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5.  Evaluation of KIR4.1 as an Immune Target in Multiple Sclerosis 
The New England journal of medicine  2016;374(15):1495-1496.
doi:10.1056/NEJMc1513302
PMCID: PMC4918464  PMID: 27074083
6.  Prospects of immune checkpoint modulators in the treatment of glioblastoma 
Nature reviews. Neurology  2015;11(9):504-514.
Glioblastoma is the most common primary brain tumour in adults. Prognosis is poor: even with the current gold-standard first-line treatment—maximal safe resection and combination of radiotherapy with temozolomide chemotherapy—the median overall survival time is only approximately 15–17 months, because the tumour recurs in virtually all patients, and no commonly accepted standard treatment for recurrent disease exists. Several targeted agents have failed to improve patient outcomes in glioblastoma. Immunotherapy with immune checkpoint inhibitors such as ipilimumab, nivolumab, and pembrolizumab has provided relevant clinical improvements in other advanced tumours for which conventional therapies have had limited success, making immunotherapy an appealing strategy in glioblastoma. This Review summarizes current knowledge on immune checkpoint modulators and evaluates their potential role in glioblastoma on the basis of preclinical studies and emerging clinical data. Furthermore, we discuss challenges that need to be considered in the clinical development of drugs that target immune checkpoint pathways in glioblastoma, such as specific properties of the immune system in the CNS, issues with radiological response assessment, and potential interactions with established and emerging treatment strategies.
doi:10.1038/nrneurol.2015.139
PMCID: PMC4782584  PMID: 26260659
7.  Sodium-activated macrophages: the salt mine expands 
Cell Research  2015;25(8):885-886.
doi:10.1038/cr.2015.91
PMCID: PMC4528060  PMID: 26215700
8.  Polarization of the Effects of Autoimmune and Neurodegenerative Risk Alleles in Leukocytes 
Science (New York, N.Y.)  2014;344(6183):519-523.
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+ 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.
doi:10.1126/science.1249547
PMCID: PMC4910825  PMID: 24786080
9.  Genetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli 
Science translational medicine  2015;7(291):291ra93.
The transcription factor NFκB is a central regulator of inflammation and genome-wide association studies in subjects with autoimmune disease have identified a number of variants within the NFκB signaling cascade. In addition, causal variant fine-mapping has demonstrated that autoimmune disease susceptibility variants for multiple sclerosis (MS) and ulcerative colitis are strongly enriched within binding sites for NFkB. Here, we report that MS-associated variants proximal to NFκB1 and in an intron of TNFRSF1A (TNFR1) are associated with increased NFκB signaling after TNFα stimulation. Both variants result in increased degradation of IκBα, a negative regulator of NFκB, and nuclear translocation of p65 NFκB. The variant proximal to NFκB1 controls signaling responses by altering expression of NFκB itself, with the GG risk genotype expressing 20-fold more p50 NFκB and diminished expression of the negative regulators of the NFκB pathway TNFAIP3, BCL3, and CIAP1. Finally naïve CD4 T cells from patients with MS express enhanced activation of p65 NFκB. These results demonstrate that genetic variants associated with risk of developing MS alter NFκB signaling pathways, resulting in enhanced NFκB activation and greater responsiveness to inflammatory stimuli. As such, this suggests that rapid genetic screening for variants associated with NFκB signaling may identify individuals amenable to NFκB or cytokine blockade.
doi:10.1126/scitranslmed.aaa9223
PMCID: PMC4574294  PMID: 26062845
10.  Genetic basis of autoimmunity 
The Journal of Clinical Investigation  2015;125(6):2234-2241.
Autoimmune diseases affect up to approximately 10% of the population. While rare Mendelian autoimmunity syndromes can result from monogenic mutations disrupting essential mechanisms of central and peripheral tolerance, more common human autoimmune diseases are complex disorders that arise from the interaction between polygenic risk factors and environmental factors. Although the risk attributable to most individual nucleotide variants is modest, genome-wide association studies (GWAS) have the potential to provide an unbiased view of biological pathways that drive human autoimmune diseases. Interpretation of GWAS requires integration of multiple genomic datasets including dense genotyping, cis-regulatory maps of primary immune cells, and genotyped studies of gene expression in relevant cell types and cellular conditions. Improved understanding of the genetic basis of autoimmunity may lead to a more sophisticated understanding of underlying cellular phenotypes and, eventually, novel diagnostics and targeted therapies.
doi:10.1172/JCI78086
PMCID: PMC4497748  PMID: 26030227
11.  Class II HLA interactions modulate genetic risk for multiple sclerosis 
Nature genetics  2015;47(10):1107-1113.
Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01–HLA-DRB1*15:01 and HLA-DQB1*03:01–HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles.
doi:10.1038/ng.3395
PMCID: PMC4874245  PMID: 26343388
12.  Distinct Inflammatory Profiles of Myelin-Reactive T cells from Patients with Multiple Sclerosis 
Science translational medicine  2015;7(287):287ra74.
Myelin-reactive T cells have been identified in patients with multiple sclerosis (MS) and healthy subjects with comparable frequencies, but the functional programs of self-reactive T cells that promote disease remain unknown. A total of 13,324 T cell libraries generated from blood of 23 patients and 22 healthy controls were interrogated for reactivity to myelin antigens. Libraries derived from CCR6+ myelin-reactive T cells from patients with MS exhibited significantly enhanced production of IFN-γ, IL-17, and GM-CSF compared to healthy controls. Single-cell clones isolated by MHC/peptide tetramers from CCR6+ T cell libraries also secreted more pro-inflammatory cytokines while clones isolated from controls secreted more IL-10. The transcriptomes of myelin-specific CCR6+ T cells from patients with MS were distinct from those derived from healthy controls, and of note, were enriched in Th17-induced experimental autoimmune encephalitis (EAE) gene signatures and gene signatures derived from Th17 cells isolated other human autoimmune diseases. These data, although not casual, imply that functional differences between antigen specific T cells from MS and healthy controls is fundamental to disease development and support the notion that IL-10 production from myelin-reactive T cells may act to limit disease progression, or even pathogenesis.
doi:10.1126/scitranslmed.aaa8038
PMCID: PMC4497538  PMID: 25972006
13.  PD-1 marks dysfunctional regulatory T cells in malignant gliomas 
JCI insight  2016;1(5):e85935.
Immunotherapies targeting the immune checkpoint receptor programmed cell death protein 1 (PD-1) have shown remarkable efficacy in treating cancer. CD4+CD25hiFoxP3+ Tregs are critical regulators of immune responses in autoimmunity and malignancies, but the functional status of human Tregs expressing PD-1 remains unclear. We examined functional and molecular features of PD-1hi Tregs in healthy subjects and patients with glioblastoma multiforme (GBM), combining functional assays, RNA sequencing, and cytometry by time of flight (CyTOF). In both patients with GBM and healthy subjects, circulating PD-1hi Tregs displayed reduced suppression of CD4+ effector T cells, production of IFN-γ, and molecular signatures of exhaustion. Transcriptional profiling of tumor-resident Tregs revealed that several genes coexpressed with PD-1 and associated with IFN-γ production and exhaustion as well as enrichment in exhaustion signatures compared with circulating PD-1hi Tregs. CyTOF analysis of circulating and tumor-infiltrating Tregs from patients with GBM treated with PD-1-blocking antibodies revealed that treatment shifts the profile of circulating Tregs toward a more exhausted phenotype reminiscent of that of tumor-infiltrating Tregs, further increasing IFN-γ production. Thus, high PD-1 expression on human Tregs identifies dysfunctional, exhausted Tregs secreting IFN-γ that exist in healthy individuals and are enriched in tumor infiltrates, possibly losing function as they attempt to modulate the antitumoral immune responses.
doi:10.1172/jci.insight.85935
PMCID: PMC4864991  PMID: 27182555
14.  PD-1 marks dysfunctional regulatory T cells in malignant gliomas 
JCI Insight  null;1(5):e85935.
Immunotherapies targeting the immune checkpoint receptor programmed cell death protein 1 (PD-1) have shown remarkable efficacy in treating cancer. CD4+CD25hiFoxP3+ Tregs are critical regulators of immune responses in autoimmunity and malignancies, but the functional status of human Tregs expressing PD-1 remains unclear. We examined functional and molecular features of PD-1hi Tregs in healthy subjects and patients with glioblastoma multiforme (GBM), combining functional assays, RNA sequencing, and cytometry by time of flight (CyTOF). In both patients with GBM and healthy subjects, circulating PD-1hi Tregs displayed reduced suppression of CD4+ effector T cells, production of IFN-γ, and molecular signatures of exhaustion. Transcriptional profiling of tumor-resident Tregs revealed that several genes coexpressed with PD-1 and associated with IFN-γ production and exhaustion as well as enrichment in exhaustion signatures compared with circulating PD-1hi Tregs. CyTOF analysis of circulating and tumor-infiltrating Tregs from patients with GBM treated with PD-1-blocking antibodies revealed that treatment shifts the profile of circulating Tregs toward a more exhausted phenotype reminiscent of that of tumor-infiltrating Tregs, further increasing IFN-γ production. Thus, high PD-1 expression on human Tregs identifies dysfunctional, exhausted Tregs secreting IFN-γ that exist in healthy individuals and are enriched in tumor infiltrates, possibly losing function as they attempt to modulate the antitumoral immune responses.
PD-1 expressing Tregs in glioblastoma and healthy donors display molecular signatures of exhaustion, and anti-PD-1 treatment may enhance dysfunction.
doi:10.1172/jci.insight.85935
PMCID: PMC4864991  PMID: 27182555
15.  Prolonged Proinflammatory Cytokine Production in Monocytes Modulated by Interleukin 10 After Influenza Vaccination in Older Adults 
The Journal of Infectious Diseases  2014;211(7):1174-1184.
We evaluated in vivo innate immune responses in monocyte populations from 67 young (aged 21–30 years) and older (aged ≥65 years) adults before and after influenza vaccination. CD14+CD16+ inflammatory monocytes were induced after vaccination in both young and older adults. In classical CD14+CD16– and inflammatory monocytes, production of tumor necrosis factor α and interleukin 6, as measured by intracellular staining, was strongly induced after vaccination. Cytokine production was strongly associated with influenza vaccine antibody response; the highest levels were found as late as day 28 after vaccination in young subjects and were substantially diminished in older subjects. Notably, levels of the anti-inflammatory cytokine interleukin 10 (IL-10) were markedly elevated in monocytes from older subjects before and after vaccination. In purified monocytes, we found age-associated elevation in phosphorylated signal transducer and activator of transcription-3, and decreased serine 359 phosphorylation of the negative IL-10 regulator dual-specificity phosphatase 1. These findings for the first time implicate dysregulated IL-10 production in impaired vaccine responses in older adults.
doi:10.1093/infdis/jiu573
PMCID: PMC4366602  PMID: 25367297
aging; influenza vaccine; monocyte; cytokine; innate immunity
16.  Multiple sclerosis—a quiet revolution 
Nature reviews. Neurology  2015;11(3):134-142.
Multiple sclerosis (MS) has been thought to be a complex and indecipherable disease, and poorly understood with regards to aetiology. Here, we suggest an emphatically positive view of progress over several decades in the understanding and treatment of MS, particularly focusing on advances made within the past 20 years. As with virtually all complex disorders, MS is caused by the interaction of genetic and environmental factors. In recent years, formidable biochemical, bioinformatic, epidemiological and neuroimaging tools have been brought to bear on research into the causes of MS. While susceptibility to the disease is now relatively well accounted for, disease course is not and remains a salient challenge. In the therapeutic realm, numerous agents have become available, reflecting the fact that the disease can be attacked successfully at many levels and using varied strategies. Tailoring therapies to individuals, risk mitigation and selection of first-line as compared with second-line medications remain to be completed. In our view, the MS landscape has been comprehensively and irreversibly transformed by this progress. Here we focus on MS therapeutics—the most meaningful outcome of research efforts.
doi:10.1038/nrneurol.2015.14
PMCID: PMC4556342  PMID: 25686758
17.  Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells 
The Journal of Clinical Investigation  null;125(11):4212-4222.
FOXP3+ Tregs are central for the maintenance of self-tolerance and can be defective in autoimmunity. In multiple sclerosis and type-1 diabetes, dysfunctional self-tolerance is partially mediated by a population of IFNγ-secreting Tregs. It was previously reported that increased NaCl concentrations promote the induction of proinflammatory Th17 cells and that high-salt diets exacerbate experimental models of autoimmunity. Here, we have shown that increasing NaCl, either in vitro or in murine models via diet, markedly impairs Treg function. NaCl increased IFNγ secretion in Tregs, and reducing IFNγ — either by neutralization with anti-IFNγ antibodies or shRNA-mediated knockdown — restored suppressive activity in Tregs. The heightened IFNγ secretion and loss of Treg function were mediated by the serum/glucocorticoid-regulated kinase (SGK1). A high-salt diet also impaired human Treg function and was associated with the induction of IFNγ-secreting Tregs in a xenogeneic graft-versus-host disease model and in adoptive transfer models of experimental colitis. Our results demonstrate a putative role for an environmental factor that promotes autoimmunity by inducing proinflammatory responses in CD4 effector cells and Treg pathways.
doi:10.1172/JCI81151
PMCID: PMC4639983  PMID: 26524592
18.  Unraveling the autoimmune translational research process layer by layer 
Nature medicine  2012;18(1):35-41.
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.
doi:10.1038/nm.2632
PMCID: PMC4592149  PMID: 22227670
19.  Enhanced Suppressor Function of TIM-3+ FoxP3+ Regulatory T cells 
European journal of immunology  2014;44(9):2703-2711.
T cell Immunoglobulin and Mucin domain 3 (TIM-3) is an Ig superfamily member expressed on IFNγ-secreting Th1 and Tc1 cells identified as a negative regulator of immune tolerance. TIM-3 is expressed by a subset of activated CD4+ T cells, and anti-CD3/anti-CD28 stimulation increases both the level of expression and the number of TIM-3+ T cells. In mice, TIM-3 is constitutively expressed on natural regulatory T cells and has been identified as a regulatory molecule of alloimmunity through its ability to modulate CD4+ T cell differentiation. Here, we examined TIM-3 expression on human Tregs to determine its role in T cell suppression. In contrast to mice, TIM-3 is not expressed on Tregs ex vivo but is upregulated after activation. While TIM-3+ Tregs with increased gene expression of lag3, ctla4 and foxp3 are highly efficient suppressors of effector T cells (Teff), TIM-3— Tregs poorly suppressed Th17 as compared to Th1 cells that was associated with decreased STAT-3 expression and phosphorylation with reduced gene expression of il10, ebi3, gzmB, prf1, il1Rα, and ccr6. Thus, our results suggest that TIM-3 expression on Tregs identifies a population highly effective in inhibiting pathogenic Th1 and Th17 responses.
doi:10.1002/eji.201344392
PMCID: PMC4165702  PMID: 24838857
TIM-3; regulatory T cells; Th17; FoxP3
20.  Genetic and Epigenetic Fine-Mapping of Causal Autoimmune Disease Variants 
Nature  2014;518(7539):337-343.
Summary
Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4+ T-cell subsets, regulatory T-cells, CD8+ T-cells, B-cells, and monocytes. We find that ~90% of causal variants are noncoding, with ~60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10–20% directly alter recognizable transcription factor binding motifs. Rather, most noncoding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.
doi:10.1038/nature13835
PMCID: PMC4336207  PMID: 25363779
21.  Genetic and Epigenetic Fine-Mapping of Causal Autoimmune Disease Variants 
Nature  2014;518(7539):337-343.
Summary
Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4+ T-cell subsets, regulatory T-cells, CD8+ T-cells, B-cells, and monocytes. We find that ~90% of causal variants are noncoding, with ~60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10-20% directly alter recognizable transcription factor binding motifs. Rather, most noncoding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.
doi:10.1038/nature13835
PMCID: PMC4336207  PMID: 25363779
22.  Antibodies from Inflamed Central Nervous System Tissue Recognize Myelin Oligodendrocyte Glycoprotein1 
Autoantibodies to myelin oligodendrocyte glycoprotein (MOG) can induce demyelination and oligodendrocyte loss in models of multiple sclerosis (MS). Whether anti-MOG Abs play a similar role in patients with MS or inflammatory CNS diseases by epitope spreading is unclear. We have therefore examined whether autoantibodies that bind properly folded MOG protein are present in the CNS parenchyma of MS patients. IgG was purified from CNS tissue of 14 postmortem cases of MS and 8 control cases, including cases of encephalitis. Binding was assessed using two independent assays, a fluorescence-based solid-phase assay and a solution-phase RIA. MOG autoantibodies were identified in IgG purified from CNS tissue by solid-phase immunoassay in 7 of 14 cases with MS and 1 case of subacute sclerosing panencephalitis, but not in IgG from noninflamed control tissue. This finding was confirmed with a solution-phase RIA, which measures higher affinity autoantibodies. These data demonstrate that autoantibodies recognizing MOG are present in substantially higher concentrations in the CNS parenchyma compared with cerebrospinal fluid and serum in subjects with MS, indicating that local production/accumulation is an important aspect of autoantibody-mediated pathology in demyelinating CNS diseases. Moreover, chronic inflammatory CNS disease may induce autoantibodies by virtue of epitope spreading.
PMCID: PMC4515951  PMID: 16034142
23.  pRESTO: a toolkit for processing high-throughput sequencing raw reads of lymphocyte receptor repertoires 
Bioinformatics  2014;30(13):1930-1932.
Summary: Driven by dramatic technological improvements, large-scale characterization of lymphocyte receptor repertoires via high-throughput sequencing is now feasible. Although promising, the high germline and somatic diversity, especially of B-cell immunoglobulin repertoires, presents challenges for analysis requiring the development of specialized computational pipelines. We developed the REpertoire Sequencing TOolkit (pRESTO) for processing reads from high-throughput lymphocyte receptor studies. pRESTO processes raw sequences to produce error-corrected, sorted and annotated sequence sets, along with a wealth of metrics at each step. The toolkit supports multiplexed primer pools, single- or paired-end reads and emerging technologies that use single-molecule identifiers. pRESTO has been tested on data generated from Roche and Illumina platforms. It has a built-in capacity to parallelize the work between available processors and is able to efficiently process millions of sequences generated by typical high-throughput projects.
Availability and implementation: pRESTO is freely available for academic use. The software package and detailed tutorials may be downloaded from http://clip.med.yale.edu/presto.
Contact: steven.kleinstein@yale.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btu138
PMCID: PMC4071206  PMID: 24618469
24.  Systems Immunology Reveals Markers of Susceptibility to West Nile Virus Infection 
West Nile virus (WNV) infection is usually asymptomatic but can cause severe neurological disease and death, particularly in older patients, and how individual variations in immunity contribute to disease severity is not yet defined. Animal studies identified a role for several immunity-related genes that determine the severity of infection. We have integrated systems-level transcriptional and functional data sets from stratified cohorts of subjects with a history of WNV infection to define whether these markers can distinguish susceptibility in a human population. Transcriptional profiles combined with immunophenotyping of primary cells identified a predictive signature of susceptibility that was detectable years after acute infection (67% accuracy), with the most prominent alteration being decreased IL1B induction following ex vivo infection of macrophages with WNV. Deconvolution analysis also determined a significant role for CXCL10 expression in myeloid dendritic cells. This systems analysis identified markers of pathogenic mechanisms and offers insights into potential therapeutic strategies.
doi:10.1128/CVI.00508-14
PMCID: PMC4278927  PMID: 25355795
25.  CD2 Costimulation Reveals Defective Activity by Human CD4+CD25hi Regulatory Cells in Patients with Multiple Sclerosis 
Studying the activity of homogeneous regulatory T cell (Treg) populations will advance our understanding of their mechanisms of action and their role in human disease. Although isolating human Tregs exhibiting low expression of CD127 markedly increases purity, the resulting Treg populations are still heterogeneous. To examine the complexity of the Tregs defined by the CD127 phenotype in comparison with the previously described CD4+CD25hi subpopulations, we subdivided the CD25hi population of memory Tregs into subsets based on expression of CD127 and HLA-DR. These subsets exhibited differences in suppressive capacity, ability to secrete IL-10 and IL-17, Foxp3 gene methylation, cellular senescence, and frequency in neonatal and adult blood. The mature, short telomere, effector CD127loHLA-DR+ cells most strongly suppressed effector T cells within 48 h, whereas the less mature CD127lo HLA-DR− cells required 96 h to reach full suppressive capacity. In contrast, whereas the CD127+HLA-DR− cells also suppressed proliferation of effector cells, they could alternate between suppression or secretion of IL-17 depending upon the stimulation signals. When isolated from patients with multiple sclerosis, both the nonmature and the effector subsets of memory CD127lo Tregs exhibited kinetically distinct defects in suppression that were evident with CD2 costimulation. These data demonstrate that natural and not induced Tregs are less suppressive in patients with multiple sclerosis.
doi:10.4049/jimmunol.1002502
PMCID: PMC4467560  PMID: 21300823

Results 1-25 (125)