TY  - JOUR
A1  - Sadovnick, A. Dessa
A1  - Traboulsee, Anthony L.
A1  - Bernales, Cecily Q.
A1  - Ross, Jay P.
A1  - Forwell, Amanda L.
A1  - Yee, Irene M.
A1  - Guillot-Noel, Lena
A1  - Fontaine, Bertrand
A1  - Cournu-Rebeix, Isabelle
A1  - Alcina, Antonio
A1  - Fedetz, Maria
A1  - Izquierdo, Guillermo
A1  - Matesanz, Fuencisla
A1  - Hilven, Kelly
A1  - Dubois, Bénédicte
A1  - Goris, An
A1  - Astobiza, Ianire
A1  - Alloza, Iraide
A1  - Antigüedad, Alfredo
A1  - Vandenbroeck, Koen
A1  - Akkad, Denis A.
A1  - Aktas, Orhan
A1  - Blaschke, Paul
A1  - Buttmann, Mathias
A1  - Chan, Andrew
A1  - Epplen, Joerg T.
A1  - Gerdes, Lisa-Ann
A1  - Kroner, Antje
A1  - Kubisch, Christian
A1  - Kümpfel, Tania
A1  - Lohse, Peter
A1  - Rieckmann, Peter
A1  - Zettl, Uwe K.
A1  - Zipp, Frauke
A1  - Bertram, Lars
A1  - Lill, Christina M.
A1  - Fernandez, Oscar
A1  - Urbaneja, Patricia
A1  - Leyva, Laura
A1  - Alvarez-Cermeño, Jose Carlos
A1  - Arroyo, Rafael
A1  - Garagorri, Aroa M.
A1  - García-Martínez, Angel
A1  - Villar, Luisa M.
A1  - Urcelay, Elena
A1  - Malhotra, Sunny
A1  - Montalban, Xavier
A1  - Comabella, Manuel
A1  - Berger, Thomas
A1  - Fazekas, Franz
A1  - Reindl, Markus
A1  - Schmied, Mascha C.
A1  - Zimprich, Alexander
A1  - Vilariño-Güell, Carles
T1  - Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients
JF  - G3: Genes Genomes Genetics
N2  - Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93–1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.
KW  - multiple sclerosis
KW  - genetics
KW  - linkage
KW  - association
KW  - plasminogen
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165405
VL  - 6
IS  - 7
ER  - 
TY  - JOUR
A1  - Rovituso, Damiano M.
A1  - Scheffler, Laura
A1  - Wunsch, Marie
A1  - Kleinschnitz, Christoph
A1  - Dörck, Sebastian
A1  - Ulzheimer, Jochen
A1  - Bayas, Antonios
A1  - Steinman, Lawrence
A1  - Ergün, Süleyman
A1  - Kuerten, Stefanie
T1  - CEACAM1 mediates B cell aggregation in central nervous system autoimmunity
JF  - Scientific Reports
N2  - B cell aggregates in the central nervous system (CNS) have been associated with rapid disease progression in patients with multiple sclerosis (MS). Here we demonstrate a key role of carcinoembryogenic antigen-related cell adhesion molecule1 (CEACAM1) in B cell aggregate formation in MS patients and a B cell-dependent mouse model of MS. CEACAM1 expression was increased on peripheral blood B cells and CEACAM1\(^+\) B cells were present in brain infiltrates of MS patients. Administration of the anti-CEACAM1 antibody T84.1 was efficient in blocking aggregation of B cells derived from MS patients. Along these lines, application of the monoclonal anti-CEACAM1 antibody mCC1 was able to inhibit CNS B cell aggregate formation and significantly attenuated established MS-like disease in mice in the absence of any adverse effects. CEACAM1 was co-expressed with the regulator molecule T cell immunoglobulin and mucin domain −3 (TIM-3) on B cells, a novel molecule that has recently been described to induce anergy in T cells. Interestingly, elevated coexpression on B cells coincided with an autoreactive T helper cell phenotype in MS patients. Overall, these data identify CEACAM1 as a clinically highly interesting target in MS pathogenesis and open new therapeutic avenues for the treatment of the disease.
KW  - autoimmunity
KW  - multiple sclerosis
KW  - neuroimmunology
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-147690
VL  - 6
ER  - 
TY  - JOUR
A1  - Buttmann, Mathias
A1  - Seuffert, Linda
A1  - Mäder, Uwe
A1  - Toyka, Klaus V.
T1  - Malignancies after mitoxantrone for multiple sclerosis: a retrospective cohort study
JF  - Neurology
N2  - Objective:
To assess the therapy-related risk of malignancies in mitoxantrone-treated patients with multiple sclerosis.

Methods:
This retrospective observational cohort study included all mitoxantrone-treated patients with multiple sclerosis seen at our department between 1994 and 2007. We collected follow-up information on medically confirmed malignancies, life status, and cause of death, as of 2010. Malignancy rates were compared to the German national cancer registry matched for sex, age, and year of occurrence.

Results:
Follow-up was completed in 676 of 677 identified patients. Median follow-up time was 8.7 years (interquartile range 6.8-11.2), corresponding to 6,220 person-years. Median cumulative mitoxantrone dose was 79.0 mg/m(2) (interquartile range 50.8-102.4). Thirty-seven patients (5.5%) were diagnosed with a malignancy after mitoxantrone initiation, revealing a standardized incidence ratio of 1.50 (95% confidence interval CI] 1.05-2.08). Entities included breast cancer (n = 9), colorectal cancer (n = 7), acute myeloid leukemia (n = 4, 0.6%), and others (each entity n = 1 or 2). The standardized incidence ratio of colorectal cancer was 2.98 (95% CI 1.20-6.14) and of acute myeloid leukemia 10.44 (95% CI 3.39-24.36). It was not increased for other entities including breast cancer. Multivariate Cox regression identified higher age at treatment initiation but neither cumulative mitoxantrone dose (>75 vs 75 mg/m(2)) nor treatment with other immunosuppressive drugs or sex as a risk factor. Fifty-five patients had died, among them 12 of a malignancy and 43 reportedly of other causes.

Conclusions:
While the overall incidence of malignancies was only mildly increased, the risk of leukemia and colorectal cancer was heightened. If confirmed, posttherapy colonoscopy could become advisable.
KW  - multiple sclerosis
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188300
VL  - 86
ER  -