22).…”

mentioning

confidence: 99%

CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells

Poppensieker

Otte

Schürmann

et al. 2012

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

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Dendritic cells (DCs) are pivotal for the development of experimental autoimmune encephalomyelitis (EAE). However, the mechanisms by which they control disease remain to be determined. This study demonstrates that expression of CC chemokine receptor 4 (CCR4) by DCs is required for EAE induction. CCR4 −/− mice presented enhanced resistance to EAE associated with a reduction in IL-23 and GM-CSF expression in the CNS. Restoring CCR4 on myeloid cells in bone marrow chimeras or intracerebral microinjection of CCR4-competent DCs, but not macrophages, restored EAE in CCR4 −/− mice, indicating that CCR4 + DCs are cellular mediators of EAE development. Mechanistically, CCR4 −/− DCs were less efficient in GM-CSF and IL-23 production and also T H -17 maintenance. Intraspinal IL-23 reconstitution restored EAE in CCR4 −/− mice, whereas intracerebral inoculation using IL-23 −/− DCs or GM-CSF −/− DCs failed to induce disease. Thus, CCR4-dependent GM-CSF production in DCs required for IL-23 release in these cells is a major component in the development of EAE. Our study identified a unique role for CCR4 in regulating DC function in EAE, harboring therapeutic potential for the treatment of CNS autoimmunity by targeting CCR4 on this specific cell type.chemokines | neuroinflammation M ultiple sclerosis (MS) is a chronic demyelinating disease of the human CNS (1). Experimental autoimmune encephalomyelitis (EAE), the animal model of MS, is mediated by myelin-specific CD4 + T cells activated by professional antigenpresenting cells (APCs) in peripheral lymphoid tissues (2, 3). In recent studies, both peripherally derived macrophages and DCs have been shown to present myelin antigens to invading autoreactive T cells in the CNS. This presentation initiates the recruitment of a second wave of leukocytes that damage the target organ via demyelination and axonal degeneration (4-8). Understanding the mechanisms responsible for the recruitment of APCs to the CNS and their local function is essential for the development of therapeutic strategies targeting the effector phase and thereby controlling disease progression.Chemokines and their G protein-coupled receptors are key regulators of leukocyte trafficking (9, 10). The CC chemokine receptor 4 (CCR4) is the cognate receptor for the CC chemokines CCL17 and CCL22, and is expressed on functionally distinct subsets of T cells, including activated T cells, T H 2 cells, and Treg cells. CCR4 has also been found on platelets, NK cells, macrophages, and DCs (11-15). DCs are important cellular sources for CCL17 and, in concert with macrophages, produce CCL22 during both homeostasis and inflammation (16,17). Different studies have suggested a critical role for CCR4 in the pathogenesis of EAE and MS. For example, elevated levels of the CCR4 ligands CCL17 or CCL22 have been found in the cerebrospinal fluid of MS patients (18-20). CCL22 protein has been identified in CNS-infiltrating leukocytes and microglia of EAE-induced mice, and CCR4 is expressed by invading leukocyte subsets (21,22). However, it rema...

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MDC/CCL22 intrathecal levels in patients with multiple sclerosis

Cited by 26 publications

References 11 publications

Confirmation of five novel susceptibility loci for Systemic Lupus Erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci

Confirmation of five novel susceptibility loci for Systemic Lupus Erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci

Progranulin gene variability increases the risk for primary progressive multiple sclerosis in males

CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells

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