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3. Author Correction: A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis (Nature Communications, (2019), 10, 1, (2236), 10.1038/s41467-019-09773-y)

Author

Madireddy, L. (Lohith), Patsopoulos, N.A. (Nikolaos A.), Cotsapas, C. (Chris), Bos, S.D. (Steffan), Beecham, A.H. (Ashley), McCauley, J. (John William), Kim, K. (Kicheol), Jia, X. (Xiaoming), Santaniello, A. (Adam), Caillier, S.J. (Stacy), Andlauer, T.F.M. (Till F. M.), Barcellos, L.F. (Lisa), Berge, T. (Tone), Bernardinelli, L. (Luisa), Martinelli-Boneschi, F. (Filippo), Booth, D. (David), Briggs, F. (Farren), Celius, E.G. (Elisabeth), Comabella, M. (Manuel), Comi, G. (Giancarlo), Cree, B.A.C. (Bruce A. C.), Dalfonso, S., Dedham, K. (Katrina), Duquette, P. (Pierre), Dardiotis, E. (Efthimios), Esposito, F. (Francesco), Fontaine, B. (Bertrand), Gasperi, C. (Christiane), Goris, A. (An), Dubois, B. (Bénédicte), Gourraud, P.-A. (Pierre-Antoine), Hadjigeorgiou, G.M. (Georgios M.), Haines, J.L. (Jonathan), Hawkins, C. (Clive), Hemmer`, B. (Bernhard), Hintzen, R.Q. (Rogier), Horáková, D., Isobe, N. (Noriko), Kalra, S. (Seema), Kira, J.-I. (Jun-ichi), Khalil, M. (Michael), Kockum, I. (I.), Lill, C.M. (Christina), Lincoln, M.R. (Matthew R.), Luessi, F. (Felix), Martin, R. (Roland), Oturai, A. (Annette), Palotie, A. (Aarno), Kunkle, B. (Brian), Henry, R. (Roland), Saarela, O. (Olli), Ivinson, A.J. (Adrian), Olsson, T., Taylor, B. (Bruce), Stewart, G. (Graeme), Harbo, H.F. (H.), Compston, J.E. (Juliet), Hauser, S.L. (Stephen), Hafler, D.A. (David A.), Zipp, F. (Frauke), De Jager, P., Sawcer, S.J. (Stephen), Oksenberg, J.R. (Jorge), Baranzini, S.E. (Sergio), Madireddy, L. (Lohith), Patsopoulos, N.A. (Nikolaos A.), Cotsapas, C. (Chris), Bos, S.D. (Steffan), Beecham, A.H. (Ashley), McCauley, J. (John William), Kim, K. (Kicheol), Jia, X. (Xiaoming), Santaniello, A. (Adam), Caillier, S.J. (Stacy), Andlauer, T.F.M. (Till F. M.), Barcellos, L.F. (Lisa), Berge, T. (Tone), Bernardinelli, L. (Luisa), Martinelli-Boneschi, F. (Filippo), Booth, D. (David), Briggs, F. (Farren), Celius, E.G. (Elisabeth), Comabella, M. (Manuel), Comi, G. (Giancarlo), Cree, B.A.C. (Bruce A. C.), Dalfonso, S., Dedham, K. (Katrina), Duquette, P. (Pierre), Dardiotis, E. (Efthimios), Esposito, F. (Francesco), Fontaine, B. (Bertrand), Gasperi, C. (Christiane), Goris, A. (An), Dubois, B. (Bénédicte), Gourraud, P.-A. (Pierre-Antoine), Hadjigeorgiou, G.M. (Georgios M.), Haines, J.L. (Jonathan), Hawkins, C. (Clive), Hemmer`, B. (Bernhard), Hintzen, R.Q. (Rogier), Horáková, D., Isobe, N. (Noriko), Kalra, S. (Seema), Kira, J.-I. (Jun-ichi), Khalil, M. (Michael), Kockum, I. (I.), Lill, C.M. (Christina), Lincoln, M.R. (Matthew R.), Luessi, F. (Felix), Martin, R. (Roland), Oturai, A. (Annette), Palotie, A. (Aarno), Kunkle, B. (Brian), Henry, R. (Roland), Saarela, O. (Olli), Ivinson, A.J. (Adrian), Olsson, T., Taylor, B. (Bruce), Stewart, G. (Graeme), Harbo, H.F. (H.), Compston, J.E. (Juliet), Hauser, S.L. (Stephen), Hafler, D.A. (David A.), Zipp, F. (Frauke), De Jager, P., Sawcer, S.J. (Stephen), Oksenberg, J.R. (Jorge), and Baranzini, S.E. (Sergio)

Abstract

The original version of this Article contained an error in the spelling of the author Nikolaos A. Patsopoulos, which was incorrectly given as Niklaos A. Patsopoulos, and author Efthimios Dardiotis, which was incorrectly given as Dardiotis Efthimios. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019
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5. Minimum Information about T Regulatory Cells: A Step toward Reproducibility and Standardization

Author

Fuchs, A., Gliwinski, M., Grageda, N., Spiering, R., Abbas, A.K., Appel, S., Bacchetta, R., Battaglia, M., Berglund, D., Blazar, B., Bluestone, J.A., Bornhauser, M., Brinke, A. Ten, Brusko, T.M., Cools, N., Cuturi, M.C., Geissler, E., Giannoukakis, N., Golab, K., Hafler, D.A., Ham, S.M. van, Hester, J., Hippen, K., Ianni, M. Di, Ilic, N., Isaacs, J., Issa, F., Iwaszkiewicz-Grzes, D., Jaeckel, E., Joosten, I., Klatzmann, D., Koenen, H., Kooten, C. van, Korsgren, O., Kretschmer, K., Levings, M., Marek-Trzonkowska, N.M., Martinez-Llordella, M., Miljkovic, D., Mills, K.H., Miranda, J.P., Piccirillo, C.A., Putnam, A.L., Ritter, T., Roncarolo, M.G., Sakaguchi, S., Sanchez-Ramon, S., Sawitzki, B., Sofronic-Milosavljevic, L., Sykes, M., Tang, Q., Vives-Pi, M., Waldmann, H., Witkowski, P., Wood, K.J., Gregori, S., Hilkens, C.M., Lombardi, G., Lord, P., Martinez-Caceres, E.M., Trzonkowski, P., Fuchs, A., Gliwinski, M., Grageda, N., Spiering, R., Abbas, A.K., Appel, S., Bacchetta, R., Battaglia, M., Berglund, D., Blazar, B., Bluestone, J.A., Bornhauser, M., Brinke, A. Ten, Brusko, T.M., Cools, N., Cuturi, M.C., Geissler, E., Giannoukakis, N., Golab, K., Hafler, D.A., Ham, S.M. van, Hester, J., Hippen, K., Ianni, M. Di, Ilic, N., Isaacs, J., Issa, F., Iwaszkiewicz-Grzes, D., Jaeckel, E., Joosten, I., Klatzmann, D., Koenen, H., Kooten, C. van, Korsgren, O., Kretschmer, K., Levings, M., Marek-Trzonkowska, N.M., Martinez-Llordella, M., Miljkovic, D., Mills, K.H., Miranda, J.P., Piccirillo, C.A., Putnam, A.L., Ritter, T., Roncarolo, M.G., Sakaguchi, S., Sanchez-Ramon, S., Sawitzki, B., Sofronic-Milosavljevic, L., Sykes, M., Tang, Q., Vives-Pi, M., Waldmann, H., Witkowski, P., Wood, K.J., Gregori, S., Hilkens, C.M., Lombardi, G., Lord, P., Martinez-Caceres, E.M., and Trzonkowski, P.

Abstract

Contains fulltext : 191000.pdf (publisher's version ) (Open Access), Cellular therapies with CD4+ T regulatory cells (Tregs) hold promise of efficacious treatment for the variety of autoimmune and allergic diseases as well as posttransplant complications. Nevertheless, current manufacturing of Tregs as a cellular medicinal product varies between different laboratories, which in turn hampers precise comparisons of the results between the studies performed. While the number of clinical trials testing Tregs is already substantial, it seems to be crucial to provide some standardized characteristics of Treg products in order to minimize the problem. We have previously developed reporting guidelines called minimum information about tolerogenic antigen-presenting cells, which allows the comparison between different preparations of tolerance-inducing antigen-presenting cells. Having this experience, here we describe another minimum information about Tregs (MITREG). It is important to note that MITREG does not dictate how investigators should generate or characterize Tregs, but it does require investigators to report their Treg data in a consistent and transparent manner. We hope this will, therefore, be a useful tool facilitating standardized reporting on the manufacturing of Tregs, either for research purposes or for clinical application. This way MITREG might also be an important step toward more standardized and reproducible testing of the Tregs preparations in clinical applications.

Published
2017

6. Protective and therapeutic role for αB-crystallin in autoimmune demyelination

Author

Ousman, S.S., Tomooka, B.H., Noort, J.M. van, Wawrousek, E.F., O'Conner, K., Hafler, D.A., Sobel, R.A., Robinson, W.H., Steinman, L., and TNO Kwaliteit van Leven

Subjects
Biomedical Research, Apoptosis, animal cell, multiple sclerosis, immune response, Mice, allergic encephalomyelitis, myelin sheath, antibody, caspase 3, cytokine, T lymphocyte, Th1 cell, Mus, rodent, article, NF-kappa B, T-Lymphocytes, Helper-Inducer, female, Neuroprotective Agents, cytokine release, priority journal, gamma interferon, demyelination, wild type, Neuroglia, recombinant alphab crystallin, Encephalomyelitis, Autoimmune, Experimental, MAP Kinase Signaling System, tumor necrosis factor, brain, animal experiment, nick end labeling, macrophage, interleukin 2, cerebrospinal fluid, animal tissue, astrocyte, Animals, Humans, controlled study, human, gene, mouse, Inflammation, nonhuman, animal model, Macrophages, interleukin 12p40, alpha-Crystallin B Chain, central nervous system, immune system, gene function, Astrocytes, interleukin 17, recombinant protein, nervous system disorder
Abstract

αB-crystallin (CRYAB) is the most abundant gene transcript present in early active multiple sclerosis lesions, whereas such transcripts are absent in normal brain tissue. This crystallin has anti-apoptotic and neuroprotective functions. CRYAB is the major target of CD4+ T-cell immunity to the myelin sheath from multiple sclerosis brain. The pathophysiological implications of this immune response were investigated here. We demonstrate that CRYAB is a potent negative regulator acting as a brake on several inflammatory pathways in both the immune system and central nervous system (CNS). Cryab-/- mice showed worse experimental autoimmune encephalomyelitis (EAE) at the acute and progressive phases, with higher Th1 and Th17 cytokine secretion from T cells and macrophages, and more intense CNS inflammation, compared with their wild-type counterparts. Furthermore, Cryab-/- astrocytes showed more cleaved caspase-3 and more TUNEL staining, indicating an anti-apoptotic function of Cryab. Antibody to CRYAB was detected in cerebrospinal fluid from multiple sclerosis patients and in sera from mice with EAE. Administration of recombinant CRYAB ameliorated EAE. Thus, the immune response against a negative regulator of inflammation, CRYAB, in multiple sclerosis, would exacerbate inflammation and demyelination. This can be countered by giving CRYAB itself for therapy of ongoing disease. ©2007 Nature Publishing Group.

Published
2007

10. Modeling the cumulative genetic risk for multiple sclerosis from genome-wide association data

Author

Wang, J.H., Pappas, D., De Jager, P.L., Pelletier, D., de Bakker, P.I.W., Kappos, L., Polman, C.H., Chibnik, L.B., Hafler, D.A., Matthews, P.M., Hauser, S.L., Baranzini, S.E., Oksenberg, J.R., Kermode, A.G., Wang, J.H., Pappas, D., De Jager, P.L., Pelletier, D., de Bakker, P.I.W., Kappos, L., Polman, C.H., Chibnik, L.B., Hafler, D.A., Matthews, P.M., Hauser, S.L., Baranzini, S.E., Oksenberg, J.R., and Kermode, A.G.

Abstract

BACKGROUND: Multiple sclerosis (MS) is the most common cause of chronic neurologic disability beginning in early to middle adult life. Results from recent genome-wide association studies (GWAS) have substantially lengthened the list of disease loci and provide convincing evidence supporting a multifactorial and polygenic model of inheritance. Nevertheless, the knowledge of MS genetics remains incomplete, with many risk alleles still to be revealed. METHODS: We used a discovery GWAS dataset (8,844 samples, 2,124 cases and 6,720 controls) and a multi-step logistic regression protocol to identify novel genetic associations. The emerging genetic profile included 350 independent markers and was used to calculate and estimate the cumulative genetic risk in an independent validation dataset (3,606 samples). Analysis of covariance (ANCOVA) was implemented to compare clinical characteristics of individuals with various degrees of genetic risk. Gene ontology and pathway enrichment analysis was done using the DAVID functional annotation tool, the GO Tree Machine, and the Pathway-Express profiling tool. RESULTS: In the discovery dataset, the median cumulative genetic risk (P-Hat) was 0.903 and 0.007 in the case and control groups, respectively, together with 79.9% classification sensitivity and 95.8% specificity. The identified profile shows a significant enrichment of genes involved in the immune response, cell adhesion, cell communication/signaling, nervous system development, and neuronal signaling, including ionotropic glutamate receptors, which have been implicated in the pathological mechanism driving neurodegeneration. In the validation dataset, the median cumulative genetic risk was 0.59 and 0.32 in the case and control groups, respectively, with classification sensitivity 62.3% and specificity 75.9%. No differences in disease progression or T2-lesion volumes were observed among four levels of predicted genetic risk groups (high, medium, low, misclassified). On the othe

Published
2011

11. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Author

Sawcer, S., Hellenthal, G., Pirinen, M., Spencer, C.C.A., Patsopoulos, N.A., Moutsianas, L., Dilthey, A., Su, Z., Freeman, C., Hunt, S.E., Edkins, S., Gray, E., Booth, D.R., Potter, S.C., Goris, A., Band, G., Bang Oturai, A., Strange, A., Saarela, J., Bellenguez, C., Fontaine, B., Gillman, M., Hemmer, B., Gwilliam, R., Zipp, F., Jayakumar, A., Martin, R., Leslie, S., Hawkins, S., Giannoulatou, E., D’alfonso, S., Blackburn, H., Martinelli Boneschi, F., Liddle, J., Harbo, H.F., Perez, M.L., Spurkland, A., Waller, M.J., Mycko, M.P., Ricketts, M., Comabella, M., Hammond, N., Kockum, I., McCann, O.T., Ban, M., Whittaker, P., Kemppinen, A., Weston, P., Hawkins, C., Widaa, S., Zajicek, J., Dronov, S., Robertson, N., Bumpstead, S.J., Barcellos, L.F., Ravindrarajah, R., Abraham, R., Alfredsson, L., Ardlie, K., Aubin, C., Baker, A., Baker, K., Baranzini, S.E., Bergamaschi, L., Bergamaschi, R., Bernstein, A., Berthele, A., Boggild, M., Bradfield, J.P., Brassat, D., Broadley, S.A., Buck, D., Butzkueven, H., Capra, R., Carroll, W.M., Cavalla, P., Celius, E.G., Cepok, S., Chiavacci, R., Clerget-Darpoux, F., Clysters, K., Comi, G., Cossburn, M., Cournu-Rebeix, I., Cox, M.B., Cozen, W., Cree, B.A.C., Cross, A.H., Cusi, D., Daly, M.J., Davis, E., de Bakker, P.I.W., Debouverie, M., D’hooghe, M.B., Dixon, K., Dobosi, R., Dubois, B., Ellinghaus, D., Elovaara, I., Esposito, F., Fontenille, C., Foote, S., Franke, A., Galimberti, D., Ghezzi, A., Glessner, J., Gomez, R., Gout, O., Graham, C., Grant, S.F.A., Rosa Guerini, F., Hakonarson, H., Hall, P., Hamsten, A., Hartung, H-P, Heard, R.N., Heath, S., Hobart, J., Hoshi, M., Infante-Duarte, C., Ingram, G., Ingram, W., Islam, T., Jagodic, M., Kabesch, M., Kermode, A.G., Kilpatrick, T.J., Kim, C., Klopp, N., Koivisto, K., Larsson, M., Lathrop, M., Lechner-Scott, J.S., Leone, M.A., Leppä, V., Liljedahl, U., Lima Bomfim, I., Lincoln, R.R., Link, J., Liu, J., Lorentzen, Å.R., Lupoli, S., Macciardi, F., Mack, T., Marriott, M., Martinelli, V., Mason, D., McCauley, J.L., Mentch, F., Mero, I-L, Mihalova, T., Montalban, X., Mottershead, J., Myhr, K-M, Naldi, P., Ollier, W., Page, A., Palotie, A., Pelletier, J., Piccio, L., Pickersgill, T., Piehl, F., Pobywajlo, S., Quach, H.L., Ramsay, P.P., Reunanen, M., Reynolds, R., Rioux, J.D., Rodegher, M., Roesner, S., Rubio, J.P., Rückert, I-M, Salvetti, M., Salvi, E., Santaniello, A., Schaefer, C.A., Schreiber, S., Schulze, C., Scott, R.J., Sellebjerg, F., Selmaj, K.W., Sexton, D., Shen, L., Simms-Acuna, B., Skidmore, S., Sleiman, P.M.A., Smestad, C., Sørensen, P.S., Søndergaard, H.B., Stankovich, J., Strange, R.C., Sulonen, A-M, Sundqvist, E., Syvänen, A-C, Taddeo, F., Taylor, B., Blackwell, J.M., Tienari, P., Bramon, E., Tourbah, A., Brown, M.A., Tronczynska, E., Casas, J.P., Tubridy, N., Corvin, A., Vickery, J., Jankowski, J., Villoslada, P., Markus, H.S., Wang, K., Mathew, C.G., Wason, J., Palmer, C.N.A., Wichmann, H-E, Plomin, R., Willoughby, E., Rautanen, A., Winkelmann, J., Wittig, M., Trembath, R.C., Yaouanq, J., Viswanathan, A.C., Zhang, H., Wood, N.W., Zuvich, R., Deloukas, P., Langford, C., Duncanson, A., Oksenberg, J.R., Pericak-Vance, M.A., Haines, J.L., Olsson, T., Hillert, J., Ivinson, A.J., De Jager, P.L., Peltonen, L., Stewart, G.J., Hafler, D.A., Hauser, S.L., McVean, G., Donnelly, P., Compston, A., Sawcer, S., Hellenthal, G., Pirinen, M., Spencer, C.C.A., Patsopoulos, N.A., Moutsianas, L., Dilthey, A., Su, Z., Freeman, C., Hunt, S.E., Edkins, S., Gray, E., Booth, D.R., Potter, S.C., Goris, A., Band, G., Bang Oturai, A., Strange, A., Saarela, J., Bellenguez, C., Fontaine, B., Gillman, M., Hemmer, B., Gwilliam, R., Zipp, F., Jayakumar, A., Martin, R., Leslie, S., Hawkins, S., Giannoulatou, E., D’alfonso, S., Blackburn, H., Martinelli Boneschi, F., Liddle, J., Harbo, H.F., Perez, M.L., Spurkland, A., Waller, M.J., Mycko, M.P., Ricketts, M., Comabella, M., Hammond, N., Kockum, I., McCann, O.T., Ban, M., Whittaker, P., Kemppinen, A., Weston, P., Hawkins, C., Widaa, S., Zajicek, J., Dronov, S., Robertson, N., Bumpstead, S.J., Barcellos, L.F., Ravindrarajah, R., Abraham, R., Alfredsson, L., Ardlie, K., Aubin, C., Baker, A., Baker, K., Baranzini, S.E., Bergamaschi, L., Bergamaschi, R., Bernstein, A., Berthele, A., Boggild, M., Bradfield, J.P., Brassat, D., Broadley, S.A., Buck, D., Butzkueven, H., Capra, R., Carroll, W.M., Cavalla, P., Celius, E.G., Cepok, S., Chiavacci, R., Clerget-Darpoux, F., Clysters, K., Comi, G., Cossburn, M., Cournu-Rebeix, I., Cox, M.B., Cozen, W., Cree, B.A.C., Cross, A.H., Cusi, D., Daly, M.J., Davis, E., de Bakker, P.I.W., Debouverie, M., D’hooghe, M.B., Dixon, K., Dobosi, R., Dubois, B., Ellinghaus, D., Elovaara, I., Esposito, F., Fontenille, C., Foote, S., Franke, A., Galimberti, D., Ghezzi, A., Glessner, J., Gomez, R., Gout, O., Graham, C., Grant, S.F.A., Rosa Guerini, F., Hakonarson, H., Hall, P., Hamsten, A., Hartung, H-P, Heard, R.N., Heath, S., Hobart, J., Hoshi, M., Infante-Duarte, C., Ingram, G., Ingram, W., Islam, T., Jagodic, M., Kabesch, M., Kermode, A.G., Kilpatrick, T.J., Kim, C., Klopp, N., Koivisto, K., Larsson, M., Lathrop, M., Lechner-Scott, J.S., Leone, M.A., Leppä, V., Liljedahl, U., Lima Bomfim, I., Lincoln, R.R., Link, J., Liu, J., Lorentzen, Å.R., Lupoli, S., Macciardi, F., Mack, T., Marriott, M., Martinelli, V., Mason, D., McCauley, J.L., Mentch, F., Mero, I-L, Mihalova, T., Montalban, X., Mottershead, J., Myhr, K-M, Naldi, P., Ollier, W., Page, A., Palotie, A., Pelletier, J., Piccio, L., Pickersgill, T., Piehl, F., Pobywajlo, S., Quach, H.L., Ramsay, P.P., Reunanen, M., Reynolds, R., Rioux, J.D., Rodegher, M., Roesner, S., Rubio, J.P., Rückert, I-M, Salvetti, M., Salvi, E., Santaniello, A., Schaefer, C.A., Schreiber, S., Schulze, C., Scott, R.J., Sellebjerg, F., Selmaj, K.W., Sexton, D., Shen, L., Simms-Acuna, B., Skidmore, S., Sleiman, P.M.A., Smestad, C., Sørensen, P.S., Søndergaard, H.B., Stankovich, J., Strange, R.C., Sulonen, A-M, Sundqvist, E., Syvänen, A-C, Taddeo, F., Taylor, B., Blackwell, J.M., Tienari, P., Bramon, E., Tourbah, A., Brown, M.A., Tronczynska, E., Casas, J.P., Tubridy, N., Corvin, A., Vickery, J., Jankowski, J., Villoslada, P., Markus, H.S., Wang, K., Mathew, C.G., Wason, J., Palmer, C.N.A., Wichmann, H-E, Plomin, R., Willoughby, E., Rautanen, A., Winkelmann, J., Wittig, M., Trembath, R.C., Yaouanq, J., Viswanathan, A.C., Zhang, H., Wood, N.W., Zuvich, R., Deloukas, P., Langford, C., Duncanson, A., Oksenberg, J.R., Pericak-Vance, M.A., Haines, J.L., Olsson, T., Hillert, J., Ivinson, A.J., De Jager, P.L., Peltonen, L., Stewart, G.J., Hafler, D.A., Hauser, S.L., McVean, G., Donnelly, P., and Compston, A.

Abstract

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability1. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals2, 3, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk4. Modestly powered genome-wide association studies (GWAS)5, 6, 7, 8, 9, 10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility11. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Published
2011

17. HLA B44

Author

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

Abstract

In addition to the main multiple sclerosis (MS) major histocompatibility complex (MHC) risk allele (HLA DRB11501), investigations of the MHC have implicated several class I MHC loci (HLA A, HLA B,and HLA C) as potential independent MS susceptibility loci. Here, we evaluate the role of 3 putative protective alleles in MS: HLA A02, HLA B44, and HLA C05.

Published
2010
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18. Enhanced B7 costimulatory molecule expression in inflammatory human sural nerve biopsies

Author

Kiefer, R., Mueller, M., Dangond, F., Hafler, D.A., Toyka, K.V., and Hartung, H-P.

Abstract

ObjectivesTo define the role of the costimulatory molecules B7-1 and B7-2 in inflammatory disorders of the peripheral nervous system. B7 molecules are essential for effective antigen presentation and may determine the differentiation of T cells into a Th-1 or Th-2 phenotype, thus modulating immune response and disease course.MethodsForty nine sural nerve biopsies from patients with neuroborreliosis, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), CIDP variants and hereditary neuropathies, and those with no detectable abnormality were investigated. The expression of B7-1 and B7-2 mRNA and protein was investigated by polymerase chain reaction (PCR) and immunocytochemistry.ResultsB7-1 mRNA was strongly upregulated in both cases of neuroborreliosis, in two cases of GBS and one case of variant CIDP. Moderate to low levels were detected in the remaining GBS and CIDP biopsies and were rarely found in a non-inflammatory control group consisting of hereditary neuropathy and normal nerves. At the immunocytochemical level, strong expression of B7-1 protein was found in both neuroborreliosis cases, and moderate or low expression in six of eight GBS cases and seven of 17 CIDP cases investigated, whereas only one of five non-inflammatory control nerves showed staining, which was very weak. In neuroborreliosis, B7-1 protein was found very pronounced in epineurial infiltrates, whereas in GBS and CIDP, labelling was predominantly endoneurial and localised to putative macrophages. B7-2 mRNA and protein were expressed only at low levels in neuroborreliosis and selected autoimmune neuropathy cases, and were essentially absent from non-inflammatory controls.ConclusionsB7 molecules are expressed in the peripheral nervous system and regulated during disease, and their presence in macrophages underlines the putative function of endoneurial macrophages as local antigen presenting cells in the immunopathology of peripheral nerve. B7-1 rather than B7-2 is preferentially upregulated, possibly promoting the induction of a Th-1-type T cell response within the nerve.

Published
2000

20. Variable Immortalizing Potential and Frequent Virus Latency in Blood-Derived T-Cell Clones Infected With Human T-Cell Leukemia Virus Type I

Author

Richardson, J.H., Höllsberg, P., Windhagen, A., Child, L.A., Hafler, D.A., and Lever, A.M.L.

Abstract

Human T-cell leukemia virus type I (HTLV-I)-infected T cells expanded in vitro by single-cell cloning provide a unique system for investigating virus-cell interactions in nonimmortalized T cells. By analysis of clones generated randomly from the blood of virus carriers, we confirm that CD4 T cells are the major reservoir of HTLV-I in vivo and show that most infected cells contain a single integrated provirus. Contrary to the situation in HTLV-I immortalized cell lines, the HTLV-I provirus was found to be transcriptionally silent in a high proportion of randomly generated T-cell clones and could not be reactivated by mitogenic stimulation. The spontaneous proliferation previously documented in HTLV-I–infected T-cell clones was not observed in silently infected cells, and therefore correlates directly with the expression of tax and other viral genes. The only cytokine mRNA found to be significantly elevated in the virus-producing clones was interleukin-6; however, receptor-blocking experiments argue against a role for IL-6 in the virus-induced cell proliferation. We observed a striking variation in the ability of individual HTLV-I–producing clones to immortalize fresh peripheral blood lymphocytes. This ability did not correlate with the levels of viral mRNA expression, gag p24 production, spontaneous proliferation, or tax-transactivation, possibly suggesting a role for host cell factors as determinants of viral infectivity or immortalization. Studies to elucidate the basis of this phenotypic heterogeneity should enhance our understanding of viral spread and pathogenesis.

Published
1997
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