An IL-5 Single-Nucleotide Polymorphism Influences Neuroinflammation and Prospective Disease Activity in Multiple Sclerosis

被引：1

作者：

Dolcetti, Ettore ^{[1
,2
]}

Buttari, Fabio ^{[1
,3
]}

Bruno, Antonio ^{[1
,2
]}

Azzolini, Federica ^{[1
]}

Gilio, Luana ^{[1
,4
]}

Borrelli, Angela ^{[1
,2
]}

Di Caprio, Veronica ^{[1
,2
]}

Lauritano, Gianluca ^{[1
]}

Galifi, Giovanni ^{[1
,2
]}

Gambardella, Stefano ^{[1
,5
]}

Ferese, Rosangela ^{[1
]}

Giardina, Emiliano ^{[6
,7
]}

Rovella, Valentina ^{[3
]}

Furlan, Roberto ^{[8
,9
]}

Finardi, Annamaria ^{[9
]}

Musella, Alessandra ^{[10
,11
]}

Balletta, Sara ^{[1
]}

Mandolesi, Georgia ^{[10
,11
]}

Centonze, Diego ^{[1
,3
]}

Stampanoni Bassi, Mario ^{[1
]}

机构：

[1] IRCCS Neuromed, Neurol Unit, Via Atinense 18, I-86077 Pozzilli, Italy

[2] Univ Roma Tor Vergata, Dept Syst Med, PhD Program Neurosci, Via Montpellier 1, I-00133 Rome, Italy

[3] Univ Roma Tor Vergata, Dept Syst Med, Via Montpellier 1, I-00133 Rome, Italy

[4] Uninettuno Telemat Int Univ, Fac Psychol, I-00186 Rome, Italy

[5] Univ Urbino Carlo Bo, Dept Biomol Sci, Via 1 Maggetti 26, I-61029 Urbino, Italy

[6] IRCCS Fdn St Lucia, Genom Med Lab, Via Ardeatina, I-00179 Rome, Italy

[7] Univ Roma Tor Vergata, Dept Biomed & Prevent, Via Montpellier 1, I-00133 Rome, Italy

[8] IRCCS San Raffaele Sci Inst, Inst Expt Neurol INSpe, Div Neurosci, Clin Neuroimmunol Unit, Via Olgettina, I-20132 Milan, Italy

[9] Vita & Salute San Raffaele Univ, Fac Med & Surg, Via Olgettina, I-20132 Milan, Italy

[10] IRCCS San Raffaele Roma, Synapt Immunopathol Lab, Via Pisana 235, I-00163 Rome, Italy

[11] Univ Rome San Raffaele, Dept Human Sci & Qual Life Promot, Via Pisana 235, I-00163 Rome, Italy

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2024年 / 25卷 / 16期

关键词：

IL-5; rs2069812; single-nucleotide polymorphism; multiple sclerosis; neuroinflammation; CYTOKINE POLYMORPHISMS; RISK; VARIANTS; PATHWAY; GENES;

D O I：

10.3390/ijms25169108

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

(1) Multiple sclerosis (MS) is identified by a complex interaction between central inflammation and neurodegeneration. Genetic individual variability could play a significative role in clinical presentation. The interleukin-5 (IL-5) rs2069812 single-nucleotide polymorphism (SNP) seems to define the clinical course of Th2 autoimmune diseases, while its role in MS has never been investigated. (2) In a group of 230 patients diagnosed with relapsing-remitting MS (RR-MS) or progressive MS (P-MS) and controls (IC), rs2069812 polymorphism, cerebrospinal fluid (CSF) levels of inflammatory mediators, and clinical and demographic characteristics were determined. In RR-MS patients, No Evidence of Disease Activity (NEDA-3) at three years of follow-up was detected. (3) We identified higher levels of proinflammatory cytokines, particularly IL-2 (median [IQR], RR-MS = 0.2 [0-0.7]; P-MS = 0.1 [0-1.6]; IC = 0.1 [0.0-0.1]; p < 0.005), IL-6 (RR-MS = 0.9 [0.3-2.3]; P-MS = 0.8 [0.1-2.7]; IC = 0.1 [0.0-0.5]; p < 0.005), IL-12 (RR-MS = 0.5 [0-1.1]; P-MS = 0.5 [0-1.1]; IC = 0.0 [0.0-0.3]; p < 0.005), and GM-CSF (RR-MS = 15.6 [4.8-26.4]; P-MS = 14 [3.3-29.7]; IC = 8.9 [4.7-11.7]; p < 0.005) in MS patients compared with IC. Conversely, anti-inflammatory cytokines, specifically IL-5 (RR-MS = 0.65 [0-2.4]; P-MS = 0.1 [0-0.8]; IC = 1.7 [0.6-2.8]; p < 0.005) and IL-1ra (RR-MS = 14.7 [4.9-26.4]; P-MS = 13.1 [4.7-22.2]; IC = 27.8 [17.7-37.6]; p < 0.005) were higher in controls. According to rs2069812, in MS patients, the T-allele was associated with higher concentrations of proinflammatory mediators (IL-2, CT/TT = 0.2 [0.0-2.0]; CC = 0.1 [0.0-0.4], p = 0.015; IL-6, CT/TT = 1.2 [0.4-3.2] vs. CC = 0.7 [0.1-1.7], p = 0.007; IL-15, CT/TT = 0.1 [0.0-9.5] vs. CC = 0.0 [0.0-0.1], p = 0.019; and GM-CSF, CT/TT = 0.1 [0.0-0.6] vs. CC = 0.05 [0.0-0.1], p < 0.001), and CC was associated with anti-inflammatory mediators (IL-5, CT/TT = 0.03 [0.0-1.9] vs. CC = 1.28 [0.0-2.7], p = 0.001; IL-1ra, CT/TT = 12.1 [4.1-25.9] vs. CC = 18.1 [12.1-26.9], p = 0.006). We found the same differences in RR-MS patients (IL-2, T-allele median [IQR] = 0.3 [0.0-2.0] vs. C-allele, median [IQR] = 0.04 [0.0-0.3]; p = 0.005; IL-6, T-allele, median [IQR] = 1.3 [0.4-3.3] vs. C-allele, median [IQR] = 0.6 [0.03-1.5]; p = 0.001; IL-15, T-allele, median [IQR] = 0.1 [0.0-9.5] vs. C-allele, median [IQR] = 0.0 [0.0-0.1]; p = 0.008; GM-CSF, T-allele, median [IQR] = 0.1 [0.0-97.9] vs. C-allele, median [IQR] = 0.0 [0.0-0.001]; p < 0.001; IL-5, T-allele, median [IQR] = 0.02 [0.0-2.2] vs. C-allele, median [IQR] = 1.5 [0.0-2.9]; p = 0.016; and IL-1ra, T-allele, median [IQR] = 12.1 [4.3-26.4] vs. C-allele, median [IQR] = 18.5 [12.7-28.3]; p = 0.006) but not in P-MS, except for IL-5 (T-allele, median [IQR] = 0.1 [0-0.23] vs. C-allele, median [IQR] = 0.6 [0.0-2.5]; p = 0.022). Finally, we identified an association between CC in RR-MS patients and NEDA-3 after three years of follow-up (p = 0.007). (4) We describe, for the first time, the role of an SNP of the IL-5 gene in regulating central neuroinflammation and influencing clinical course in MS patients.

引用

页数：11

共 33 条

[1] IL-6 in the Cerebrospinal Fluid Signals Disease Activity in Multiple Sclerosis [J].

Bassi, Mario Stampanoni ;

Iezzi, Ennio ;

Drulovic, Jelena ;

Pekmezovic, Tatjana ;

Gilio, Luana ;

Furlan, Roberto ;

Finardi, Annamaria ;

Marfia, Girolama Alessandra ;

Sica, Francesco ;

Centonze, Diego ;

Buttari, Fabio .

FRONTIERS IN CELLULAR NEUROSCIENCE, 2020, 14

[2] Th2 Cytokines (Interleukin-5 and-9) Polymorphism Affects the Response to Anti-TNF Treatment in Polish Patients with Ankylosing Spondylitis [J].

Bialy, Sylwia ;

Iwaszko, Milena ;

Swierkot, Jerzy ;

Bugaj, Bartosz ;

Kolossa, Katarzyna ;

Jeka, Slawomir ;

Bogunia-Kubik, Katarzyna .

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2022, 23 (21)

[3] Interleukin 6 SNP rs1818879 Regulates Radiological and Inflammatory Activity in Multiple Sclerosis [J].

Bruno, Antonio ;

Dolcetti, Ettore ;

Azzolini, Federica ;

Moscatelli, Alessandro ;

Gambardella, Stefano ;

Ferese, Rosangela ;

Rizzo, Francesca Romana ;

Gilio, Luana ;

Iezzi, Ennio ;

Galifi, Giovanni ;

Borrelli, Angela ;

Buttari, Fabio ;

Furlan, Roberto ;

Finardi, Annamaria ;

De Vito, Francesca ;

Musella, Alessandra ;

Guadalupi, Livia ;

Mandolesi, Georgia ;

Centonze, Diego ;

Bassi, Mario Stampanoni .

GENES, 2022, 13 (05)

[4] Single Nucleotide Polymorphism Clustering in Systemic Autoimmune Diseases [J].

Charlon, Thomas ;

Martinez-Bueno, Manuel ;

Bossini-Castillo, Lara ;

Carmona, F. David ;

Di Cara, Alessandro ;

Wojcik, Jerome ;

Voloshynovskiy, Sviatoslav ;

Martin, Javier ;

Alarcon-Riquelme, Marta E. .

PLOS ONE, 2016, 11 (08)

[5] Cytokine polymorphisms in Th1/Th2 pathway genes, body mass index, and risk of non-Hodgkin lymphoma [J].

Chen, Yingtai ;

Zheng, Tongzhang ;

Lan, Qing ;

Foss, Francine ;

Kim, Christopher ;

Chen, Xuezhong ;

Dai, Min ;

Li, Yumin ;

Holford, Theodore ;

Leaderer, Brian ;

Boyle, Peter ;

Chanock, Stephen J. ;

Rothman, Nathaniel ;

Zhang, Yawei .

BLOOD, 2011, 117 (02) :585-590

[6] Multiple sclerosis [J].

Compston, Alastair ;

Coles, Alasdair .

LANCET, 2008, 372 (9648) :1502-1517

[7] Genetic regulation of IL-8 influences disease presentation of multiple sclerosis [J].

Dolcetti, Ettore ;

Bruno, Antonio ;

Azzolini, Federica ;

Gilio, Luana ;

Pavone, Luigi ;

Iezzi, Ennio ;

Galifi, Giovanni ;

Gambardella, Stefano ;

Ferese, Rosangela ;

Buttari, Fabio ;

De Vito, Francesca ;

Colantuono, Paola ;

Furlan, Roberto ;

Finardi, Annamaria ;

Musella, Alessandra ;

Mandolesi, Georgia ;

Centonze, Diego ;

Bassi, Mario Stampanoni .

MULTIPLE SCLEROSIS JOURNAL, 2023, 29 (4-5) :512-520

[8] Genetic and epigenetic fine mapping of causal autoimmune disease variants [J].

Farh, Kyle Kai-How ;

Marson, Alexander ;

Zhu, Jiang ;

Kleinewietfeld, Markus ;

Housley, William J. ;

Beik, Samantha ;

Shoresh, Noam ;

Whitton, Holly ;

Ryan, Russell J. H. ;

Shishkin, Alexander A. ;

Hatan, Meital ;

Carrasco-Alfonso, Marlene J. ;

Mayer, Dita ;

Luckey, C. John ;

Patsopoulos, Nikolaos A. ;

De Jager, Philip L. ;

Kuchroo, Vijay K. ;

Epstein, Charles B. ;

Daly, Mark J. ;

Hafler, David A. ;

Bernstein, Bradley E. .

NATURE, 2015, 518 (7539) :337-343

[9] A Polymorphism in the IL-5 Gene is Associated with Inhibitor Development in Severe Hemophilia A Patients [J].

Fidanci, Inanc Deger ;

Zulfikar, Bulent ;

Kavakli, Kaan ;

Ar, M. Cem ;

Kilinc, Yurdanur ;

Baslar, Zafer ;

Caglayan, Server Hande .

TURKISH JOURNAL OF HEMATOLOGY, 2014, 31 (01) :17-24

[10] Fatigue in Multiple Sclerosis Is Associated with Reduced Expression of Interleukin-10 and Worse Prospective Disease Activity [J].

Gilio, Luana ;

Buttari, Fabio ;

Pavone, Luigi ;

Iezzi, Ennio ;

Galifi, Giovanni ;

Dolcetti, Ettore ;

Azzolini, Federica ;

Bruno, Antonio ;

Borrelli, Angela ;

Storto, Marianna ;

Furlan, Roberto ;

Finardi, Annamaria ;

Pekmezovic, Tatjana ;

Drulovic, Jelena ;

Mandolesi, Georgia ;

Fresegna, Diego ;

Vanni, Valentina ;

Centonze, Diego ;

Bassi, Mario Stampanoni .

BIOMEDICINES, 2022, 10 (09)

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