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151. The Immune Signatures data resource, a compendium of systems vaccinology datasets.

Author

Diray-Arce, Joann, Miller, Helen E. R., Henrich, Evan, Gerritsen, Bram, Mulè, Matthew P., Fourati, Slim, Gygi, Jeremy, Hagan, Thomas, Tomalin, Lewis, Rychkov, Dmitry, Kazmin, Dmitri, Chawla, Daniel G., Meng, Hailong, Dunn, Patrick, Campbell, John, The Human Immunology Project Consortium (HIPC), Deckhut-Augustine, Alison, Gottardo, Raphael, Haddad, Elias K., and Hafler, David A.

Subjects
VACCINE effectiveness, VACCINE immunogenicity, RNA sequencing, VIRAL antibodies, BATCH processing, DATA release, IMMUNOGLOBULINS
Abstract

Vaccines are among the most cost-effective public health interventions for preventing infection-induced morbidity and mortality, yet much remains to be learned regarding the mechanisms by which vaccines protect. Systems immunology combines traditional immunology with modern 'omic profiling techniques and computational modeling to promote rapid and transformative advances in vaccinology and vaccine discovery. The NIH/NIAID Human Immunology Project Consortium (HIPC) has leveraged systems immunology approaches to identify molecular signatures associated with the immunogenicity of many vaccines. However, comparative analyses have been limited by the distributed nature of some data, potential batch effects across studies, and the absence of multiple relevant studies from non-HIPC groups in ImmPort. To support comparative analyses across different vaccines, we have created the Immune Signatures Data Resource, a compendium of standardized systems vaccinology datasets. This data resource is available through ImmuneSpace, along with code to reproduce the processing and batch normalization starting from the underlying study data in ImmPort and the Gene Expression Omnibus (GEO). The current release comprises 1405 participants from 53 cohorts profiling the response to 24 different vaccines. This novel systems vaccinology data release represents a valuable resource for comparative and meta-analyses that will accelerate our understanding of mechanisms underlying vaccine responses. Measurement(s) Transcriptomics • Hemagglutination Inhibition Assay • IgG IgM IgA Total Measurement • Virus-neutralizing Antibody • ELISA Technology Type(s) Microarray • RNA sequencing • Hemagglutination Inhibition Assay • ELISA • Microneutralization Assay • serum neutralization of viral infectivity assay Sample Characteristic - Organism Homo sapiens [ABSTRACT FROM AUTHOR]

Published
2022
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152. Specific peripheral B cell tolerance defects in patients with multiple sclerosis

Author

Kinnunen, Tuure, Chamberlain, Nicolas, Morbach, Henner, Cantaert, Tineke, Lynch, Megan, Preston-Hurlburt, Paula, Herold, Kevan C., Hafler, David A., O'Connor, Kevin C., and Meffre, Eric

Subjects
Multiple sclerosis -- Development and progression -- Care and treatment -- Genetic aspects -- Research, B cells -- Physiological aspects -- Genetic aspects -- Research, Health care industry
Abstract

Multiple sclerosis (MS) is a genetically mediated autoimmune disease of the central nervous system. B cells have recently emerged as major contributors to disease pathogenesis, but the mechanisms responsible for [...]

Published
2013
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153. Sodium chloride drives autoimmune disease by the induction of pathogenic [T.sub.H]17 cells

Author

Kleinewietfeld, Markus, Manzel, Arndt, Titze, Jens, Kvakan, Heda, Yosef, Nir, Linker, Ralf A., Muller, Dominik N., and Hafler, David A.

Subjects
T cells -- Health aspects, Autoimmune diseases -- Diagnosis, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

There has been a marked increase in the incidence of autoimmune diseases in the past half-century. Although the underlying genetic basis of this class of diseases has recently been elucidated, [...]

Published
2013
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154. Microbial Reprogramming Inhibits Western Diet-Associated Obesity

Author

Poutahidis, Theofilos, primary, Kleinewietfeld, Markus, additional, Smillie, Christopher, additional, Levkovich, Tatiana, additional, Perrotta, Alison, additional, Bhela, Siddheshvar, additional, Varian, Bernard, additional, Ibrahim, Yassin, additional, Lakritz, Jessica, additional, Kearney, Sean, additional, Chatzigiagkos, Antonis, additional, Hafler, David, additional, Alm, Eric, additional, and Erdman, Susan, additional

Published
2014
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155. List of Contributors

Author

Agmon-Levin, Nancy, primary, Ahmed, S. Sohail, additional, Ali, Youssif M., additional, Aringer, Martin, additional, Bach, Jean-François, additional, Barker, Jennifer, additional, Barker, Robert N., additional, Baxter, Alan G., additional, Betterle, Corrado, additional, Birlea, Stanca A., additional, Björkström, Niklas K., additional, Blair, Paul A., additional, Bobik, Alex, additional, Borazan, Nabeel H., additional, Bosch, Xavier, additional, Brodsky, Robert A., additional, Bryceson, Yenan T., additional, Burkett, Patrick R., additional, Bussel, James B., additional, Butzkueven, Helmut, additional, Caricchio, Roberto, additional, Casciola-Rosen, Livia, additional, Caturegli, Patrizio, additional, Chatenoud, Lucienne, additional, Cohen, Philip L., additional, Coppieters, Ken, additional, Crome, Sarah Q., additional, Crystal, Ronald G., additional, Culton, Donna A., additional, Dalal, Monica D., additional, David, Chella S., additional, Davidson, Anne, additional, Delli, Ahmed J., additional, Delves, Peter J., additional, Denmark, Vera Kandror, additional, Diamond, Betty, additional, Diaz, Luis A., additional, Eaton, John E., additional, Eisenbarth, George S., additional, Falk, Ronald J., additional, Field, Judith, additional, Fleisher, Thomas A., additional, Fragoulis, George E., additional, Fritzler, Marvin J., additional, Furst, Daniel E., additional, Gallucci, Stefania, additional, Gelbman, Brian, additional, Eric Gershwin, M., additional, Getts, Daniel R., additional, Getts, Meghann Teague, additional, Gianani, Roberto, additional, Gleeson, Paul A., additional, Goding, James W., additional, Gordon, Siamon, additional, Goronzy, Jörg J., additional, Greer, Judith M., additional, Gruson, Berengere, additional, Guilherme, L., additional, Gutenberg, Angelika, additional, Hafler, David A., additional, Hahn, Bevra H., additional, Hamano, Hideaki, additional, Hamilton, Sara R., additional, Harrison, Leonard C., additional, Hernandez, Amanda L., additional, Husebye, Eystein, additional, Charles Jennette, J., additional, Jones, Richard J., additional, Jordan, Margaret A., additional, Kalil, J., additional, Königs, Christoph, additional, Kawa, Shigeyuki, additional, Kaya, Ziya, additional, King, Jennifer K., additional, King, Nicholas J.C., additional, Kiyosawa, Kendo, additional, Kronenberg, Mitchell, additional, Kuchroo, Vijay K., additional, Kyaw, Tin, additional, Lünemann, Jan, additional, Lahita, Robert G., additional, Lalezari, Parviz, additional, Lambert, Paul-Henri, additional, Lancaster, Eric, additional, Laurence, Arian, additional, Lee, Youjin, additional, Lenardo, Michael, additional, Lernmark, Åke, additional, Levinson, Arnold I., additional, Lindor, Keith D., additional, Liu, Zhi, additional, Ljunggren, Hans-Gustaf, additional, Lunardi, Claudio, additional, Lundin, Knut E.A., additional, Lunn, Michael P.T., additional, Lupi, Isabella, additional, Lustig, Livia, additional, Münz, Christian, additional, Mackay, Charles R., additional, Mackay, Ian R., additional, Malattia, Clara, additional, Mangalam, Ashutosh, additional, Martini, Alberto, additional, Mauri, Claudia, additional, Mavragani, Clio P., additional, Mayer, Lloyd, additional, McCombe, Pamela A., additional, Melchers, Fritz, additional, Mieli-Vergani, Giorgina, additional, Miller, Frederick W., additional, Miller, Stephen D., additional, Mizui, Masayuki, additional, Mjösberg, Jenny, additional, Moutsopoulos, Haralampos M., additional, Norris, David A., additional, Nussenblatt, Robert B., additional, O’Connor, Kevin C., additional, Ohashi, Pamela S., additional, O’Keeffe, Meredith, additional, Oliveira, Joao Bosco, additional, Oppenheim, Joost J., additional, Perez-Arroyo, Alicia, additional, Peters, Anneli, additional, Peterson, Pärt, additional, Plüddemann, Annette, additional, Posner, Jerome B., additional, Preston, Gloria A., additional, Puccetti, Antonio, additional, Radford, Kristen, additional, Ramos-Casals, Manuel, additional, Rao, V. Koneti, additional, Rauschkolb, Paula K., additional, Reddy, Venkat, additional, Redlich, Kurt, additional, Rival, Claudia, additional, Rose, Noel R., additional, Rosen, Antony, additional, Schrader, John W., additional, Schwaeble, Wilhelm J., additional, Selmi, Carlo, additional, Nida Sen, H., additional, Serota, Marc, additional, Sheikh, Kazim A., additional, Shoenfeld, Yehuda, additional, Shortman, Ken, additional, Sieper, Joachim, additional, Silverstein, Arthur M., additional, Sim, Robert B., additional, Simon, Anna, additional, Smolen, Josef S., additional, Sollid, Ludvig M., additional, Stoffels, Monique, additional, Su, Helen, additional, Syrbe, Uta, additional, Talwalkar, Jayant A., additional, Taneja, Veena, additional, Tincani, Angela, additional, Tipping, Peter, additional, Toh, Ban-Hock, additional, Tsokos, George C., additional, Tu, Eric, additional, Tung, Kenneth S.K., additional, van Driel, Ian R., additional, Vergani, Diego, additional, Vickers, Mark A., additional, Viegas, Stuart, additional, Vincent, Angela, additional, von Andrian, Ulrich H., additional, Herrath, Matthias von, additional, Weetman, Anthony P., additional, Wentworth, John M., additional, Weyand, Cornelia M., additional, Wingender, Gerhard, additional, Zanchetta, Renato, additional, and Zouali, Moncef, additional

Published
2014
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158. Single-cell immunophenotyping of the skin lesion erythema migrans identifies IgM memory B cells

Author

Jiang, Ruoyi, primary, Meng, Hailong, additional, Raddassi, Khadir, additional, Fleming, Ira, additional, Hoehn, Kenneth B., additional, Dardick, Kenneth R., additional, Belperron, Alexia A., additional, Montgomery, Ruth R., additional, Shalek, Alex K., additional, Hafler, David A., additional, Kleinstein, Steven H., additional, and Bockenstedt, Linda K., additional

Published
2021
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159. Cutting Edge: Distinct B Cell Repertoires Characterize Patients with Mild and Severe COVID-19

Author

Hoehn, Kenneth B., primary, Ramanathan, Palaniappan, additional, Unterman, Avraham, additional, Sumida, Tomokazu S., additional, Asashima, Hiromitsu, additional, Hafler, David A., additional, Kaminski, Naftali, additional, Dela Cruz, Charles S., additional, Sealfon, Stuart C., additional, Bukreyev, Alexander, additional, and Kleinstein, Steven H., additional

Published
2021
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160. Type I Interferon Transcriptional Network Regulates Expression of Coinhibitory Receptors in Human T cells

Author

Hafler, David, primary, Sumida, Tomokazu, additional, Dulberg, Shai, additional, Schupp, Jonas, additional, Stillwell, Helen, additional, Axisa, Pierre-Paul, additional, Comi, Michela, additional, Lincoln, Matthew, additional, Unterman, Avraham, additional, Kaminski, Naftali, additional, Madi, Asaf, additional, and Kuchroo, Vijay, additional

Published
2021
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161. Phase 2 Trial of Rituximab in Acetylcholine Receptor Antibody-Positive Generalized Myasthenia Gravis: The BeatMG Study.

Author

Nowak, Richard J, Nowak, Richard J, Coffey, Christopher S, Goldstein, Jonathan M, Dimachkie, Mazen M, Benatar, Michael, Kissel, John T, Wolfe, Gil I, Burns, Ted M, Freimer, Miriam L, Nations, Sharon, Granit, Volkan, Smith, A Gordon, Richman, David P, Ciafaloni, Emma, Al-Lozi, Muhammad T, Sams, Laura Ann, Quan, Dianna, Ubogu, Eroboghene, Pearson, Brenda, Sharma, Aditi, Yankey, Jon W, Uribe, Liz, Shy, Michael, Amato, Anthony A, Conwit, Robin, O'Connor, Kevin C, Hafler, David A, Cudkowicz, Merit E, Barohn, Richard J, NeuroNEXT NN103 BeatMG Study Team, Nowak, Richard J, Nowak, Richard J, Coffey, Christopher S, Goldstein, Jonathan M, Dimachkie, Mazen M, Benatar, Michael, Kissel, John T, Wolfe, Gil I, Burns, Ted M, Freimer, Miriam L, Nations, Sharon, Granit, Volkan, Smith, A Gordon, Richman, David P, Ciafaloni, Emma, Al-Lozi, Muhammad T, Sams, Laura Ann, Quan, Dianna, Ubogu, Eroboghene, Pearson, Brenda, Sharma, Aditi, Yankey, Jon W, Uribe, Liz, Shy, Michael, Amato, Anthony A, Conwit, Robin, O'Connor, Kevin C, Hafler, David A, Cudkowicz, Merit E, Barohn, Richard J, and NeuroNEXT NN103 BeatMG Study Team

Abstract

ObjectiveTo determine whether rituximab is safe and potentially beneficial, warranting further investigation in an efficacy trial for acetylcholine receptor antibody-positive generalized MG (AChR-Ab+ gMG).MethodsThe B-Cell Targeted Treatment in MG (BeatMG) study was a randomized, double-blind, placebo-controlled, multicenter phase-2 trial that utilized a futility design. Individuals 21-90 years of age, with AChR-Ab+ gMG (MG Foundation of America Class II-IV) and receiving prednisone ≥15 mg/day were eligible. The primary outcome was a measure of steroid-sparing effect, defined as the proportion achieving ≥75% reduction in mean daily prednisone dose in the 4-weeks prior to week 52 and with clinical improvement or no significant worsening as compared to the 4-week period prior to randomization. The co-primary outcome was safety. Secondary outcomes included MG-specific clinical assessments. Fifty-two individuals were randomized (1:1) to either a two-cycle rituximab/placebo regimen, with follow-up through 52-weeks.ResultsOf the 52 participants included, mean (±SD) age at enrollment was 55.1 (±17.1) years; 23 (44.2%) were female, and 31 (59.6%) were MGFA Class II. The mean (±SD) baseline prednisone dose was 22.1 (±9.7) mg/day. The primary steroid-sparing outcome was achieved in 60% of those on rituximab vs. 56% on placebo. The study reached its futility endpoint (p=0.03) suggesting that the pre-defined clinically meaningful improvement of 30% due to rituximab over placebo was unlikely to be achieved in a subsequent, larger trial. No safety issues identified.ConclusionsWhile rituximab was safe and well-tolerated, these results suggest that there is a low probability of observing the defined clinically meaningful steroid-sparing effect over a 12-month period in a phase-3 trial of mild-moderately symptomatic AChR-Ab+ gMG.Classification of evidenceThis study provides Class I evidence that for mild-to-moderate AChR-Ab+ gMG, compared with placebo, rituximab is safe but unlikely

Published
2021

162. Multiple sclerosis

Author

Nylander, Alyssa and Hafler, David A.

Subjects
Multiple sclerosis -- Diagnosis -- Care and treatment, Brain tumors -- Diagnosis -- Care and treatment, Genetic susceptibility -- Research, Health care industry
Abstract

Multiple sclerosis (MS) is a multifocal demyelinating disease with progressive neurodegeneration caused by an autoimmune response to self-antigens in a genetically susceptible individual. While the formation and persistence of meningeal lymphoid follicles suggest persistence of antigens to drive the continuing inflammatory and humoral response, the identity of an antigen or infectious agent leading to the oligoclonal expansion of B and T cells is unknown. In this review we examine new paradigms for understanding the immunopathology of MS, present recent data defining the common genetic variants underlying disease susceptibility, and explore how improved understanding of immune pathway disruption can inform MS prognosis and treatment decisions., Introduction MS is a multifocal demyelinating disease with progressive neurodegeneration caused by an autoimmune response to self-antigens in a genetically susceptible individual. Clinical symptoms vary based on the site of [...]

Published
2012
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163. Unraveling the autoimmune translational research process layer by layer

Author

Blumberg, Richard S., Dittel, Bonnie, Hafler, David, von Herrath, Matthias, and Nestle, Frank O.

Subjects
Immunity -- Health aspects -- Research, Autoimmune diseases -- Drug therapy -- Development and progression -- Research, Biological sciences, Health
Abstract

Autoimmune diseases have a complex etiology and despite great progress having been made in our comprehension of these disorders, there has been limited success in the development of approved medications based on these insights. Development of drugs and strategies for application in translational research and medicine are hampered by an inadequate molecular definition of the human autoimmune phenotype and the organizational models that are necessary to clarify this definition., The autoimmune problem Autoimmune diseases comprise a large number of disorders with varied pathogenesis that are currently characterized into more than 100 different types of probable syndromic conditions (1). Consequently, [...]

Published
2012

167. Genome-wide association study in a high-risk isolate for multiple sclerosis reveals associated variants in STAT3 gene

Author

Jakkula, Eveliina, Sulonen, Anna-Maija, Leppa, Virpi, Varilo, Teppo, Kallio, Suvi, Kemppinen, Anu, Purcell, Shaun, Tienari, Pentti, Koivisto, Keijo, Sumelahti, Marja-Liisa, Elovaara, Irina, Pirttila, Tuula, Reunanen, Mauri, Sondergaard, Helle Bach, Aromaa, Arpo, Oturai, Annette Bang, Harbo, Hanne F., Mero, Inger-Lise, Gabriel, Stacey B., Kappos, Ludwig, Polamn, Chris, De Jager, Philip L., Mirel, Daniel B., Hauser, Stephen L., Hafler, David A., Daly, Mark J., Palotie, Aarno, Saarela, Janna, and Peltonen, Leena

Subjects
Multiple sclerosis -- Genetic aspects, Multiple sclerosis -- Risk factors, Genetic variation -- Research, Biological sciences
Abstract

A genome-wide association study is undertaken in a high-risk isolate for multiple sclerosis (MS) in order to identify previously unreported high-impact variants associated with MS. Results reveal that SNP (rs744166) within the STAT3 gene is associated with MS.

Published
2010

168. On-chip activation and subsequent detection of individual antigen-specific T cells

Author

Song, Qing, Han, Qing, Bradshaw, Elizabeth M., Kent, Sally C., Raddassi, Khadir, Nilsson, Bjorn, Nepom, Gerald T., Hafler, David A., and Love, J. Christopher

Subjects
T cells -- Chemical properties, T cells -- Health aspects, Chemical detectors -- Usage, Activation energy -- Research, Chemistry
Abstract

The frequencies of antigen-specific CD4+ T cells in samples of human tissue have been difficult to determine accurately ex vivo, particularly for autoimmune diseases such as multiple sclerosis or type 1 diabetes. Conventional approaches involve the expansion of primary T cells in vitro to increase the numbers of cells, and a subsequent assessment of the frequencies of antigen-specific T cells in the expanded population by limiting dilution or by using fluorescently labeled tetramers of peptide-loaded major histocompatibility complex (MHC) receptors. Here we describe an alternative approach that uses arrays of subnanoliter wells coated with recombinant peptideloaded MHC class II monomers to isolate and stimulate individual CD4+ T cells in an antigen-specific manner. In these experiments, activation was monitored using microengraving to capture two cytokines (IFN[gamma] and IL17) released from single cells. This new method should enable direct enumeration of antigen-specific CD4+ T ceils ex vivo from clinical samples. 10.1021/ac9024363

Published
2010

173. A phase 1b study of nivolumab in patients with autoimmune disorders and advanced malignancies (AIM-NIVO).

Author

Dumbrava, Ecaterina Elena, primary, Dougan, Michael L., additional, Gupta, Sarthak, additional, Cappelli, Laura, additional, Katsumoto, Tamiko R., additional, Rahma, Osama E., additional, Painter, Jeane, additional, Wang, Yinghong, additional, Suarez-Almazor, Maria E., additional, Reid, Pankti, additional, Wesley, Sarah F., additional, Hafler, David A, additional, Bingham, Clifton O., additional, Warner, Blake M, additional, Chung, Lorinda, additional, Ott, Patrick Alexander, additional, Kluger, Harriet M., additional, Khosroshahi, Arezou, additional, Tawbi, Hussein Abdul-Hassan, additional, and Sharon, Elad, additional

Published
2021
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174. Joint analysis reveals shared autoimmune disease associations and identifies common mechanisms

Author

Lincoln, Matthew R, primary, Connally, Noah, additional, Axisa, Pierre-Paul, additional, Gasperi, Christiane, additional, Mitrovic, Mitja, additional, van Heel, David, additional, Wijmenga, Cisca, additional, Withoff, Sebo, additional, Jonkers, Iris H, additional, Padyukov, Leonid, additional, Consortium, International MS Genetics, additional, Rich, Stephen S, additional, Graham, Robert R, additional, Gaffney, Patrick M, additional, Langefeld, Carl D, additional, Hafler, David A, additional, Chun, Sung G, additional, Sunyaev, Shamil R, additional, and Cotsapas, Chris, additional

Published
2021
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175. Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children

Author

Ramaswamy, Anjali, primary, Brodsky, Nina N., additional, Sumida, Tomokazu S., additional, Comi, Michela, additional, Asashima, Hiromitsu, additional, Hoehn, Kenneth B., additional, Li, Ningshan, additional, Liu, Yunqing, additional, Shah, Aagam, additional, Ravindra, Neal G., additional, Bishai, Jason, additional, Khan, Alamzeb, additional, Lau, William, additional, Sellers, Brian, additional, Bansal, Neha, additional, Guerrerio, Pamela, additional, Unterman, Avraham, additional, Habet, Victoria, additional, Rice, Andrew J., additional, Catanzaro, Jason, additional, Chandnani, Harsha, additional, Lopez, Merrick, additional, Kaminski, Naftali, additional, Dela Cruz, Charles S., additional, Tsang, John S., additional, Wang, Zuoheng, additional, Yan, Xiting, additional, Kleinstein, Steven H., additional, van Dijk, David, additional, Pierce, Richard W., additional, Hafler, David A., additional, and Lucas, Carrie L., additional

Published
2021
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176. PD-1highCXCR5–CD4+ Peripheral Helper T (Tph) cells Promote Tissue-Homing Plasmablasts in COVID-19

Author

Asashima, Hiromitsu, primary, Mohanty, Subhasis, additional, Comi, Michela, additional, Ruff, William E., additional, Hoehn, Kenneth B., additional, Wong, Patrick, additional, Cohen, Inessa, additional, Coffey, Sarah, additional, Raddassi, Khadir, additional, Chaudhary, Omkar, additional, Unterman, Avraham, additional, Emu, Brinda, additional, Kleinstein, Steven H., additional, Montgomery, Ruth R., additional, Iwasaki, Akiko, additional, Cruz, Charles S. Dela, additional, Kaminski, Naftali, additional, Shaw, Albert C., additional, Hafler, David A., additional, and Sumida, Tomokazu S., additional

Published
2021
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177. Clinical Significance of PDCD4 in Melanoma by Subcellular Expression and in Tumor-Associated Immune Cells

Author

Tran, Thuy T., primary, Rane, Chetan K., additional, Zito, Christopher R., additional, Weiss, Sarah A., additional, Jessel, Shlomit, additional, Lucca, Liliana, additional, Lu, Benjamin Y., additional, Oria, Victor O., additional, Adeniran, Adebowale, additional, Chiang, Veronica L., additional, Omay, Sacit Bulent, additional, Hafler, David A., additional, Kluger, Harriet M., additional, and Jilaveanu, Lucia B., additional

Published
2021
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178. Circulating clonally expanded T cells reflect functions of tumor-infiltrating T cells

Author

Lucca, Liliana E., primary, Axisa, Pierre-Paul, additional, Lu, Benjamin, additional, Harnett, Brian, additional, Jessel, Shlomit, additional, Zhang, Le, additional, Raddassi, Khadir, additional, Zhang, Lin, additional, Olino, Kelly, additional, Clune, James, additional, Singer, Meromit, additional, Kluger, Harriet M., additional, and Hafler, David A., additional

Published
2021
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179. Single-cell transcriptomic and proteomic analysis of Parkinson’s disease brains

Author

Zhu, Biqing, Park, Jae-Min, Coffey, Sarah R., Russo, Anthony, Hsu, I-Uen, Wang, Jiawei, Su, Chang, Chang, Rui, Lam, TuKiet T., Gopal, Pallavi P., Ginsberg, Stephen D., Zhao, Hongyu, Hafler, David A., Chandra, Sreeganga S., and Zhang, Le

Abstract

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder, and recent evidence suggests that pathogenesis may be in part mediated by inflammatory processes, the molecular and cellular architectures of which are largely unknown. To identify and characterize selectively vulnerable brain cell populations in PD, we performed single-nucleus transcriptomics and unbiased proteomics to profile the prefrontal cortex from postmortem human brains of six individuals with late-stage PD and six age-matched controls. Analysis of nearly 80,000 nuclei led to the identification of eight major brain cell types, including elevated brain-resident T cells in PD, each with distinct transcriptional changes in agreement with the known genetics of PD. By analyzing Lewy body pathology in the same postmortem brain tissues, we found that α-synuclein pathology was inversely correlated with chaperone expression in excitatory neurons. Examining cell-cell interactions, we found a selective abatement of neuron-astrocyte interactions and enhanced neuroinflammation. Proteomic analyses of the same brains identified synaptic proteins in the prefrontal cortex that were preferentially down-regulated in PD. By comparing this single-cell PD dataset with a published analysis of similar brain regions in Alzheimer’s disease (AD), we found no common differentially expressed genes in neurons but identified many shared differentially expressed genes in glial cells, suggesting that the disease etiologies, especially in the context of neuronal vulnerability, in PD and AD are likely distinct.

Published
2024
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180. IL-21 and TGF-β are required for differentiation of human [T.sub.H]17 cells

Author

Yang, Li, Anderson, David E., Baecher-Allan, Clare, Hastings, William D., Bettelli, Estelle, Oukka, Mohamed, Kuchroo, Vijay K., and Hafler, David A.

Subjects
Cytokines -- Properties -- Genetic aspects, T cells -- Properties -- Identification and classification -- Genetic aspects, Cell differentiation -- Evaluation -- Genetic aspects, Autoimmune diseases -- Genetic aspects, Interleukin-1 -- Identification and classification, Environmental issues, Science and technology, Zoology and wildlife conservation, Identification and classification, Evaluation, Genetic aspects, Properties
Abstract

The recent discovery of [CD4.sup.+] T cells characterized by secretion of interleukin (IL)-17 ([T.sub.H]17 cells) and the naturally occurring regulatory [FOXP3.sup.+] CD4 T cell ([nT.sub.reg]) has had a major impact [...]

Published
2008

181. Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein

Author

O'Connor, Kevin C, McLaughlin, Katherine A, De Jager, Philip L, Chitnis, Tanuja, Bettelli, Estelle, Xu, Chenqi, Robinson, William H, Cherry, Sunil V, Bar-Or, Amit, Banwell, Brenda, Fukaura, Hikoaki, Fukazawa, Toshiyuki, Tenembaum, Silvia, Wong, Susan J, Tavakoli, Norma P, Idrissova, Zhannat, Viglietta, Vissia, Rostasy, Kevin, Pohl, Daniela, Dale, Russell C, Freedman, Mark, Steinman, Lawrence, Buckle, Guy J, Kuchroo, Vijay K, Hafler, David A, and Wucherpfennig, Kai W

Abstract

The role of autoantibodies in the pathogenesis of multiple sclerosis (MS) and other demyelinating diseases is controversial, in part because widely used western blotting and ELISA methods either do not permit the detection of conformation-sensitive antibodies or do not distinguish them from conformation-independent antibodies. We developed a sensitive assay based on self-assembling radiolabeled tetramers that allows discrimination of antibodies against folded or denatured myelin oligodendrocyte glycoprotein (MOG) by selective unfolding of the antigen domain. The tetramer radioimmunoassay (RIA) was more sensitive for MOG autoantibody detection than other methodologies, including monomer-based RIA, ELISA or fluorescent-activated cell sorting (FACS). Autoantibodies from individuals with acute disseminated encephalomyelitis (ADEM) selectively bound the folded MOG tetramer, whereas sera from mice with experimental autoimmune encephalomyelitis induced with MOG peptide immunoprecipitated only the unfolded tetramer. MOG-specific autoantibodies were identified in a subset of ADEM but only rarely in adult-onset MS cases, indicating that MOG is a more prominent target antigen in ADEM than MS., Author(s): Kevin C O'Connor [1, 2, 3, 18]; Katherine A McLaughlin [3, 4, 18]; Philip L De Jager [1, 2, 3, 5]; Tanuja Chitnis [1, 2, 3]; Estelle Bettelli [1, [...]

Published
2007
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182. New therapeutic approaches for multiple sclerosis

Author

De Jager, Philip L. and Hafler, David A.

Subjects
Multiple sclerosis -- Diagnosis, Multiple sclerosis -- Risk factors, Multiple sclerosis -- Care and treatment, Immunodiagnosis -- Analysis, Health
Abstract

New computational methods and emerging high-throughput technologies that characterize variations in DNA, RNA, proteins and metabolites to lead in a period of intense pathophysiologic investigation have synergized the progress in the understanding of the immunology of multiple sclerosis. This will begin to define subsets of patients with different forms of demyelinating disease, which will prove valuable, as it will lead to customized immunotherapy to the underlying pathophysiologic processes of individual patients.

Published
2007

184. Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis

Author

Astier, Anne L., Meiffren, Gregory, Freeman, Samuel, and Hafler, David A.

Subjects
Multiple sclerosis -- Research, Multiple sclerosis -- Development and progression, T cells -- Genetic aspects, T cells -- Physiological aspects
Abstract

Loss of Treg function appears to be a critical factor in the pathogenesis of human autoimmune diseases. Attention has focused on defects of CD[4.sup.+]CD[25.sup.high] Tregs, and techniques have been developed [...]

Published
2006

185. A high-density screen for linkage in multiple sclerosis: international multiple sclerosis genetics consortium *

Author

Sawcer, Stephen, Ban, Maria, Maranian, Mel, Yeo, Tai Wai, Compston, Alastair, Kirby, Andrew, Daly, Mark J., De Jager, Philip L., Walsh, Emily, Lander, Eric S., Rioux, John D., Hafler, David A., Ivinson, Adrian, Rimmler, Jacqueline A., Gregory, Simon, Schmidt, Silke, Pericak-Vance, Margaret A., Akesson, Eva, Hillert, Jan, Datta, Pameli, Oturai, Annette, Ryder, Lars P., Harbo, Hanne F., Spurkland, Anne, Myhr, Kjell-Morten, Laaksonen, Mikko, Booth, David, Heard, Robert, Stewart, Graeme, Lincoln, Robin, Barcellos, Lisa F., Hauser, Stephen L., Oksenberg, Jorge R., Kenealy, Shannon J., and Haines, Jonathan L.

Subjects
Multiple sclerosis -- Genetic aspects, Human genetics -- Research, Biological sciences
Published
2005

186. Post-infectious inflammatory disease in MIS-C features elevated cytotoxicity signatures and autoreactivity that correlates with severity

Author

Ramaswamy, Anjali, primary, Brodsky, Nina N., additional, Sumida, Tomokazu S., additional, Comi, Michela, additional, Asashima, Hiromitsu, additional, Hoehn, Kenneth B., additional, Li, Ningshan, additional, Liu, Yunqing, additional, Shah, Aagam, additional, Ravindra, Neal G., additional, Bishai, Jason, additional, Khan, Alamzeb, additional, Lau, William, additional, Sellers, Brian, additional, Bansal, Neha, additional, Guerrerio, Pamela, additional, Unterman, Avraham, additional, Habet, Victoria, additional, Rice, Andrew J., additional, Catanzaro, Jason, additional, Chandnani, Harsha, additional, Lopez, Merrick, additional, Kaminski, Naftali, additional, Dela Cruz, Charles S., additional, Tsang, John S., additional, Wang, Zuoheng, additional, Yan, Xiting, additional, Kleinstein, Steven H., additional, van Dijk, David, additional, Pierce, Richard W., additional, Hafler, David A., additional, and Lucas, Carrie L., additional

Published
2020
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188. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope

Author

Kent, Sally C., Chen, Yahua, Bregoli, Lisa, Clemmings, Sue M., Kenyon, Norma Sue, Ricordi, Camillo, Hering, Bernhard J., and Hafler, David A.

Subjects
T cells -- Properties -- Research, Lymph nodes -- Properties -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation, Research, Properties
Abstract

Author(s): Sally C. Kent [1, 4]; Yahua Chen [1, 4]; Lisa Bregoli [1]; Sue M. Clemmings [2]; Norma Sue Kenyon [3]; Camillo Ricordi [3]; Bernhard J. Hering [2]; David A. [...]

Published
2005
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189. A high-density admixture map for disease gene discovery in African Americans

Author

Smith, Michael W., Patterson, Nick, Lautenberger, James A., Truelove, Ann L., McDonald, Gavin J., Waliszewska, Alicja, Kessing, Bailey D., Malasky, Michael J., Scafe, Charles, Le, Ernest, De Jager, Philip L., Mignault, Andre A., Yi, Zeng, de The, Guy, Essex, Myron, Sankale, Jean-Louis, Moore, Jason H., Poku, Kwabena, Phair, John P., Goedert, James J., Vlahov, David, Williams, Scott M., Tishkoff, Sarah A., Winkler, Cheryl A., De La Vega, Francisco M., Woodage, Trevor, Sninsky, John J., Hafler, David A., Altshuler, David, Gilbert, Dennis A., O'Brien, Stephen J., and Reich, David

Subjects
Human genetics -- Research, Biological sciences
Published
2004

190. Methods for high-density admixture mapping of disease genes

Author

Patterson, Nick, Hattangadi, Neil, Lane, Barton, Lohmueller, Kirk E., Hafler, David A., Oksenberg, Jorge R., Hauser, Stephen L., Smith, Michael W., O'Brien, Stephen J., Altshuler, David, Daly, Mark J., and Reich, David

Subjects
Human genetics -- Research, Biological sciences
Published
2004

192. Automated High-Dimensional Flow Cytometric Data Analysis

Author

Pyne, Saumyadipta, primary, Hu, Xinli, additional, Wang, Kui, additional, Rossin, Elizabeth, additional, Lin, Tsung-I, additional, Maier, Lisa, additional, Baecher-Allan, Clare, additional, McLachlan, Geoffrey, additional, Tamayo, Pablo, additional, Hafler, David, additional, De Jager, Philip, additional, and Mesirov, Jill, additional

Published
2010
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194. CONTRIBUTING AUTHORS

Author

Abou Zeid, Nuhad E., primary, Ascherio, Alberto, additional, Banwell, Brenda, additional, Bates, Angela, additional, Ben-Hur, Tamir, additional, Bowling, Allen C., additional, Davis, Scott L., additional, De Jager, Philip L., additional, Dutta, Ranjan, additional, Edan, Gilles, additional, Frohman, Elliot M., additional, Frohman, Teresa C., additional, Gold, Ralf, additional, Hafler, David A., additional, Jacob, Anu, additional, jelČiĆ, Ilijas, additional, Kaplin, Adam I., additional, Kerr, Douglas A., additional, Kleinschnitz, Christoph, additional, Kozubal, Dana E., additional, Lemack, Gary E., additional, Linker, Ralf A., additional, lucchinetti, Claudia F., additional, Marriott, James J., additional, Martin, Roland, additional, Matiello, Marcelo, additional, Melzer, Nico, additional, Meuth, Sven G., additional, Morrissey, Sean P., additional, Munger, Kassandra L., additional, O'Connor, Paul W., additional, Amato, Maria Pia, additional, Pirko, Istvan, additional, Pittock, Sean Joseph, additional, Schröder, Alexandra, additional, Shah, Anjali, additional, Trapp, Bruce D., additional, Trecker, Carrilin C., additional, Venkateswaran, Sunita, additional, Voskuhl, Rhonda, additional, Weinshenker, Brian G., additional, Wiendl, Heinz, additional, Wingerchuk, Dean M., additional, Young, Nathan P., additional, and Zipoli, Valentina, additional

Published
2010
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199. Interrogating the complex role of chromosome 16p13.13 in multiple sclerosis susceptibility: independent genetic signals in the CIITA–CLEC16A–SOCS1 gene complex

Author

Zuvich, Rebecca L., Bush, William S., McCauley, Jacob L., Beecham, Ashley H., De Jager, Philip L., Ivinson, Adrian J., Compston, Alastair, Hafler, David A., Hauser, Stephen L., Sawcer, Stephen J., Pericak-Vance, Margaret A., Barcellos, Lisa F., Mortlock, Douglas P., and Haines, Jonathan L.

Published
2011
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200. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Author

Sawcer, Stephen, Hellenthal, Garrett, Pirinen, Matti, Spencer, Chris C. A., Patsopoulos, Nikolaos A., Moutsianas, Loukas, Dilthey, Alexander, Su, Zhan, Freeman, Colin, Hunt, Sarah E., Edkins, Sarah, Gray, Emma, Booth, David R., Potter, Simon C., Goris, An, Band, Gavin, Bang Oturai, Annette, Strange, Amy, Saarela, Janna, Bellenguez, Céline, Fontaine, Bertrand, Gillman, Matthew, Hemmer, Bernhard, Gwilliam, Rhian, Zipp, Frauke, Jayakumar, Alagurevathi, Martin, Roland, Leslie, Stephen, Hawkins, Stanley, Giannoulatou, Eleni, D’alfonso, Sandra, Blackburn, Hannah, Martinelli Boneschi, Filippo, Liddle, Jennifer, Harbo, Hanne F., Perez, Marc L., Spurkland, Anne, Waller, Matthew J., Mycko, Marcin P., Ricketts, Michelle, Comabella, Manuel, Hammond, Naomi, Kockum, Ingrid, McCann, Owen T., Ban, Maria, Whittaker, Pamela, Kemppinen, Anu, Weston, Paul, Hawkins, Clive, Widaa, Sara, Zajicek, John, Dronov, Serge, Robertson, Neil, Bumpstead, Suzannah J., Barcellos, Lisa F., Ravindrarajah, Rathi, Abraham, Roby, Alfredsson, Lars, Ardlie, Kristin, Aubin, Cristin, Baker, Amie, Baker, Katharine, Baranzini, Sergio E., Bergamaschi, Laura, Bergamaschi, Roberto, Bernstein, Allan, Berthele, Achim, Boggild, Mike, Bradfield, Jonathan P., Brassat, David, Broadley, Simon A., Buck, Dorothea, Butzkueven, Helmut, Capra, Ruggero, Carroll, William M., Cavalla, Paola, Celius, Elisabeth G., Cepok, Sabine, Chiavacci, Rosetta, Clerget-Darpoux, Françoise, Clysters, Katleen, Comi, Giancarlo, Cossburn, Mark, Cournu-Rebeix, Isabelle, Cox, Mathew B., Cozen, Wendy, Cree, Bruce A. C., Cross, Anne H., Cusi, Daniele, Daly, Mark J., Davis, Emma, de Bakker, Paul I. W., Debouverie, Marc, D’hooghe, Marie Beatrice, Dixon, Katherine, Dobosi, Rita, Dubois, Bénédicte, Ellinghaus, David, Elovaara, Irina, Esposito, Federica, Fontenille, Claire, Foote, Simon, Franke, Andre, Galimberti, Daniela, Ghezzi, Angelo, Glessner, Joseph, Gomez, Refujia, Gout, Olivier, Graham, Colin, Grant, Struan F. A., Rosa Guerini, Franca, Hakonarson, Hakon, Hall, Per, Hamsten, Anders, Hartung, Hans-Peter, Heard, Rob N., Heath, Simon, Hobart, Jeremy, Hoshi, Muna, Infante-Duarte, Carmen, Ingram, Gillian, Ingram, Wendy, Islam, Talat, Jagodic, Maja, Kabesch, Michael, Kermode, Allan G., Kilpatrick, Trevor J., Kim, Cecilia, Klopp, Norman, Koivisto, Keijo, Larsson, Malin, Lathrop, Mark, Lechner-Scott, Jeannette S., Leone, Maurizio A., Leppä, Virpi, Liljedahl, Ulrika, Lima Bomfim, Izaura, Lincoln, Robin R., Link, Jenny, Liu, Jianjun, Lorentzen, Åslaug R., Lupoli, Sara, Macciardi, Fabio, Mack, Thomas, Marriott, Mark, Martinelli, Vittorio, Mason, Deborah, McCauley, Jacob L., Mentch, Frank, Mero, Inger-Lise, Mihalova, Tania, Montalban, Xavier, Mottershead, John, Myhr, Kjell-Morten, Naldi, Paola, Ollier, William, Page, Alison, Palotie, Aarno, Pelletier, Jean, Piccio, Laura, Pickersgill, Trevor, Piehl, Fredrik, Pobywajlo, Susan, Quach, Hong L., Ramsay, Patricia P., Reunanen, Mauri, Reynolds, Richard, Rioux, John D., Rodegher, Mariaemma, Roesner, Sabine, Rubio, Justin P., Rückert, Ina-Maria, Salvetti, Marco, Salvi, Erika, Santaniello, Adam, Schaefer, Catherine A., Schreiber, Stefan, Schulze, Christian, Scott, Rodney J., Sellebjerg, Finn, Selmaj, Krzysztof W., Sexton, David, Shen, Ling, Simms-Acuna, Brigid, Skidmore, Sheila, Sleiman, Patrick M. A., Smestad, Cathrine, Sørensen, Per Soelberg, Søndergaard, Helle Bach, Stankovich, Jim, Strange, Richard C., Sulonen, Anna-Maija, Sundqvist, Emilie, Syvänen, Ann-Christine, Taddeo, Francesca, Taylor, Bruce, Blackwell, Jenefer M., Tienari, Pentti, Bramon, Elvira, Tourbah, Ayman, Brown, Matthew A., Tronczynska, Ewa, Casas, Juan P., Tubridy, Niall, Corvin, Aiden, Vickery, Jane, Jankowski, Janusz, Villoslada, Pablo, Markus, Hugh S., Wang, Kai, Mathew, Christopher G., Wason, James, Palmer, Colin N. A., Wichmann, H-Erich, Plomin, Robert, Willoughby, Ernest, Rautanen, Anna, Winkelmann, Juliane, Wittig, Michael, Trembath, Richard C., Yaouanq, Jacqueline, Viswanathan, Ananth C., Zhang, Haitao, Wood, Nicholas W., Zuvich, Rebecca, Deloukas, Panos, Langford, Cordelia, Duncanson, Audrey, Oksenberg, Jorge R., Pericak-Vance, Margaret A., Haines, Jonathan L., Olsson, Tomas, Hillert, Jan, Ivinson, Adrian J., De Jager, Philip L., Peltonen, Leena, Stewart, Graeme J., Hafler, David A., Hauser, Stephen L., McVean, Gil, Donnelly, Peter, and Compston, Alastair

Published
2011
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