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Bergamaschi L.,The Interdisciplinary Center | Leone M.A.,Ospedale Maggiore and IRCAD | Fasano M.E.,Transplantation Immunology | Guerini F.R.,Foundation Medicine | And 18 more authors.
Genes and Immunity | Year: 2010

Previous studies reported an association with multiple sclerosis (MS) of distinct HLA-class I markers, namely HLA-A02, HLA-Cw05 and MOG-142L. In this work, we tested the association with MS of A02 and Cw05 in 1273 Italian MS patients and 1075 matched controls, which were previously analyzed for MOG-142, and explored the relationship among these three markers in modulating MS risk. HLA-A02 conferred a statistically robust MS protection (odds ratio, OR0.61; 95% confidence intervals, CI0.51-0.72, P10 9), which was independent of DRB115 and of any other DRB1 allele and remained similar after accounting for the other two analyzed class I markers. Conversely, the protective effect we previously observed for MOG-142L was secondary to its linkage disequilibrium with A02. Cw05 was not associated considering the whole sample, but its presence significantly enhanced the protection in the HLA-A02-positive group, independently of DRB1: the OR conferred by A02 in Cw05-positive individuals (0.22, 95% CI0.13-0.38) was significantly lower than in Cw05-negative individuals (0.69, 95% CI0.58-0.83) with a significant (P4.94 × 10 5) multiplicative interaction between the two markers. In the absence of A02, Cw05 behaved as a risk factor, particularly in combination with DRB103 (OR3.89, P0.0006), indicating that Cw05 might be a marker of protective or risk haplotypes, respectively. © 2010 Macmillan Publishers Limited All rights reserved.

Benedetti L.,Osp. S. Andrea | Zardini E.,University of Pavia | Briani C.,University of Padua | Beronio A.,Osp. S. Andrea | And 5 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2011

Background: Antimyelin-associated glycoprotein (MAG) polyneuropathy is a slowly progressive distal form of mixed motor-sensory polyneuropathy that is scarcely responsive to conventional immunosuppressive therapy. Rituximab, a B-cell depleting antibody, is a promising therapeutic choice for anti-MAG polyneuropathy, and the evaluation of factors, such as B-cell-activating factor (BAFF), that control B-cell homeostasis is important to understand how this drug works. Methods: Using an ELISA method, the authors measured serum BAFF concentrations in 23 patients with anti-MAG polyneuropathy, before and after rituximab therapy, in 20 neurological controls and in 14 healthy subjects. The patients were followed up over a mean period of 38±12 months and categorised as responders/non-responders, and, between the responders, as relapsing/non-relapsing. Results: Pretherapy serum BAFF concentrations in non-responders were higher than in responders (cut-off 1665 pg/ml; sensitivity 71.4%; specificity 93.7%; likelihood ratio 11.4), with the highest post-therapy increases in responders. In the responders who relapsed, relapses occurred when serum BAFF concentrations returned to baseline values, 1-2 years after blood B-cell reappearance. Conclusions: Before and during therapy, measurements of serum BAFF in rituximab-treated patients with anti-MAG polyneuropathy may help predict the response to the therapy. The findings in this study also provide information about rituximab-induced modifications on B-cell homeostatic regulation.

Bergamaschi L.,The Interdisciplinary Center | Ban M.,University of Cambridge | Barizzone N.,The Interdisciplinary Center | Leone M.,AOU Maggiore Della Carita | And 19 more authors.
Journal of Medical Genetics | Year: 2011

Background The association of HLA A*02 with multiple sclerosis (MS) was recently confirmed by the authors, and it was observed that the combined presence of HLA Cw*05 significantly enhanced (threefold) the protective effect of HLA A*02. Objectives and methods Since A*02-Cw*05 is carried by two HLA extended haplotypes characterised by the B*4402 and B*1801 alleles, respectively, the association analysis was extended to HLA B*44 and B*18 in an Italian sample (1445 MS cases and 973 controls) and these associations were verified in a UK cohort (721 MS cases, 408 controls and 480 family trios). Results A strong protective effect, independent of DR15, of the A*02-Cw*05 combination carrying B*44 (OR 0.27, p=3.3×10-5) was seen in the Italian samples and confirmed in UK family trios (OR 0.33, p=5.5×10-4) and in a combined cohort of UK families and caseecontrols (OR 0.53, p=0.044). This protective effect was significantly stronger than that mediated by A*02 alone. Logistic regression showed that A*02-Cw*05 maintained a significant protection when adjusted for B alleles (Italy: OR 0.38, p=6.5×10-7; UK: OR 0.60, p=0.0029), indicating that it was not secondary to linkage disequilibrium with B*44. Different from A*02, the other HLA class I tested markers individually showed no significant (Cw*05, B*18) or a modest (B*44) protection when adjusted for the remaining markers. Conclusions This study identified at least two independent protective effects which are tagged by A*02eCw*05 and A*02, respectively. Further studies are needed to elucidate whether this protective effect is due to the presence of an unanalysed factor characterising the HLA extended haplotype(s) carrying A*02 and Cw*05 or to a direct interaction between these alleles.

Cazzola R.,University of Milan | Rondanelli M.,University of Milan | Rondanelli M.,University of Pavia | Trotti R.,Neurological Institute C Mondino | Cestaro B.,University of Milan
Journal of Nutritional Biochemistry | Year: 2011

A previous study showed chemical and physical impairment of the erythrocyte membrane of overweight and moderately obese women. The present study investigated the effects of a low-calorie diet (800 kcal/day deficit for 8 weeks) on erythrocyte membrane properties in 70 overweight and moderately obese (body mass index, 25-33 kg/m2) normotensive, nondiabetic women. At the end of dietary intervention, 24.3% of women dropped out, 45.7% lost less than 5% of their initial weight (Group I) and only 30% of patients lost at least 5% of their initial body weight (Group II). Group I showed no significant changes in erythrocyte membrane composition and function. The erythrocyte membranes of Group II showed significant reductions in malondialdehyde, lipofuscin, cholesterol, sphingomyelin, palmitic acid and nervonic acid and an increase in di-homo-γ-linolenic acid, arachidonic acid and membrane fluidity. Moreover, Group II showed an improvement in total cholesterol, low-density lipoprotein cholesterol, glycemia and insulin resistance. These changes in erythrocyte membrane composition could reflect a virtuous cycle resulting from the reduction in insulin resistance associated with increased membrane fluidity that, in turn, results in a sequence of metabolic events that concur to further improve membrane fluidity. © 2011 Elsevier Inc.

Laura A.,University of Milan | Mirko P.,Neurology Unit | Tommaso C.,University of Milan | Giorgia R.,University of Milan | And 9 more authors.
Environmental Research | Year: 2016

Background: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system, characterized by recurrent relapses of inflammation that cause mild to severe disability. Exposure to airborne particulate matter (PM) has been associated with acute increases in systemic inflammatory responses and neuroinflammation. In the present study, we hypothesize that exposure to PM < 10 μm in diameter (PM10) might increase the occurrence of MS-related hospitalizations. Methods: We obtained daily concentrations of PM10 from 53 monitoring sites covering the study area and we identified 8287 MS-related hospitalization through hospital admission-discharge records of the Lombardy region, Italy, between 2001 and 2009. We used a Poisson regression analysis to investigate the association between exposure to PM10 and risk of hospitalization. Results: A higher RR of hospital admission for MS relapse was associated with exposure to PM10 at different time intervals. The maximum effect of PM10 on MS hospitalization was found for exposure between days 0 and 7: Hospital admission for MS increased 42% (95%CI 1.39-1.45) on the days preceded by one week with PM10 levels in the highest quartile. The p-value for trend across quartiles was <0.001. Conclusions: These data support the hypothesis that air pollution may have a role in determining MS occurrence and relapses. Our findings could open new avenues for determining the pathogenic mechanisms of MS and potentially be applied to other autoimmune diseases. © 2015 Elsevier Inc.

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