Gender-specific influence of the chromosome 16 chemokine gene cluster on the susceptibility to Multiple Sclerosis

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

doi:10.1016/j.jns.2007.10.001

Cited by 29 publications

(17 citation statements)

References 26 publications

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“…For instance, variants in the macrophage-derived chemokine (MDC/CCL22) encoding gene have been shown to act as protective factors toward the development of MS in males, but not in females. 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.…”

Section: Progranulin Gene Variability In Ppms C Fenoglio Et Alsupporting

confidence: 57%

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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Section: Progranulin Gene Variability In Ppms C Fenoglio Et Alsupporting

confidence: 57%

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

et al. 2010

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“…Our results demonstrated that CGS significantly reduced the expression levels of CCR4 mRNA. CCR4 has a key pathogenic role in inflammatory conditions in allergies and autoimmune diseases [56,57]. CCR4 exerts its immunomodulatory effects by modulating Th cell function, as well as reducing the induction of regulatory T cells and the elevation of the differentiation of Th17 cells [58].…”

Section: Discussionmentioning

confidence: 99%

Immune Alterations in CD8+ T Cells Are Associated with Neuronal C-C and C-X-C Chemokine Receptor Regulation Through Adenosine A2A Receptor Signaling in a BTBR T+ Itpr3tf/J Autistic Mouse Model

et al. 2017

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Associative studies on a range of neurodevelopmental disorders have identified relationships between behavioral deficits and immune system function. The BTBR T Itpr3/J (BTBR) mouse strain displays aberrant characteristics in its social behavior and immune responses, providing a significant opportunity to examine the relationship between behavior and the immune system. This study investigated the influence of adenosine A2A receptor activity on C-C and C-X-C chemokine receptors involved in autism in the BTBR mouse model. A2A receptors have previously been targeted in clinical trials by potential therapeutics with neuroprotective, immunomodulatory, and analgesic properties. In this study, we examined the effects of A2A receptor antagonist SCH5826 (SCH) and A2A receptor agonist CGS21680 (CGS) on C-C and C-X-C chemokine receptors (CCR3, CCR4, CCR5, CCR6, CCR7, CXCR3, CXCR4, and CXCR5) on splenic CD8 T cells in the BTBR autistic mouse model. We also assessed the C-C and C-X-C chemokine receptors mRNA levels in brain tissue. Our results showed that CCR3, CCR4, CCR5, CCR6, CCR7, CXCR3, CXCR4, and CXCR5 production in splenic CD8 T cells decreased significantly in BTBR-CGS-treated mice in comparison with that in BTBR control and BTBR-SCH-treated mice. In addition, RT-PCR analysis revealed decreased gene expression levels for C-C and C-X-C chemokine receptors in the brain tissue of BTBR-CGS-treated mice, whereas these levels were significantly increased in BTBR control and BTBR-SCH-treated mice. Our results suggest that treating BTBR mice with CGS decreases C-C and C-X-C chemokine receptor signaling and might therefore provide a unique avenue for developing future therapies for autism and neuroimmunological disorders.

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“…Interestingly, genes related to these three classes of pathological states have been mapped on chromosome 16 (8,33,48,69,80,86,112,121,165), the chromosome where zonulin gene is located (Fig. 11).…”

Section: Diseases In Which Zonulin Has Been Identified As a Biomarkermentioning

confidence: 99%

Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer

Fasano

2011

Physiological Reviews

769

633

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The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and to electrolytes and water homeostasis. A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiological modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the finely tuned zonulin pathway is deregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune, inflammatory, and neoplastic disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing the zonulin-dependent intestinal barrier function. This review is timely given the increased interest in the role of a “leaky gut” in the pathogenesis of several pathological conditions targeting both the intestine and extraintestinal organs.

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Gender-specific influence of the chromosome 16 chemokine gene cluster on the susceptibility to Multiple Sclerosis

Cited by 29 publications

References 26 publications

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

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

Immune Alterations in CD8+ T Cells Are Associated with Neuronal C-C and C-X-C Chemokine Receptor Regulation Through Adenosine A2A Receptor Signaling in a BTBR T+ Itpr3tf/J Autistic Mouse Model

Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer

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