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393 results on '"Hafler, D. A."'

1. Locus for severity implicates CNS resilience in progression of multiple sclerosis

Author

Harroud, A, Stridh, PJ, McCauley, JH, Saarela, J, van den Bosch, AMR, Engelenburg, H, Beecham, A, Alfredsson, L, Alikhani, K, Amezcua, L, Andlauer, TFM, Ban, M, Barcellos, L, Barizzone, N, Berge, T, Berthele, A, Bittner, S, Bos, S, Briggs, FBS, Caillier, S, Calabresi, P, Caputo, D, Carmona-Burgos, D, Cavalla, P, Celius, E, Cerono, G, Chinea, A, Chitnis, T, Clarelli, F, Comabella, M, Comi, G, Cotsapas, C, Cree, BCA, D'Alfonso, S, Dardiotis, E, De Jager, P, Delgado, S, Dubois, B, Engel, S, Esposito, F, Fabis-Pedrini, M, Filippi, M, Fitzgerald, K, Gasperi, C, Gomez, L, Gomez, R, Hadjigeorgiou, G, Hamann, J, Held, F, Henry, R, Hillert, J, Huang, J, Huitinga, I, Islam, T, Isobe, N, Jagodic, M, Kermode, AL, Khalil, M, Kilpatrick, T, Konidari, I, Kreft, K, Lechner-Scott, J, Leone, M, Luessi, F, Malhotra, S, Manouchehrinia, A, Manrique, C, Martinelli-Boneschi, F, Martinez, A, Martinez-Maldonado, V, Mascia, E, Metz, L, Midaglia, L, Montalban, X, Oksenberg, J, Olsson, T, Oturai, A, Paakkonen, K, Parnell, GP, Patsopoulos, N, Pericak-Vance, M, Piehl, F, Rubio, J, Santaniello, A, Santoro, S, Schaefer, C, Sellebjerg, F, Shams, H, Shchetynsky, K, Silva, C, Siokas, V, Sondergaard, H, Sorosina, M, Taylor, B, Vandebergh, M, Vasileiou, E, Vecchio, D, Voortman, M, Weiner, H, Wever, D, Yong, VW, Hafler, D, Stewart, G, Compston, A, Zipp, F, Harbo, H, Hemmer, B, Goris, A, Smolders, J, Hauser, S, Kockum, I, Sawcer, S, Baranzini, S, Jonsdottir, I, Blanco, Y, Llufriu, S, Madireddy, L, Saiz, A, Villoslada, P, Stefansson, K, Harbo, HF, Sawcer, SJ, Baranzini, SE, Harroud, A, Stridh, PJ, McCauley, JH, Saarela, J, van den Bosch, AMR, Engelenburg, H, Beecham, A, Alfredsson, L, Alikhani, K, Amezcua, L, Andlauer, TFM, Ban, M, Barcellos, L, Barizzone, N, Berge, T, Berthele, A, Bittner, S, Bos, S, Briggs, FBS, Caillier, S, Calabresi, P, Caputo, D, Carmona-Burgos, D, Cavalla, P, Celius, E, Cerono, G, Chinea, A, Chitnis, T, Clarelli, F, Comabella, M, Comi, G, Cotsapas, C, Cree, BCA, D'Alfonso, S, Dardiotis, E, De Jager, P, Delgado, S, Dubois, B, Engel, S, Esposito, F, Fabis-Pedrini, M, Filippi, M, Fitzgerald, K, Gasperi, C, Gomez, L, Gomez, R, Hadjigeorgiou, G, Hamann, J, Held, F, Henry, R, Hillert, J, Huang, J, Huitinga, I, Islam, T, Isobe, N, Jagodic, M, Kermode, AL, Khalil, M, Kilpatrick, T, Konidari, I, Kreft, K, Lechner-Scott, J, Leone, M, Luessi, F, Malhotra, S, Manouchehrinia, A, Manrique, C, Martinelli-Boneschi, F, Martinez, A, Martinez-Maldonado, V, Mascia, E, Metz, L, Midaglia, L, Montalban, X, Oksenberg, J, Olsson, T, Oturai, A, Paakkonen, K, Parnell, GP, Patsopoulos, N, Pericak-Vance, M, Piehl, F, Rubio, J, Santaniello, A, Santoro, S, Schaefer, C, Sellebjerg, F, Shams, H, Shchetynsky, K, Silva, C, Siokas, V, Sondergaard, H, Sorosina, M, Taylor, B, Vandebergh, M, Vasileiou, E, Vecchio, D, Voortman, M, Weiner, H, Wever, D, Yong, VW, Hafler, D, Stewart, G, Compston, A, Zipp, F, Harbo, H, Hemmer, B, Goris, A, Smolders, J, Hauser, S, Kockum, I, Sawcer, S, Baranzini, S, Jonsdottir, I, Blanco, Y, Llufriu, S, Madireddy, L, Saiz, A, Villoslada, P, Stefansson, K, Harbo, HF, Sawcer, SJ, and Baranzini, SE

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults1,2. Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF-ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3-PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility3, these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS.

Published
2023

7. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

Author

Patsopoulos, NA, Baranzini, SE, Santaniello, A, Shoostari, P, Cotsapas, C, Wong, G, Beecham, AH, James, T, Replogle, J, Vlachos, IS, McCabe, C, Pers, TH, Brandes, A, White, C, Keenan, B, Cimpean, M, Winn, P, Panteliadis, IP, Robbins, A, Andlauer, TFM, Zarzycki, O, Dubois, B, Goris, A, Sondergaard, HB, Sellebjerg, F, Sorensen, PS, Ullum, H, Thorner, LW, Saarela, J, Cournu-Rebeix, I, Damotte, V, Fontaine, B, Guillot-Noel, L, Lathrop, M, Vukusic, S, Berthele, A, Pongratz, V, Gasperi, C, Graetz, C, Grummel, V, Hemmer, B, Hoshi, M, Knier, B, Korn, T, Lill, CM, Luessi, F, Muhlau, M, Zipp, F, Dardiotis, E, Agliardi, C, Amoroso, A, Barizzone, N, Benedetti, MD, Bernardinelli, L, Cavalla, P, Clarelli, F, Comi, G, Cusi, D, Esposito, F, Ferre, L, Galimberti, D, Guaschino, C, Leone, MA, Martinelli, V, Moiola, L, Salvetti, M, Sorosina, M, Vecchio, D, Zauli, A, Santoro, S, Mancini, N, Zuccala, M, Mescheriakova, J, van Duijn, C, Bos, SD, Celius, EG, Spurkland, A, Comabella, M, Montalban, X, Alfredsson, L, Bomfim, IL, Gomez-Cabrero, D, Hillert, J, Jagodic, M, Linden, M, Piehl, F, Jelcic, I, Martin, R, Sospedra, M, Baker, A, Ban, M, Hawkins, C, Hysi, P, Kalra, S, Karpe, F, Khadake, J, Lachance, G, Molyneux, P, Neville, M, Thorpe, J, Bradshaw, E, Caillier, SJ, Calabresi, P, Cree, BAC, Cross, A, Davis, M, de Bakker, PWI, Delgado, S, Dembele, M, Edwards, K, Fitzgerald, K, Frohlich, IY, Gourraud, PA, Haines, JL, Hakonarson, H, Kimbrough, D, Isobe, N, Konidari, I, Lathi, E, Lee, MH, Li, T, An, D, Zimmer, A, Madireddy, L, Manrique, CP, Mitrovic, M, Olah, M, Patrick, E, Pericak-Vance, MA, Piccio, L, Schaefer, C, Weiner, H, Lage, K, Scott, RJ, Lechner-Scott, J, Leal, R, Moscato, P, Booth, DR, Stewart, GJ, Vucic, S, Pame, G, BamettO, M, Mason, D, GriffithS, L, Broadley, S, Tajouri, L, Baxter, A, Slee, M, Taylor, BV, Charlesworth, J, Kilpatrick, TJ, Rubio, J, Jokubaitis, V, Wiley, J, Butzkueven, H, Leslie, S, Motyer, A, Stankovich, J, Carroll, WM, Kermode, AG, Edrin, M, Barclay, M, Peyrin-Biroulet, L, Chamaillard, M, Colombe, JF, Cottone, M, Croft, A, D'Inca, R, Halfvarson, J, Hanigan, K, Henderson, P, Hugot, JP, Karban, A, Kennedy, NA, Khan, MA, Lemann, M, Levine, A, Massey, D, Milla, M, Motoey, GW, Ng, SME, Oikonomnou, J, Peeters, H, Proctor, DD, Rahier, JF, Roberts, R, Rutgeerts, P, Seibold, F, Stronati, L, Taylor, KM, Torkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, MH, Zhang, H, Zhang, W, Donnelly, P, Barroso, I, Blackwe, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Sul, Z, Vukcevic, DA, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Compston, A, Hafler, D, Harbo, HF, Hauser, SL, Stewart, G, D'Alfonso, S, Hadjigeorgiou, G, Taylor, B, Barcellos, LF, Booth, D, Hintzen, R, Kockum, I, Martinelli-Boneschi, F, McCauley, JL, Oksenberg, JR, Oturai, A, Sawcer, S, Ivinson, AJ, Olsson, T, De Jager, PL, Patsopoulos, Na, Baranzini, Se, Santaniello, A, Shoostari, P, Cotsapas, C, Wong, G, Beecham, Ah, James, T, Replogle, J, Vlachos, I, Mccabe, C, Pers, Th, Brandes, A, White, C, Keenan, B, Cimpean, M, Winn, P, Panteliadis, Ip, Robbins, A, Andlauer, Tfm, Zarzycki, O, Dubois, B, Goris, A, Sondergaard, Hb, Sellebjerg, F, Sorensen, P, Ullum, H, Thorner, Lw, Saarela, J, Cournu-Rebeix, I, Damotte, V, Fontaine, B, Guillot-Noel, L, Lathrop, M, Vukusic, S, Berthele, A, Pongratz, V, Gasperi, C, Graetz, C, Grummel, V, Hemmer, B, Hoshi, M, Knier, B, Korn, T, Lill, Cm, Luessi, F, Muhlau, M, Zipp, F, Dardiotis, E, Agliardi, C, Amoroso, A, Barizzone, N, Benedetti, Md, Bernardinelli, L, Cavalla, P, Clarelli, F, Comi, G, Cusi, D, Esposito, F, Ferre, L, Galimberti, D, Guaschino, C, Leone, Ma, Martinelli, V, Moiola, L, Salvetti, M, Sorosina, M, Vecchio, D, Zauli, A, Santoro, S, Mancini, N, Zuccala, M, Mescheriakova, J, van Duijn, C, Bos, Sd, Celius, Eg, Spurkland, A, Comabella, M, Montalban, X, Alfredsson, L, Bomfim, Il, Gomez-Cabrero, D, Hillert, J, Jagodic, M, Linden, M, Piehl, F, Jelcic, I, Martin, R, Sospedra, M, Baker, A, Ban, M, Hawkins, C, Hysi, P, Kalra, S, Karpe, F, Khadake, J, Lachance, G, Molyneux, P, Neville, M, Thorpe, J, Bradshaw, E, Caillier, Sj, Calabresi, P, Cree, Bac, Cross, A, Davis, M, de Bakker, Pwi, Delgado, S, Dembele, M, Edwards, K, Fitzgerald, K, Frohlich, Iy, Gourraud, Pa, Haines, Jl, Hakonarson, H, Kimbrough, D, Isobe, N, Konidari, I, Lathi, E, Lee, Mh, Li, T, An, D, Zimmer, A, Madireddy, L, Manrique, Cp, Mitrovic, M, Olah, M, Patrick, E, Pericak-Vance, Ma, Piccio, L, Schaefer, C, Weiner, H, Lage, K, Scott, Rj, Lechner-Scott, J, Leal, R, Moscato, P, Booth, Dr, Stewart, Gj, Vucic, S, Pame, G, Bametto, M, Mason, D, Griffiths, L, Broadley, S, Tajouri, L, Baxter, A, Slee, M, Taylor, Bv, Charlesworth, J, Kilpatrick, Tj, Rubio, J, Jokubaitis, V, Wiley, J, Butzkueven, H, Leslie, S, Motyer, A, Stankovich, J, Carroll, Wm, Kermode, Ag, Edrin, M, Barclay, M, Peyrin-Biroulet, L, Chamaillard, M, Colombe, Jf, Cottone, M, Croft, A, D'Inca, R, Halfvarson, J, Hanigan, K, Henderson, P, Hugot, Jp, Karban, A, Kennedy, Na, Khan, Ma, Lemann, M, Levine, A, Massey, D, Milla, M, Motoey, Gw, Ng, Sme, Oikonomnou, J, Peeters, H, Proctor, Dd, Rahier, Jf, Roberts, R, Rutgeerts, P, Seibold, F, Stronati, L, Taylor, Km, Torkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, Mh, Zhang, H, Zhang, W, Donnelly, P, Barroso, I, Blackwe, Jm, Bramon, E, Brown, Ma, Casas, Jp, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, H, Mathew, Cg, Palmer, Cna, Plomin, R, Rautanen, A, Sawcer, Sj, Trembath, Rc, Viswanathan, Ac, Wood, Nw, Spencer, Cca, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Sul, Z, Vukcevic, Da, Langford, C, Hunt, Se, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, Sj, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, Mccann, Ot, Liddle, J, Potter, Sc, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Compston, A, Hafler, D, Harbo, Hf, Hauser, Sl, Stewart, G, D'Alfonso, S, Hadjigeorgiou, G, Taylor, B, Barcellos, Lf, Booth, D, Hintzen, R, Kockum, I, Martinelli-Boneschi, F, Mccauley, Jl, Oksenberg, Jr, Oturai, A, Sawcer, S, Ivinson, Aj, Olsson, T, De Jager, Pl, Neurology, and Immunology

Subjects
0301 basic medicine, Multiple Sclerosis, Quantitative Trait Loci, Inheritance Patterns, Cell Cycle Proteins, Genome-wide association study, Biology, Major histocompatibility complex, Polymorphism, Single Nucleotide, Major Histocompatibility Complex, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Immune system, Gene Frequency, Autoimmune Process, medicine, Humans, RNA-Seq, X chromosome, Genetics, Chromosomes, Human, X, Multidisciplinary, Microglia, Multiple sclerosis, GTPase-Activating Proteins, Chromosome Mapping, Genomics, medicine.disease, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Genetic Loci, Case-Control Studies, biology.protein, Genome-Wide Association Study, 030217 neurology & neurosurgery
Abstract

Genetic roots of multiple sclerosis The genetics underlying who develops multiple sclerosis (MS) have been difficult to work out. Examining more than 47,000 cases and 68,000 controls with multiple genome-wide association studies, the International Multiple Sclerosis Genetics Consortium identified more than 200 risk loci in MS (see the Perspective by Briggs). Focusing on the best candidate genes, including a model of the major histocompatibility complex region, the authors identified statistically independent effects at the genome level. Gene expression studies detected that every major immune cell type is enriched for MS susceptibility genes and that MS risk variants are enriched in brain-resident immune cells, especially microglia. Up to 48% of the genetic contribution of MS can be explained through this analysis. Science , this issue p. eaav7188 ; see also p. 1383

Published
2019

12. Autoantibodies against Neurologic Antigens in Nonneurologic Autoimmunity

Author

Stathopoulos, P, Chastre, A, Waters, P, Irani, S, Fichtner, M, Benotti, E, Guthridge, J, Seifert, J, Nowak, R, Buckner, J, Holers, V, James, J, Hafler, D, and O'Connor, K

Subjects
Male, B-Lymphocytes, HEK293 Cells, Humans, Female, Nerve Tissue Proteins, Clinical and Human Immunology, Middle Aged, Autoantigens, Autoantibodies, Autoimmune Diseases
Abstract

The aim of this study was to test whether autoantibodies against neurologic surface Ags are found in nonneurologic autoimmune diseases, indicating a broader loss of tolerance. Patient and matched healthy donor (HD) sera were derived from four large cohorts: 1) rheumatoid arthritis (RA) (n = 194, HD n = 64), 2) type 1 diabetes (T1D) (n = 200, HD n = 200), 3) systemic lupus erythematosus (SLE) (n = 200, HD n = 67; neuro-SLE n = 49, HD n = 33), and 4) a control cohort of neurologic autoimmunity (relapsing-remitting multiple sclerosis [MS] n = 110, HD n = 110; primary progressive MS n = 9; secondary progressive MS n = 10; neuromyelitis optica spectrum disorders n = 15; and other neurologic disorders n = 26). Screening of 1287 unique serum samples against four neurologic surface Ags (myelin oligodendrocyte glycoprotein, aquaporin 4, acetylcholine receptor, and muscle-specific kinase) was performed with live cell-based immunofluorescence assays using flow cytometry. Positive samples identified in the screening were further validated using autoantibody titer quantification by serial dilutions or radioimmunoassay. Autoantibodies against neurologic surface Ags were not observed in RA and T1D patients, whereas SLE patients harbored such autoantibodies in rare cases (2/200, 1%). Within the CNS autoimmunity control cohort, autoantibodies against aquaporin 4 and high-titer Abs against myelin oligodendrocyte glycoprotein were, as expected, specific for neuromyelitis optica spectrum disorders. We conclude that neurologic autoantibodies do not cross disease barriers in RA and T1D. The finding of mildly increased neurologic autoantibodies in SLE may be consistent with a broader loss of B cell tolerance in this form of systemic autoimmunity.

Published
2018

18. Association of genetic markers with CSF oligoclonal bands in multiple sclerosis patients

Author

Leone, M, Barizzone, N, Esposito, F, Harbo, H, Goris, A, Kockum, I, Oturai, A, Celius, E, Mero, I, Dubois, B, Olsson, T, Søndergaard, H, Cusi, D, Lupoli, S, Andreassen, B, Barcellos, L, Booth, D, Comabella, M, Compston, A, D'Alfonso, S, De Jager, P, Fontaine, B, Hafler, D, Haines, J, Hauser, S, Hawkins, C, Hemmer, B, Hillert, J, Ivinson, A, Martin, R, Martinelli Boneschi, F, Mccauley, J, Oksenberg, J, Patsopoulos, N, Pericak Vance, M, Saarela, J, Sawcer, S, Spurkland, A, Stewart, G, Zipp, F, Myhr, K, Guerini, F, Naldi, P, Galimberti, D, Scarpini, E, Bergamaschi, R, Di Sapio, A, Caputo, D, Rosso, G, Cordera, S, Cavalla, P, Cavallo, R, Benedetti, M, Salvetti, M, Capra, R, Ghezzi, A, Annovazzi, P, Coniglio, G, Liberatore, G, Rodegher, M, Moiola, L, Colombo, B, Radaelli, M, Rossi, P, Martinelli, V, Comi, G, D'Alfonso, S., LUCENTI, AUSILIATRICE, Leone, M, Barizzone, N, Esposito, F, Lucenti, A, Harbo, H, Goris, A, Kockum, I, Oturai, A, Celius, E, Mero, I, Dubois, B, Olsson, T, Søndergaard, H, Cusi, D, Lupoli, S, Andreassen, B, Barcellos, L, Booth, D, Comabella, M, Compston, A, D'Alfonso, S, De Jager, P, Fontaine, B, Hafler, D, Haines, J, Hauser, S, Hawkins, C, Hemmer, B, Hillert, J, Ivinson, A, Martin, R, Martinelli Boneschi, F, Mccauley, J, Oksenberg, J, Patsopoulos, N, Pericak Vance, M, Saarela, J, Sawcer, S, Spurkland, A, Stewart, G, Zipp, F, Myhr, K, Guerini, F, Naldi, P, Galimberti, D, Scarpini, E, Bergamaschi, R, Di Sapio, A, Caputo, D, Rosso, G, Cordera, S, Cavalla, P, Cavallo, R, Benedetti, M, Salvetti, M, Capra, R, Ghezzi, A, Annovazzi, P, Coniglio, G, Liberatore, G, Rodegher, M, Moiola, L, Colombo, B, Radaelli, M, Rossi, P, Martinelli, V, Comi, G, and Villoslada, Pablo

Subjects
Oncology, Male, lcsh:Medicine, Genome-wide association study, Biochemistry, Major Histocompatibility Complex, 0302 clinical medicine, Genetic Marker, Multiple Sclerosi, Genetics of the Immune System, 2.1 Biological and endogenous factors, Aetiology, lcsh:Science, Genetics, adult, female, genetic markers, hla-drb1 chains, humans, male, meta-analysis as topic, middle aged, multiple sclerosis, oligoclonal bands, polymorphism, single nucleotide, young adult, genome-wide association study, biochemistry, genetics and molecular biology (all), agricultural and biological sciences (all), 0303 health sciences, Multidisciplinary, Medicine (all), Single Nucleotide, Middle Aged, Neurology, Medicine, HLA-DRB1 Chain, Female, Research Article, Human, Genetic Markers, Adult, medicine.medical_specialty, Multiple Sclerosis, General Science & Technology, Immunology, Single-nucleotide polymorphism, Human leukocyte antigen, Biology, Autoimmune Disease, Polymorphism, Single Nucleotide, Autoimmune Diseases, 03 medical and health sciences, Young Adult, Meta-Analysis as Topic, Oligoclonal Band, Clinical Research, Internal medicine, medicine, Genetic predisposition, SNP, Humans, PROGRESSO Group, Polymorphism, 030304 developmental biology, Evolutionary Biology, Biochemistry, Genetics and Molecular Biology (all), Population Biology, Multiple sclerosis, Wellcome Trust Case Control Consortium 2, Oligoclonal Bands, Human Genome, lcsh:R, Proteins, Computational Biology, Odds ratio, Major Histocompatibility Antigens, medicine.disease, Demyelinating Disorders, International Multiple Sclerosis Genetics Consortium, PROGEMUS Group, Agricultural and Biological Sciences (all), Genetic marker, Genetic Polymorphism, Clinical Immunology, lcsh:Q, 030217 neurology & neurosurgery, Population Genetics, HLA-DRB1 Chains, Genome-Wide Association Study
Abstract

Objective:to explore the association between genetic markers and Oligoclonal Bands (OCB) in the Cerebro Spinal Fluid (CSF) of Italian Multiple Sclerosis patients.Methods:We genotyped 1115 Italian patients for HLA-DRB1*15 and HLA-A*02. In a subset of 925 patients we tested association with 52 non-HLA SNPs associated with MS susceptibility and we calculated a weighted Genetic Risk Score. Finally, we performed a Genome Wide Association Study (GWAS) with OCB status on a subset of 562 patients. The best associated SNPs of the Italian GWAS were replicated in silico in Scandinavian and Belgian populations, and meta-analyzed.Results:HLA-DRB1*15 is associated with OCB+: p = 0.03, Odds Ratio (OR) = 1.6, 95% Confidence Limits (CL) = 1.1-2.4. None of the 52 non-HLA MS susceptibility loci was associated with OCB, except one SNP (rs2546890) near IL12B gene (OR: 1.45; 1.09-1.92). The weighted Genetic Risk Score mean was significantly (p = 0.0008) higher in OCB+ (7.668) than in OCB- (7.412) patients. After meta-analysis on the three datasets (Italian, Scandinavian and Belgian) for the best associated signals resulted from the Italian GWAS, the strongest signal was a SNP (rs9320598) on chromosome 6q (p = 9.4×10-7) outside the HLA region (65 Mb).Discussion:genetic factors predispose to the development of OCB. © 2013 Leone et al.

Published
2013
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19. Polarization of the Effects of Autoimmune and Neurodegenerative Risk Alleles in Leukocytes

Author

Massachusetts Institute of Technology. Department of Biology, Regev, Aviv, Raj, T., Rothamel, K., Mostafavi, S., Ye, C., Lee, M. N., Replogle, J. M., Feng, T., Lee, M., Asinovski, N., Frohlich, I., Imboywa, S., Von Korff, A., Okada, Y., Patsopoulos, N. A., Davis, S., McCabe, C., Paik, H.-i., Srivastava, G. P., Raychaudhuri, S., Hafler, D. A., Koller, D., Hacohen, N., Mathis, D., Benoist, C., Stranger, B. E., De Jager, P. L., Massachusetts Institute of Technology. Department of Biology, Regev, Aviv, Raj, T., Rothamel, K., Mostafavi, S., Ye, C., Lee, M. N., Replogle, J. M., Feng, T., Lee, M., Asinovski, N., Frohlich, I., Imboywa, S., Von Korff, A., Okada, Y., Patsopoulos, N. A., Davis, S., McCabe, C., Paik, H.-i., Srivastava, G. P., Raychaudhuri, S., Hafler, D. A., Koller, D., Hacohen, N., Mathis, D., Benoist, C., Stranger, B. E., and De Jager, P. L.

Abstract

To extend our understanding of the genetic basis of human immune function and dysfunction, we performed an expression quantitative trait locus (eQTL) study of purified CD4[superscript +] T cells and monocytes, representing adaptive and innate immunity, in a multi-ethnic cohort of 461 healthy individuals. Context-specific cis- and trans-eQTLs were identified, and cross-population mapping allowed, in some cases, putative functional assignment of candidate causal regulatory variants for disease-associated loci. We note an over-representation of T cell–specific eQTLs among susceptibility alleles for autoimmune diseases and of monocyte-specific eQTLs among Alzheimer’s and Parkinson’s disease variants. This polarization implicates specific immune cell types in these diseases and points to the need to identify the cell-autonomous effects of disease susceptibility variants.

Published
2017

20. JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants

Author

Sundqvist, E, Buck, D, Warnke, C, Albrecht, E, Gieger, C, Khademi, M, Lima Bomfim, I, Fogdell-Hahn, A, Link, J, Alfredsson, L, Søndergaard, HB, Hillert, J, Barcellos, L, Booth, D, McCauley, JL, Comabella, M, Compston, A, DAlfonso, S, De Jager, P, Fontaine, B, Goris, A, Hafler, D, Haines, J, Harbo, HF, Hauser, SL, Hawkins, C, Hemmer, B, Ivinson, A, Kockum, I, Martin, R, Boneschi, FM, Oksenberg, J, Olsson, T, Oturai, A, Patsopoulos, N, Pericak-Vance, M, Saarela, J, Sawcer, S, Spurkland, A, Stewart, G, Zipp, F, Oturai, AB, and Hemme, B

Subjects
viruses, virus diseases
Abstract

JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50-60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0.42, p = 7×10-15) and controls (OR = 0.53, p = 2×10-5). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR = 1.63, p = 0.006), and controls (OR = 2.69, p = 1×10-5). The German dataset confirmed these findings (OR = 0.54, p = 1×10-4and OR = 1.58, p = 0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention. © 2014 Sundqvist et al.

Published
2014
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21. Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles

Author

Mero, I., Gustavsen, M.W., Sã¦ther, H.S., Flã¥m, S.T., Berg-Hansen, P., Sã¸ndergaard, H.B., Jensen, P.E.H., Berge, T., Bjã¸lgerud, A., Muggerud, A., Aarseth, J.H., International Multiple Sclerosis Genetics Consortium, Myhr, K., Celius, E.G., Sellebjerg, F., Hillert, J., Alfredsson, L., Olsson, T., Oturai, A.B., Kockum, I., Lie, B.A., Andreassen, B.K., Harbo, Collaborators: Barcellos L, H.F., Booth, D., Comabella, M., Compston, A., D'Alfonso, S., De Jager, P., Fontaine, B., Goris, A., Hafler, D., Haines, J., Harbo, H., Hauser, S., Hawkins, C., Hemmer, B., Ivinson, A., Martin, R., Martinelli Boneschi, F., Mccauley, J., Oksenberg, J., Oturai, A., Patsopoulos, N., Pericak-Vance, M., Saarela, J., Sawcer, S., Spurkland, A., Stewart, G., and Zipp, F.

Subjects
Male, Genetics and Molecular Biology (all), Oncology, Non-Clinical Medicine, Denmark, lcsh:Medicine, Genome-wide association study, Biochemistry, Adult, Alleles, Case-Control Studies, Female, Gene Frequency, Genotype, HLA-DRB1 Chains, Humans, Multiple Sclerosis, Norway, Oligoclonal Bands, Polymorphism, Single Nucleotide, Sweden, Genome-Wide Association Study, Medicine (all), Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), 0302 clinical medicine, lcsh:Science, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, Single Nucleotide, 3. Good health, Neurology, Medicine, Settore MED/26 - Neurologia, Research Article, medicine.medical_specialty, Oligoclonal band, Population, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, Internal medicine, Genome-Wide Association Studies, medicine, Polymorphism, Risk factor, education, Allele frequency, Genetic Association Studies, 030304 developmental biology, Health Care Policy, Multiple sclerosis, lcsh:R, Case-control study, Health Risk Analysis, Human Genetics, medicine.disease, Demyelinating Disorders, Genetics of Disease, lcsh:Q, 030217 neurology & neurosurgery
Abstract

The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in multiple sclerosis (MS). We applied data from Norwegian, Swedish and Danish (i.e. Scandinavian) MS patients from a genome-wide association study (GWAS) to search for genetic differences in MS relating to OCB status. GWAS data was compared in 1367 OCB positive and 161 OCB negative Scandinavian MS patients, and nine of the most associated SNPs were genotyped for replication in 3403 Scandinavian MS patients. HLA-DRB1 genotypes were analyzed in a subset of the OCB positive (n = 2781) and OCB negative (n = 292) MS patients and compared to 890 healthy controls. Results from the genome-wide analyses showed that single nucleotide polymorphisms (SNPs) from the HLA complex and six other loci were associated to OCB status. In SNPs selected for replication, combined analyses showed genome-wide significant association for two SNPs in the HLA complex; rs3129871 (p = 5.7×10(-15)) and rs3817963 (p = 5.7×10(-10)) correlating with the HLA-DRB1*15 and the HLA-DRB1*04 alleles, respectively. We also found suggestive association to one SNP in the Calsyntenin-2 gene (p = 8.83×10(-7)). In HLA-DRB1 analyses HLA-DRB1*15∶01 was a stronger risk factor for OCB positive than OCB negative MS, whereas HLA-DRB1*04∶04 was associated with increased risk of OCB negative MS and reduced risk of OCB positive MS. Protective effects of HLA-DRB1*01∶01 and HLA-DRB1*07∶01 were detected in both groups. The groups were different with regard to age at onset (AAO), MS outcome measures and gender. This study confirms both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicates different clinical characteristics between the groups. This suggests differences in disease mechanisms between OCB negative and OCB positive MS with implications for patient management, which need to be further studied.

Published
2013
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22. The Genetic Association of Variants in CD6, TNFRSF1A and IRF8 to Multiple Sclerosis: A Multicenter Case-Control Study

Author

Leppa, International Multiple Sclerosis Genetics Consortium V., Surakka, I., Tienari, P. J., Elovaara, I., Compston, A., Sawcer, S., Robertson, N., De Jager, P. L., Aubin, C., Hafler, D. A., Oturai, A. B., Sondergaard, H. B., Sellebjerg, F., Sorensen, P. S., Hemmer, B., Cepok, S., Winkelmann, J., Wichmann, H. E., Comabella, M., Bustamante, M. F., Montalban, X., Olsson, T., Kockum, I., Hillert, J., Alfredsson, L., Goris, A., Dubois, B., Mero, I. L., Smestad, C., Celius, E. G., Harbo, H. F., D'Alfonso, S., Bergamaschi, L., Leone, M., Ristori, Giovanni, Kappos, L., Hauser, S. L., Cournu Rebeix, I., Fontaine, B., Boonen, S., Polman, C., Palotie, A., Peltonen, L., Saarela, J., Harvard University--MIT Division of Health Sciences and Technology, Hafler, David A., Neurology, and NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases

Subjects
Antigens, Differentiation, T-Lymphocyte, Multiple Sclerosis, Clinical Research Design, Immunology, lcsh:Medicine, Autoimmunity, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Autoimmune Diseases, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Antigens, CD, Genetics, medicine, Humans, SNP, lcsh:Science, Genetic Association Studies, 030304 developmental biology, Genetic association, 0303 health sciences, Multidisciplinary, Multiple sclerosis, lcsh:R, Case-control study, Human Genetics, medicine.disease, Demyelinating Disorders, R1, 3. Good health, Neurology, Receptors, Tumor Necrosis Factor, Type I, Case-Control Studies, Genetics of Disease, Interferon Regulatory Factors, Etiology, Medicine, Clinical Immunology, lcsh:Q, Meta-Analyses, 030217 neurology & neurosurgery, Research Article
Abstract

Background In the recently published meta-analysis of multiple sclerosis genome-wide association studies De Jager et al. identified three single nucleotide polymorphisms associated to MS: rs17824933 (CD6), rs1800693 (TNFRSF1A) and rs17445836 (61.5 kb from IRF8). To refine our understanding of these associations we sought to replicate these findings in a large more extensive independent sample set of 11 populations of European origin. Principal Findings We calculated individual and combined associations using a meta-analysis method by Kazeem and Farral (2005). We confirmed the association of rs1800693 in TNFRSF1A (p 4.19×10−7, OR 1.12, 7,665 cases, 8,051 controls) and rs17445836 near IRF8 (p 5.35×10−10, OR 0.84, 6,895 cases, 7,580 controls and 596 case-parent trios) The SNP rs17824933 in CD6 also showed nominally significant evidence for association (p 2.19×10−5, OR 1.11, 8,047 cases, 9,174 controls, 604 case-parent trios). Conclusions Variants in TNFRSF1A and in the vicinity of IRF8 were confirmed to be associated in these independent cohorts, which supports the role of these loci in etiology of multiple sclerosis. The variant in CD6 reached genome-wide significance after combining the data with the original meta-analysis. Fine mapping is required to identify the predisposing variants in the loci and future functional studies will refine their molecular role in MS pathogenesis., United States. National Institutes of Health (grant RO1 NS 43559), United States. National Institutes of Health (grant RO1 NS049477), Academy of Finland. Center of Excellence for Complex Disease Genetics (grant 213506), Academy of Finland. Center of Excellence for Complex Disease Genetics (grant 129680), Sigrid Jusélius stiftelse, Biocentrum Helsinki Foundation, Helsinki University. Central Hospital Research Foundation, Neuropromise EU project (grant LSHM-CT-2005-018637), Wellcome Trust (London, England) (grant 089061/Z/09/Z), Cambridge NIHR Biomedical Research Centre, The Danish Council for Strategic Research (grant 2142-08-0039), Italian Foundation for Multiple Sclerosis (FISM grants 2008/R/11), Regione Piemonte Ricerca Sanitaria Finalizzata (2007, 2008), Fondazione Cariplo (grant n° 2010- 0728), Italian Ministry of Health, CRT Foundation, National Multiple Sclerosis Society (U.S.), Swiss Multiple Sclerosis Society, United States. National Institutes of Health (R01 NS067305)

Published
2011
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23. T-cell presentation of antigen requires cell-to-cell contact for proliferation and anergy induction. Differential MHC requirements for superantigen and autoantigen

Author

Janine LaSalle, Toneguzzo, F., Saadeh, M., Golan, D. E., Taber, R., and Hafler, D. A.

Subjects
Immunology, Immunology and Allergy
Abstract

MHC class II+ human T-cell clones are able to simultaneously present and respond to peptide Ag and superantigen resulting in both proliferation and subsequent anergy. A major question remains as to whether a single T cell can present to itself or whether T-T cell interactions are required. We have employed a novel technique for inhibiting cell-to-cell contact that encapsulates individual T cells in agarose gel microdrops. Myelin basic protein-reactive individual CD4+ T-cell clones entrapped within these microdrops neither proliferated nor became anergized to either peptide Ag or Staphylococcal enterotoxin B (SEB), suggesting that cell-to-cell contact was required for T-cell presentation of Ag leading to proliferation and anergy. PMA treatment induced T-cell migration out of gel microdrops, restoring cell-to-cell contact and resulting in proliferation and anergy after T-cell coculture with peptide or superantigen. However, analysis of [Ca+2]i release revealed differences in T-cell responses to SEB versus peptide Ag. The addition of SEB, but not peptide Ag, induced a calcium flux in solitary T cells. Additionally, alpha HLA-DR mAb blocked peptide but not SEB-induced proliferation and anergy induction. Thus, SEB generated an early signal in solitary T cells that may not be a result of self stimulation via MHC class II. However, subsequent cell-to-cell contact was required for proliferation and anergy induction by SEB. These results indicate that peptide Ag requires a MHC class II-dependent cell-to-cell interaction for calcium flux, proliferation, and anergy induction, whereas SEB requires a MHC class II independent cell-to-cell interaction for proliferation and anergy induction after a TCR-generated calcium flux.

Published
1993
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24. Characterization of HTLV-I in vivo infected T cell clones. IL-2-independent growth of nontransformed T cells

Author

Hollsberg, P., Wucherpfennig, K. W., Ausubel, L. J., Calvo, V., Barbara Bierer, and Hafler, D. A.

Subjects
Immunology, Immunology and Allergy
Abstract

Mononuclear cells from subjects infected with human T lymphotrophic virus type I (HTLV-I) display a unique ability to proliferate in vitro in the absence of mitogens or exogenous growth factors. Subjects who have developed an HTLV-I-associated myelopathy (HAM) show an even higher degree of spontaneous proliferation concomitant with transcription of the HTLV-I provirus. The mechanism underlying HTLV-I-induced T cell activation was investigated by characterizing a series of HTLV-I-infected T cell clones generated from the blood of subjects with HAM. Approximately 15% of the T cell clones generated were HTLV-I infected as determined by polymerase chain reaction and Southern blotting. Infected T cell clones displayed altered growth kinetics as they continued to incorporate tritiated thymidine 7 to 14 days after stimulation, a time when noninfected T cell clones had returned to a resting state. This was not due to transformation as all the T cell clones required periodic restimulation with mitogens and feeder cells for continued growth. Although HTLV-I-infected T cell clones showed increased expression of the IL-2 receptor p55 chain, the spontaneous clonal proliferation was not inhibited by anti-IL-2 receptor mAb. Moreover, the spontaneous clonal proliferation was insensitive to cyclosporin A and FK 506 while being highly sensitive to rapamycin, which is known to inhibit IL-2-mediated signaling. Together these results demonstrate that IL-2 is not required for the HTLV-I-induced spontaneous clonal proliferation and further suggest that HTLV-I may induce signaling pathways replacing an IL-2 receptor signal proximal to the site of action of rapamycin.

Published
1992
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25. Infection-Triggered Familial or Recurrent Cases of Acute Necrotizing Encephalopathy Caused by Mutations in a Component of the Nuclear Pore, RANBP2

Author

Neilson, D.E. Adams, M.D. Orr, C.M.D. Schelling, D.K. Eiben, R.M. Kerr, D.S. Anderson, J. Bassuk, A.G. Bye, A.M. Childs, A.-M. Clarke, A. Crow, Y.J. Di Rocco, M. Dohna-Schwake, C. Dueckers, G. Fasano, A.E. Gika, A.D. Gionnis, D. Gorman, M.P. Grattan-Smith, P.J. Hackenberg, A. Kuster, A. Lentschig, M.G. Lopez-Laso, E. Marco, E.J. Mastroyianni, S. Perrier, J. Schmitt-Mechelke, T. Servidei, S. Skardoutsou, A. Uldall, P. van der Knaap, M.S. Goglin, K.C. Tefft, D.L. Aubin, C. de Jager, P. Hafler, D. Warman, M.L.

Abstract

Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C→T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude that missense mutations in RANBP2 are susceptibility alleles for familial and recurrent cases of ANE. © 2009 The American Society of Human Genetics.

Published
2009

26. Presentation of autoantigen by human T cells

Author

Janine LaSalle, Ota, K., and Hafler, D. A.

Subjects
Immunology, Immunology and Allergy
Abstract

Activated human T cells express MHC class II and have been shown to present foreign Ag to autologous T cells. We now demonstrate that MHC class II+ T cell clones can present myelin basic protein (MBP) peptide autoantigen in the absence of traditional APC to autologous MBP reactive T cell clones. MBP peptide-pulsed T cell clones specifically stimulated autologous MBP-reactive T cell clones to flux calcium and proliferate. Activation responses were peptide epitope specific and blocked by mAb to MHC class II, indicating a TCR-mediated response. In addition, mAb to the adhesion molecules LFA-3, CD2, LFA-1, CD29, and to the tyrosine phosphatase CD45 also inhibited proliferation, indicating the involvement of T to T cell interactions. In contrast to peptide Ag, T cell clones did not respond to autologous T cells pulsed with HPLC-purified MBP, suggesting that T cells are unable to process whole MBP. However, batch-purified MBP Ag preparations containing lower m.w. breakdown products were presented by T cells, indicating that naturally occurring breakdown products of autoantigens could be presented by activated T cells in vivo. These results raise the possibility that T cell presentation of autoantigen at inflammatory sites may be important in regulation of immune responses to self Ag.

Published
1991
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28. Association of Genetic Markers with CSF Oligoclonal Bands in Multiple Sclerosis Patients

Author

Leone, MA, Barizzone, N, Esposito, F, Lucenti, A, Harbo, HF, Goris, A, Kockum, I, Oturai, AB, Celius, EG, Mero, IL, Dubois, B, Olsson, T, Søndergaard, HB, Cusi, D, Lupoli, S, Andreassen, BK, Barcellos, L, Booth, D, Comabella, M, Compston, A, D'Alfonso, S, De Jager, P, Fontaine, B, Hafler, D, Haines, J, Hauser, SL, Hawkins, C, Hemmer, B, Hillert, J, Ivinson, A, Martin, R, Martinelli Boneschi, F, McCauley, JL, Oksenberg, J, Oturai, A, Patsopoulos, N, Pericak-Vance, M, Saarela, J, Sawcer, S, Spurkland, A, Stewart, G, Zipp, F, Myhr, KM, Guerini, FR, Naldi, P, Galimberti, D, Scarpini, E, Bergamaschi, R, Di Sapio, A, Caputo, D, Rosso, G, Cordera, S, Cavalla, P, Cavallo, R, Benedetti, MD, Salvetti, M, Capra, R, Ghezzi, A, Annovazzi, P, Coniglio, G, Liberatore, G, Rodegher, M, Moiola, L, Colombo, B, Radaelli, M, Rossi, P, Martinelli, V, Comi, G, Martinelli-Boneschi, F, Leone, MA, Barizzone, N, Esposito, F, Lucenti, A, Harbo, HF, Goris, A, Kockum, I, Oturai, AB, Celius, EG, Mero, IL, Dubois, B, Olsson, T, Søndergaard, HB, Cusi, D, Lupoli, S, Andreassen, BK, Barcellos, L, Booth, D, Comabella, M, Compston, A, D'Alfonso, S, De Jager, P, Fontaine, B, Hafler, D, Haines, J, Hauser, SL, Hawkins, C, Hemmer, B, Hillert, J, Ivinson, A, Martin, R, Martinelli Boneschi, F, McCauley, JL, Oksenberg, J, Oturai, A, Patsopoulos, N, Pericak-Vance, M, Saarela, J, Sawcer, S, Spurkland, A, Stewart, G, Zipp, F, Myhr, KM, Guerini, FR, Naldi, P, Galimberti, D, Scarpini, E, Bergamaschi, R, Di Sapio, A, Caputo, D, Rosso, G, Cordera, S, Cavalla, P, Cavallo, R, Benedetti, MD, Salvetti, M, Capra, R, Ghezzi, A, Annovazzi, P, Coniglio, G, Liberatore, G, Rodegher, M, Moiola, L, Colombo, B, Radaelli, M, Rossi, P, Martinelli, V, Comi, G, and Martinelli-Boneschi, F

Abstract

Objective:to explore the association between genetic markers and Oligoclonal Bands (OCB) in the Cerebro Spinal Fluid (CSF) of Italian Multiple Sclerosis patients.Methods:We genotyped 1115 Italian patients for HLA-DRB1*15 and HLA-A*02. In a subset of 925 patients we tested association with 52 non-HLA SNPs associated with MS susceptibility and we calculated a weighted Genetic Risk Score. Finally, we performed a Genome Wide Association Study (GWAS) with OCB status on a subset of 562 patients. The best associated SNPs of the Italian GWAS were replicated in silico in Scandinavian and Belgian populations, and meta-analyzed.Results:HLA-DRB1*15 is associated with OCB+: p = 0.03, Odds Ratio (OR) = 1.6, 95% Confidence Limits (CL) = 1.1-2.4. None of the 52 non-HLA MS susceptibility loci was associated with OCB, except one SNP (rs2546890) near IL12B gene (OR: 1.45; 1.09-1.92). The weighted Genetic Risk Score mean was significantly (p = 0.0008) higher in OCB+ (7.668) than in OCB- (7.412) patients. After meta-analysis on the three datasets (Italian, Scandinavian and Belgian) for the best associated signals resulted from the Italian GWAS, the strongest signal was a SNP (rs9320598) on chromosome 6q (p = 9.4×10 -7 ) outside the HLA region (65 Mb).Discussion:genetic factors predispose to the development of OCB. © 2013 Leone et al.

Published
2013

29. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Author

Beecham, A.H., Patsopoulos, N.A., Xifara, D.K., Davis, M.F., Kemppinen, A., Cotsapas, C., Shah, T.S., Spencer, C., Booth, D., Goris, A., Oturai, A., Saarela, J., Fontaine, B., Hemmer, B., Martin, C., Zipp, F., D'Alfonso, S., Martinelli-Boneschi, F., Taylor, B., Harbo, H.F., Kockum, I., Hillert, J., Olsson, T., Ban, M., Oksenberg, J.R., Hintzen, R., Barcellos, L.F., Agliardi, C., Alfredsson, L., Alizadeh, M., Anderson, C., Andrews, R., Søndergaard, H.B., Baker, A., Band, G., Baranzini, S.E., Barizzone, N., Barrett, J., Bellenguez, C., Bergamaschi, L., Bernardinelli, L., Berthele, A., Biberacher, V., Binder, T.M.C., Blackburn, H., Bomfim, I.L., Brambilla, P., Broadley, S., Brochet, B., Brundin, L., Buck, D., Butzkueven, H., Caillier, S.J., Camu, W., Carpentier, W., Cavalla, P., Celius, E.G., Coman, I., Comi, G., Corrado, L., Cosemans, L., Cournu-Rebeix, I., Cree, B.A.C., Cusi, D., Damotte, V., Defer, G., Delgado, S.R., Deloukas, P., di Sapio, A., Dilthey, A.T., Donnelly, P., Dubois, B., Duddy, M., Edkins, S., Elovaara, I., Esposito, F., Evangelou, N., Fiddes, B., Field, J., Franke, A., Freeman, C., Frohlich, I.Y., Galimberti, D., Gieger, C., Gourraud, P-A, Graetz, C., Graham, A., Grummel, V., Guaschino, C., Hadjixenofontos, A., Hakonarson, H., Halfpenny, C., Hall, G., Hall, P., Hamsten, A., Harley, J., Harrower, T., Hawkins, C., Hellenthal, G., Hillier, C., Hobart, J., Hoshi, M., Hunt, S.E., Jagodic, M., Jelčić, I., Jochim, A., Kendall, B., Kermode, A., Kilpatrick, T., Koivisto, K., Konidari, I., Korn, T., Kronsbein, H., Langford, C., Larsson, M., Lathrop, M., Lebrun-Frenay, C., Lechner-Scott, J., Lee, M.H., Leone, M.A., Leppä, V., Liberatore, G., Lie, B.A., Lill, C.M., Linden, M., Link, J., Luessi, F., Lycke, J., Macciardi, F., Männistö, S., Manrique, C.P., Martin, R., Martinelli, V., Mason, D., Mazibrada, G., McCabe, C., Mero, I-L, Mescheriakova, J., Moutsianas, L., Myhr, K-M, Nagels, G., Nicholas, R., Nilsson, P., Piehl, F., Pirinen, M., Price, S.E., Quach, H., Reunanen, M., Robberecht, W., Robertson, N.P., Rodegher, M., Rog, D., Salvetti, M., Schnetz-Boutaud, N.C., Sellebjerg, F., Selter, R.C., Schaefer, C., Shaunak, S., Shen, L., Shields, S., Siffrin, V., Slee, M., Sorensen, P.S., Sorosina, M., Sospedra, M., Spurkland, A., Strange, A., Sundqvist, E., Thijs, V., Thorpe, J., Ticca, A., Tienari, P., van Duijn, C., Visser, E.M., Vucic, S., Westerlind, H., Wiley, J.S., Wilkins, A., Wilson, J.F., Winkelmann, J., Zajicek, J., Zindler, E., Haines, J.L., Pericak-Vance, M.A., Ivinson, A.J., Stewart, G., Hafler, D., Hauser, S.L., Compston, A., McVean, G., De Jager, P., Sawcer, S.J., McCauley, J.L., Beecham, A.H., Patsopoulos, N.A., Xifara, D.K., Davis, M.F., Kemppinen, A., Cotsapas, C., Shah, T.S., Spencer, C., Booth, D., Goris, A., Oturai, A., Saarela, J., Fontaine, B., Hemmer, B., Martin, C., Zipp, F., D'Alfonso, S., Martinelli-Boneschi, F., Taylor, B., Harbo, H.F., Kockum, I., Hillert, J., Olsson, T., Ban, M., Oksenberg, J.R., Hintzen, R., Barcellos, L.F., Agliardi, C., Alfredsson, L., Alizadeh, M., Anderson, C., Andrews, R., Søndergaard, H.B., Baker, A., Band, G., Baranzini, S.E., Barizzone, N., Barrett, J., Bellenguez, C., Bergamaschi, L., Bernardinelli, L., Berthele, A., Biberacher, V., Binder, T.M.C., Blackburn, H., Bomfim, I.L., Brambilla, P., Broadley, S., Brochet, B., Brundin, L., Buck, D., Butzkueven, H., Caillier, S.J., Camu, W., Carpentier, W., Cavalla, P., Celius, E.G., Coman, I., Comi, G., Corrado, L., Cosemans, L., Cournu-Rebeix, I., Cree, B.A.C., Cusi, D., Damotte, V., Defer, G., Delgado, S.R., Deloukas, P., di Sapio, A., Dilthey, A.T., Donnelly, P., Dubois, B., Duddy, M., Edkins, S., Elovaara, I., Esposito, F., Evangelou, N., Fiddes, B., Field, J., Franke, A., Freeman, C., Frohlich, I.Y., Galimberti, D., Gieger, C., Gourraud, P-A, Graetz, C., Graham, A., Grummel, V., Guaschino, C., Hadjixenofontos, A., Hakonarson, H., Halfpenny, C., Hall, G., Hall, P., Hamsten, A., Harley, J., Harrower, T., Hawkins, C., Hellenthal, G., Hillier, C., Hobart, J., Hoshi, M., Hunt, S.E., Jagodic, M., Jelčić, I., Jochim, A., Kendall, B., Kermode, A., Kilpatrick, T., Koivisto, K., Konidari, I., Korn, T., Kronsbein, H., Langford, C., Larsson, M., Lathrop, M., Lebrun-Frenay, C., Lechner-Scott, J., Lee, M.H., Leone, M.A., Leppä, V., Liberatore, G., Lie, B.A., Lill, C.M., Linden, M., Link, J., Luessi, F., Lycke, J., Macciardi, F., Männistö, S., Manrique, C.P., Martin, R., Martinelli, V., Mason, D., Mazibrada, G., McCabe, C., Mero, I-L, Mescheriakova, J., Moutsianas, L., Myhr, K-M, Nagels, G., Nicholas, R., Nilsson, P., Piehl, F., Pirinen, M., Price, S.E., Quach, H., Reunanen, M., Robberecht, W., Robertson, N.P., Rodegher, M., Rog, D., Salvetti, M., Schnetz-Boutaud, N.C., Sellebjerg, F., Selter, R.C., Schaefer, C., Shaunak, S., Shen, L., Shields, S., Siffrin, V., Slee, M., Sorensen, P.S., Sorosina, M., Sospedra, M., Spurkland, A., Strange, A., Sundqvist, E., Thijs, V., Thorpe, J., Ticca, A., Tienari, P., van Duijn, C., Visser, E.M., Vucic, S., Westerlind, H., Wiley, J.S., Wilkins, A., Wilson, J.F., Winkelmann, J., Zajicek, J., Zindler, E., Haines, J.L., Pericak-Vance, M.A., Ivinson, A.J., Stewart, G., Hafler, D., Hauser, S.L., Compston, A., McVean, G., De Jager, P., Sawcer, S.J., and McCauley, J.L.

Abstract

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10−4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10−8), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Published
2013

30. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Author

Beecham, AH, Patsopoulos, NA, Xifara, DK, Davis, MF, Kemppinen, A, Cotsapas, C, Shah, TS, Spencer, C, Booth, D, Goris, A, Oturai, A, Saarela, J, Fontaine, B, Hemmer, B, Martin, C, Zipp, F, D'Alfonso, S, Martinelli-Boneschi, F, Taylor, B, Harbo, HF, Kockum, I, Hillert, J, Olsson, T, Ban, M, Oksenberg, JR, Hintzen, R, Barcellos, LF, Agliardi, C, Alfredsson, L, Alizadeh, M, Anderson, C, Andrews, R, Sondergaard, HB, Baker, A, Band, G, Baranzini, SE, Barizzone, N, Barrett, J, Bellenguez, C, Bergamaschi, L, Bernardinelli, L, Berthele, A, Biberacher, V, Binder, TMC, Blackburn, H, Bomfim, IL, Brambilla, P, Broadley, S, Brochet, B, Brundin, L, Buck, D, Butzkueven, H, Caillier, SJ, Camu, W, Carpentier, W, Cavalla, P, Celius, EG, Coman, I, Comi, G, Corrado, L, Cosemans, L, Cournu-Rebeix, I, Cree, BAC, Cusi, D, Damotte, V, Defer, G, Delgado, SR, Deloukas, P, di Sapio, A, Dilthey, AT, Donnelly, P, Dubois, B, Duddy, M, Edkins, S, Elovaara, I, Esposito, F, Evangelou, N, Fiddes, B, Field, J, Franke, A, Freeman, C, Frohlich, IY, Galimberti, D, Gieger, C, Gourraud, P-A, Graetz, C, Graham, A, Grummel, V, Guaschino, C, Hadjixenofontos, A, Hakonarson, H, Halfpenny, C, Hall, G, Hall, P, Hamsten, A, Harley, J, Harrower, T, Hawkins, C, Hellenthal, G, Hillier, C, Hobart, J, Hoshi, M, Hunt, SE, Jagodic, M, Jelcic, I, Jochim, A, Kendall, B, Kermode, A, Kilpatrick, T, Koivisto, K, Konidari, I, Korn, T, Kronsbein, H, Langford, C, Larsson, M, Lathrop, M, Lebrun-Frenay, C, Lechner-Scott, J, Lee, MH, Leone, MA, Leppa, V, Liberatore, G, Lie, BA, Lill, CM, Linden, M, Link, J, Luessi, F, Lycke, J, Macciardi, F, Mannisto, S, Manrique, CP, Martin, R, Martinelli, V, Mason, D, Mazibrada, G, McCabe, C, Mero, I-L, Mescheriakova, J, Moutsianas, L, Myhr, K-M, Nagels, G, Nicholas, R, Nilsson, P, Piehl, F, Pirinen, M, Price, SE, Quach, H, Reunanen, M, Robberecht, W, Robertson, NP, Rodegher, M, Rog, D, Salvetti, M, Schnetz-Boutaud, NC, Sellebjerg, F, Selter, RC, Schaefer, C, Shaunak, S, Shen, L, Shields, S, Siffrin, V, Slee, M, Sorensen, PS, Sorosina, M, Sospedra, M, Spurkland, A, Strange, A, Sundqvist, E, Thijs, V, Thorpe, J, Ticca, A, Tienari, P, van Duijn, C, Visser, EM, Vucic, S, Westerlind, H, Wiley, JS, Wilkins, A, Wilson, JF, Winkelmann, J, Zajicek, J, Zindler, E, Haines, JL, Pericak-Vance, MA, Ivinson, AJ, Stewart, G, Hafler, D, Hauser, SL, Compston, A, McVean, G, De Jager, P, Sawcer, SJ, McCauley, JL, Beecham, AH, Patsopoulos, NA, Xifara, DK, Davis, MF, Kemppinen, A, Cotsapas, C, Shah, TS, Spencer, C, Booth, D, Goris, A, Oturai, A, Saarela, J, Fontaine, B, Hemmer, B, Martin, C, Zipp, F, D'Alfonso, S, Martinelli-Boneschi, F, Taylor, B, Harbo, HF, Kockum, I, Hillert, J, Olsson, T, Ban, M, Oksenberg, JR, Hintzen, R, Barcellos, LF, Agliardi, C, Alfredsson, L, Alizadeh, M, Anderson, C, Andrews, R, Sondergaard, HB, Baker, A, Band, G, Baranzini, SE, Barizzone, N, Barrett, J, Bellenguez, C, Bergamaschi, L, Bernardinelli, L, Berthele, A, Biberacher, V, Binder, TMC, Blackburn, H, Bomfim, IL, Brambilla, P, Broadley, S, Brochet, B, Brundin, L, Buck, D, Butzkueven, H, Caillier, SJ, Camu, W, Carpentier, W, Cavalla, P, Celius, EG, Coman, I, Comi, G, Corrado, L, Cosemans, L, Cournu-Rebeix, I, Cree, BAC, Cusi, D, Damotte, V, Defer, G, Delgado, SR, Deloukas, P, di Sapio, A, Dilthey, AT, Donnelly, P, Dubois, B, Duddy, M, Edkins, S, Elovaara, I, Esposito, F, Evangelou, N, Fiddes, B, Field, J, Franke, A, Freeman, C, Frohlich, IY, Galimberti, D, Gieger, C, Gourraud, P-A, Graetz, C, Graham, A, Grummel, V, Guaschino, C, Hadjixenofontos, A, Hakonarson, H, Halfpenny, C, Hall, G, Hall, P, Hamsten, A, Harley, J, Harrower, T, Hawkins, C, Hellenthal, G, Hillier, C, Hobart, J, Hoshi, M, Hunt, SE, Jagodic, M, Jelcic, I, Jochim, A, Kendall, B, Kermode, A, Kilpatrick, T, Koivisto, K, Konidari, I, Korn, T, Kronsbein, H, Langford, C, Larsson, M, Lathrop, M, Lebrun-Frenay, C, Lechner-Scott, J, Lee, MH, Leone, MA, Leppa, V, Liberatore, G, Lie, BA, Lill, CM, Linden, M, Link, J, Luessi, F, Lycke, J, Macciardi, F, Mannisto, S, Manrique, CP, Martin, R, Martinelli, V, Mason, D, Mazibrada, G, McCabe, C, Mero, I-L, Mescheriakova, J, Moutsianas, L, Myhr, K-M, Nagels, G, Nicholas, R, Nilsson, P, Piehl, F, Pirinen, M, Price, SE, Quach, H, Reunanen, M, Robberecht, W, Robertson, NP, Rodegher, M, Rog, D, Salvetti, M, Schnetz-Boutaud, NC, Sellebjerg, F, Selter, RC, Schaefer, C, Shaunak, S, Shen, L, Shields, S, Siffrin, V, Slee, M, Sorensen, PS, Sorosina, M, Sospedra, M, Spurkland, A, Strange, A, Sundqvist, E, Thijs, V, Thorpe, J, Ticca, A, Tienari, P, van Duijn, C, Visser, EM, Vucic, S, Westerlind, H, Wiley, JS, Wilkins, A, Wilson, JF, Winkelmann, J, Zajicek, J, Zindler, E, Haines, JL, Pericak-Vance, MA, Ivinson, AJ, Stewart, G, Hafler, D, Hauser, SL, Compston, A, McVean, G, De Jager, P, Sawcer, SJ, and McCauley, JL

Abstract

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Published
2013

31. Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2

Author

Neilson, De, Adams, Md, Orr, Cmd, Schelling, Dk, Eiben, Rm, Kerr, D, Anderson, J, Bassuk, Ag, Bye, Am, Childs, A, Clarke, A, Crow, Yj, Di Rocco, M, Dohna Schwake, C, Dueckers, G, Fasano, Ae, Gika, Ad, Gionnis, D, Gorman, Mp, Grattan Smith, Pj, Hackenberg, A, Kuster, A, Lentschig, Mg, Lopez Laso, E, Marco, Ej, Mastroyianni, S, Perrier, J, Schmitt Mechelke, T, Servidei, Serenella, Skardoutsou, A, Uldall, P, Van Der Knaap, M, Goglin, Kc, Tefft, Dl, Aubin, C, De Jager, P, Hafler, D, Warman, Ml, Servidei, Serenella (ORCID:0000-0001-8478-2799), Neilson, De, Adams, Md, Orr, Cmd, Schelling, Dk, Eiben, Rm, Kerr, D, Anderson, J, Bassuk, Ag, Bye, Am, Childs, A, Clarke, A, Crow, Yj, Di Rocco, M, Dohna Schwake, C, Dueckers, G, Fasano, Ae, Gika, Ad, Gionnis, D, Gorman, Mp, Grattan Smith, Pj, Hackenberg, A, Kuster, A, Lentschig, Mg, Lopez Laso, E, Marco, Ej, Mastroyianni, S, Perrier, J, Schmitt Mechelke, T, Servidei, Serenella, Skardoutsou, A, Uldall, P, Van Der Knaap, M, Goglin, Kc, Tefft, Dl, Aubin, C, De Jager, P, Hafler, D, Warman, Ml, and Servidei, Serenella (ORCID:0000-0001-8478-2799)

Abstract

Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C-->T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude that missense mutations in RANBP2 are susceptibility alleles for familial and recurrent cases of ANE.

Published
2009

34. HLA B*44: Protective effects in MS susceptibility and MRI outcome measures

Author

Healy, B. C., primary, Liguori, M., additional, Tran, D., additional, Chitnis, T., additional, Glanz, B., additional, Wolfish, C., additional, Gauthier, S., additional, Buckle, G., additional, Houtchens, M., additional, Stazzone, L., additional, Khoury, S., additional, Hartzmann, R., additional, Fernandez-Vina, M., additional, Hafler, D. A., additional, Weiner, H. L., additional, Guttmann, C. R. G., additional, and De Jager, P. L., additional

Published
2010
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35. CTLA4Ig treatment in patients with multiple sclerosis

Author

Viglietta, V., primary, Bourcier, K., additional, Buckle, G. J., additional, Healy, B., additional, Weiner, H. L., additional, Hafler, D. A., additional, Egorova, S., additional, Guttmann, C.R.G., additional, Rusche, J. R., additional, and Khoury, S. J., additional

Published
2008
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45. B7.2 expressed by T cells does not induce CD28-mediated costimulatory activity but retains CTLA4 binding: implications for induction of antitumor immunity to T cell tumors.

Author

Greenfield, E A, primary, Howard, E, additional, Paradis, T, additional, Nguyen, K, additional, Benazzo, F, additional, McLean, P, additional, Höllsberg, P, additional, Davis, G, additional, Hafler, D A, additional, Sharpe, A H, additional, Freeman, G J, additional, and Kuchroo, V K, additional

Published
1997
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