The Cation Channel Trpv2 Is A New Suppressor Of Arthritis Severity, Joint Damage, And Synovial Fibroblast Invasion,
2015
Northwell Health
The Cation Channel Trpv2 Is A New Suppressor Of Arthritis Severity, Joint Damage, And Synovial Fibroblast Invasion, T. Laragione, K. F. Cheng, M. R. Tanner, M. He, C. Beeton, Y. Al-Abed, P. S. Gulko
Journal Articles
Little is known about the regulation of arthritis severity and joint damage in rheumatoid arthritis (RA). Fibroblast-like synoviocytes (FLS) have a central role in joint damage and express increased levels of the cation channel Trpv2. We aimed at determining the role of Trpv2 in arthritis. Treatment with Trpv2-specific agonists decreased the in vitro invasiveness of FLS from RA patients and arthritic rats and mice. Trpv2 stimulation suppressed IL-1beta-induced expression of MMP-2 and MMP-3. Trpv2 agonists, including the new and more potent LER13, significantly reduced disease severity in KRN serum- and collagen-induced arthritis, and reduced histologic joint damage, synovial inflammation, and …
Cholinergic Anti-Inflammatory Pathway Activity In Dialysis Patients: A Role For Neuroimmunomodulation?,
2015
Zucker School of Medicine at Hofstra/Northwell
Cholinergic Anti-Inflammatory Pathway Activity In Dialysis Patients: A Role For Neuroimmunomodulation?, M. Hilderman, A. R. Qureshi, Y. Al-Abed, F. Abtahi, K. Lindecrantz, B. Anderstam, A. Bruchfeld
Journal Articles
BACKGROUND: The cholinergic anti-inflammatory pathway (CAP) modulates inflammatory responses through the vagus nerve and the alpha-7-nicotinic acetylcholine receptor (alpha7nAChR) on macrophages and immune cells. Sympathetic/parasympathetic imbalance and chronic inflammation are both linked to poor outcome in dialysis patients. The aim of this study was to investigate CAP activity in these patients. METHODS: Twenty dialysis patients, 12 hemodialysis (HD) and 8 peritoneal dialysis (PD) patients (12 male, 8 female; age range 47-83 years) and 8 controls (5 male, 3 female; age range 31-52 years) were analyzed for C-reactive protein (CRP), tumor necrosis factor (TNF), interleukin-1b (IL-1b), IL-6 and IL-10 at baseline. …
Crossing The Atlantic: The Euro-Lupus Nephritis Regimen In North America,
2015
Zucker School of Medicine at Hofstra/Northwell
Crossing The Atlantic: The Euro-Lupus Nephritis Regimen In North America, D. Wofsy, B. Diamond, F. A. Houssiau
Journal Articles
No abstract provided.
Functional Loss Of I Kappa B Epsilon Leads To Nf-Kappa B Deregulation In Aggressive Chronic Lymphocytic Leukemia,
2015
Northwell Health
Functional Loss Of I Kappa B Epsilon Leads To Nf-Kappa B Deregulation In Aggressive Chronic Lymphocytic Leukemia, L. Mansouri, L. A. Sutton, V. Ljungstrom, S. Bondza, L. Arngarden, S. Bhoi, X. J. Yan, N. Chiorazzi, R. Rosenquist, +25 Additional Authors
Journal Articles
NF-kappa B is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-kappa B pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes I kappa B epsilon, a negative regulator of NF-kappa B in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic …
Calhm1 Deletion In Mice Affects Glossopharyngeal Taste Responses, Food Intake, Body Weight, And Life Span,
2015
Northwell Health
Calhm1 Deletion In Mice Affects Glossopharyngeal Taste Responses, Food Intake, Body Weight, And Life Span, G. Hellekant, J. Schmolling, P. Marambaud, T. A. Rose-Hellekant
Journal Articles
Stimulation of Type II taste receptor cells (TRCs) with T1R taste receptors causes sweet or umami taste, whereas T2Rs elicit bitter taste. Type II TRCs contain the calcium channel, calcium homeostasis modulator protein 1 (CALHM1), which releases adenosine triphosphate (ATP) transmitter to taste fibers. We have previously demonstrated with chorda tympani nerve recordings and two-bottle preference (TBP) tests that mice with genetically deleted Calhm1 (knockout [KO]) have severely impaired perception of sweet, bitter, and umami compounds, whereas their sour and salty tasting ability is unaltered. Here, we present data from KO mice of effects on glossopharyngeal (NG) nerve responses, TBP, …
Defects In Germinal Center Selection In Sle,
2015
Zucker School of Medicine at Hofstra/Northwell
Defects In Germinal Center Selection In Sle, M. Woods, Y. R. Zou, A. Davidson
Journal Articles
Germinal centers (GCs) are the primary site at which clonal expansion and affinity maturation of B cells occur. B cells encounter antigen and receive T cell help in the GC light zone (LZ) and then migrate to the dark zone where they proliferate and undergo somatic mutation before cycling back to the LZ for further rounds of selection. Tolerance to autoantigens is frequently lost de novo as GC B cells undergo class switching and somatic mutation. This loss of tolerance is regulated by a variety of mechanisms including cell death, failure to compete for T cell help, and failure to …
Dna-Containing Immunocomplexes Promote Inflammasome Assembly And Release Of Pyrogenic Cytokines By Cd14+ Cd16+ Cd64high Cd32low Inflammatory Monocytes From Malaria Patients,
2015
Zucker School of Medicine at Hofstra/Northwell
Dna-Containing Immunocomplexes Promote Inflammasome Assembly And Release Of Pyrogenic Cytokines By Cd14+ Cd16+ Cd64high Cd32low Inflammatory Monocytes From Malaria Patients, I. C. Hirako, C. Gallego-Marin, M. A. Ataide, W. A. Andrade, H. Gravina, B. C. Rocha, R. B. De Oliveira, D. B. Pereira, B. Diamond, R. T. Gazzinelli, +3 Additional Authors
Journal Articles
High levels of circulating immunocomplexes (ICs) are found in patients with either infectious or sterile inflammation. We report that patients with either Plasmodium falciparum or Plasmodium vivax malaria have increased levels of circulating anti-DNA antibodies and ICs containing parasite DNA. Upon stimulation with malaria-induced ICs, monocytes express an NF-kappaB transcriptional signature. The main source of IC-induced proinflammatory cytokines (i.e., tumor necrosis factor alpha [TNF-alpha] and interleukin-1beta [IL-1beta])in peripheral blood mononuclear cells from acute malaria patients was found to be a CD14(+) CD16 (FcgammaRIIIA)(+) CD64 (FcgammaRI)(high) CD32 (FcgammaRIIB)(low) monocyte subset. Monocytes from convalescent patients were predominantly of the classical phenotype (CD14(+) …
Enrichment Of Genetic Variants For Rheumatoid Arthritis Within T-Cell And Nk-Cell Enhancer Regions,
2015
Northwell Health
Enrichment Of Genetic Variants For Rheumatoid Arthritis Within T-Cell And Nk-Cell Enhancer Regions, J. Freudenberg, P. Gregersen, W. Li
Journal Articles
To identify disease-causative variants, we intersected the published results of a metaanalysis of genome-wide association studies (GWAS) for rheumatoid arthritis (RA) with the set of enhancer regions for 71 primary cell types that was provided by the FANTOM consortium. We first retrieved all single nucleotide polymorphisms (SNPs) that are associated (P < 5 x 10(8)) with RA in the GWAS meta-analysis and that are located in any of these enhancer regions. After excluding the major histocompatibility complex (MHC) region, we identified 50 such RA-associated SNPs that are located in enhancer regions. Enhancer sets from different cell types were then compared with each other for their number of RA-associated SNPs by permutation analysis. This analysis showed that RA-associated SNPs are preferentially located in enhancers from several immunological cell types. In particular, we see a strong relative enrichment in enhancer regions that are active in T cells (P < 0.001) and NK cells (P < 0.001). Several loci display multiple RA-associated SNPs in tight linkage disequilibrium that are located within the same or neighboring enhancers. These haplotypes may have a greater likelihood to influence enhancer activity than any SNP on its own. Taken together, these results support the hypothesis that RA-causative variants often act through altering the activity of immune cell enhancers. The enrichment in T-cell and NK-cell enhancer regions indicates that expression changes in these cell types are particularly relevant for the pathogenesis of RA. The specific SNPs that account for this enrichment can be used as a basis for focused genotype-phenotype studies of these cell types.
Excessive Antigen Reactivity May Underlie The Clinical Aggressiveness Of Chronic Lymphocytic Leukemia Stereotyped Subset #8,
2015
Northwell Health
Excessive Antigen Reactivity May Underlie The Clinical Aggressiveness Of Chronic Lymphocytic Leukemia Stereotyped Subset #8, M. Gounari, S. Ntoufa, B. Apollonio, N. Papakonstantinou, M. Ponzoni, C. C. Chu, D. Rossi, G. Gaidano, N. Chiorazzi, P. Ghia, +1 Additional Author
Journal Articles
Subset #8 is a distinctive subset of patients with chronic lymphocytic leukemia (CLL) defined by the expression of stereotyped IGHV4-39/IGKV1(D)-39 B-cell receptors. Subset #8 patients experience aggressive disease and exhibit the highest risk for Richter transformation among all CLL. In order to obtain biological insight into this behavior, we profiled the antigen reactivity and signaling capacity of subset #8 vs other clinically aggressive stereotyped subsets, namely subsets #1 and #2. Twenty-seven monoclonal antibodies (mAbs) from subsets #1, #2, and #8 CLL clones were prepared as recombinant human immunoglobulin G1 and used as primary antibodies in enzyme-linked immuno-sorbent assays against representatives …
Genome-Wide Association Study Identifies Hla 8.1 Ancestral Haplotype Alleles As Major Genetic Risk Factors For Myositis Phenotypes,
2015
Zucker School of Medicine at Hofstra/Northwell
Genome-Wide Association Study Identifies Hla 8.1 Ancestral Haplotype Alleles As Major Genetic Risk Factors For Myositis Phenotypes, F. W. Miller, W. Chen, T. P. O'Hanlon, R. G. Cooper, J. Vencovsky, L. G. Rider, K. Danko, A. Lee, P. K. Gregersen, C. I. Amos, +17 Additional Authors
Journal Articles
Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P10-8) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for …
Fundamental Role Of C1q In Autoimmunity And Inflammation,
2015
Northwell Health
Fundamental Role Of C1q In Autoimmunity And Inflammation, M. Son, B. Diamond, F. Santiago-Schwarz
Journal Articles
C1q, historically viewed as the initiating component of the classical complement pathway, also exhibits a variety of complement-independent activities in both innate and acquired immunity. Recent studies focusing on C1q's suppressive role in the immune system have provided new insight into how abnormal C1q expression and bioactivity may contribute to autoimmunity. In particular, molecular networks involving C1q interactions with cell surface receptors and other ligands are emerging as mechanisms involved in C1q's modulation of immunity. Here, we discuss the role of C1q in controlling immune cell function, including recently elucidated mechanisms of action, and suggest how these processes are critical …
A Genetic Study On C5-Traf1 And Progression Of Joint Damage In Rheumatoid Arthritis,
2015
Zucker School of Medicine at Hofstra/Northwell
A Genetic Study On C5-Traf1 And Progression Of Joint Damage In Rheumatoid Arthritis, H. W. Van Steenbergen, L. Rodriguez-Rodriguez, E. Berglin, A. Zhernakova, R. Knevel, J. Ivorra-Cortes, T. W. J. Huizinga, B. Fernandez-Gutierrez, P. K. Gregersen, A. H. M. Van Der Helm-Van Mil, +1 Additional Author
Journal Articles
Introduction: The severity of joint damage progression in rheumatoid arthritis (RA) is heritable. Several genetic variants have been identified, but together explain only part of the total genetic effect. Variants in Interleukin-6 (IL-6), Interleukin-10 (IL-10), C5-TRAF1, and Fc-receptor-like-3 (FCRL3) have been described to associate with radiographic progression, but results of different studies were incongruent. We aimed to clarify associations of these variants with radiographic progression by evaluating six independent cohorts. Methods: In total 5,895 sets of radiographs of 2,493 RA-patients included in six different independent datasets from the Netherlands, Sweden, Spain and North-America were studied in relation to rs1800795 (IL-6), …
The Hiv Protease Inhibitor Saquinavir Inhibits Hmgb1 Driven Inflammation By Targeting The Interaction Of Cathepsin V With Tlr4/Myd88,
2015
Zucker School of Medicine at Hofstra/Northwell
The Hiv Protease Inhibitor Saquinavir Inhibits Hmgb1 Driven Inflammation By Targeting The Interaction Of Cathepsin V With Tlr4/Myd88, J. P. Pribis, Y. Al-Abed, H. Yang, D. Gero, H. Xu, M. F. Montenegro, E. M. Bauer, S. Kim, K. J. Tracey, T. R. Billiar, +5 Additional Authors
Journal Articles
Extracellular HMGB1 (disulfide form), via activation of Toll-Like-Receptor (TLR4)-dependent signaling, is a strong driver of pathologic inflammation in both acute and chronic conditions. Identification of selective inhibitors of HMGB1-TLR4 signaling could offer novel therapies that selectively target proximal endogenous activators of inflammation. A cell-based screening strategy led us to identify first generation HIV-protease inhibitors (PI) as potential inhibitors of HMGB1-TLR4 driven cytokine production. Here we report, that the first-generation HIV-PI saquinavir (SQV), as well as a newly identified mammalian protease inhibitor STO33438 (334), potently block disulfide HMGB1 induced TLR4 activation, as assayed by the production of TNF-alpha by human monocyte-derived …
Genome-Wide Meta-Analysis In Alopecia Areata Resolves Hla Associations And Reveals Two New Susceptibility Loci,
2015
Zucker School of Medicine at Hofstra/Northwell
Genome-Wide Meta-Analysis In Alopecia Areata Resolves Hla Associations And Reveals Two New Susceptibility Loci, R. C. Betz, L. Petukhova, S. Ripke, H. Huang, A. Menelaou, S. Redler, A. Lee, P. K. Gregersen, A. M. Christiano, +23 Additional Authors
Journal Articles
Alopecia areata (AA) is a prevalent autoimmune disease with 10 known susceptibility loci. Here we perform the first meta-analysis of research on AA by combining data from two genome-wide association studies (GWAS), and replication with supplemented ImmunoChip data for a total of 3,253 cases and 7,543 controls. The strongest region of association is the major histocompatibility complex, where we fine-map four independent effects, all implicating human leukocyte antigen-DR as a key aetiologic driver. Outside the major histocompatibility complex, we identify two novel loci that exceed the threshold of statistical significance, containing ACOXL/BCL2L11(BIM) (2q13); GARP (LRRC32) (11q13.5), as well as a …
Genome-Wide Association Study Of Late-Onset Myasthenia Gravis: Confirmation Of Tnfrsf11a, And Identification Of Zbtb10 And Three Distinct Hla Associations,
2015
Zucker School of Medicine at Hofstra/Northwell
Genome-Wide Association Study Of Late-Onset Myasthenia Gravis: Confirmation Of Tnfrsf11a, And Identification Of Zbtb10 And Three Distinct Hla Associations, M. F. Seldin, O. K. Alkhairy, A. T. Lee, J. A. Lamb, J. Sussman, R. Pirskanen-Matell, F. Piehl, J. J. Verschuuren, P. K. Gregersen, L. Hammarstrom, +9 Additional Authors
Journal Articles
To investigate the genetics of late-onset myasthenia gravis (LOMG), we conducted a genome-wide association study imputation of >6 million SNPs in 532 LOMG cases (anti-acetylcholine receptor (AChR) antibody positive, onset age >/=50 years) and 2,128 controls matched for sex and population substructure. The data confirm reported TNFRSF11A associations [rs4574025, P = 3.9x10-07, odds ratio (OR) = 1.42] and identify a novel candidate gene, ZBTB10, achieving genome-wide significance (rs6998967, P = 8.9x10-10, OR = 0.53). Several other SNPs showed suggestive significance including rs2476601 (P = 6.5x10-06, OR =1.62) encoding the PTPN22 R620W variant noted in early-onset MG (EOMG) and other autoimmune …
Genome-Wide Association Analysis Of Psoriatic Arthritis And Cutaneous Psoriasis Reveals Differences In Their Genetic Architecture,
2015
Zucker School of Medicine at Hofstra/Northwell
Genome-Wide Association Analysis Of Psoriatic Arthritis And Cutaneous Psoriasis Reveals Differences In Their Genetic Architecture, P. E. Stuart, R. P. Nair, L. C. Tsoi, T. Tejasvi, S. Das, H. M. Kang, E. Ellinghaus, V. Chandran, K. Callis-Duffin, R. Ike, Y. Li, X. Wen, C. Enerback, J. E. Gudjonsson, S. Koks, K. Kingo, J. Winkelmann, P. K. Gregersen, J. T. Elder, +30 Additional Authors
Journal Articles
Psoriasis vulgaris (PsV) is a common inflammatory and hyperproliferative skin disease. Up to 30% of people with PsV eventually develop psoriatic arthritis (PsA), an inflammatory musculoskeletal condition. To discern differences in genetic risk factors for PsA and cutaneous-only psoriasis (PsC), we carried out a genome-wide association study (GWAS) of 1,430 PsA case subjects and 1,417 unaffected control subjects. Meta-analysis of this study with three other GWASs and two targeted genotyping studies, encompassing a total of 9,293 PsV case subjects, 3,061 PsA case subjects, 3,110 PsC case subjects, and 13,670 unaffected control subjects of European descent, detected 10 regions associated with …
Immunological Function Of Blimp-1 In Dendritic Cells And Relevance To Autoimmune Diseases,
2015
Zucker School of Medicine at Hofstra/Northwell
Immunological Function Of Blimp-1 In Dendritic Cells And Relevance To Autoimmune Diseases, S. J. Kim
Journal Articles
Previous studies have identified the immunological functions of transcription factor B lymphocyte-induced maturation protein-1 (Blimp-1) in various adaptive immune cell types such as T and B lymphocytes. More recently, it has been shown that Blimp-1 extends its functional roles to dendritic cells (DCs) and macrophages, two cell types belonging to the innate immune system. The protein acts as a direct and indirect regulator of target genes by recruiting chromatin modification factors and by regulating microRNA expression, respectively. In DCs, Blimp-1 has been identified as one of the components involved in antigen presentation. Genome-wide association studies identified polymorphisms associated with multiple …
Hmgb1-Driven Inflammation And Intimal Hyperplasia After Arterial Injury Involves Cell-Specific Actions Mediated By Tlr4,
2015
Northwell Health
Hmgb1-Driven Inflammation And Intimal Hyperplasia After Arterial Injury Involves Cell-Specific Actions Mediated By Tlr4, J. Cai, H. Yuan, Q. Wang, H. Yang, Yousef Al-Abed, Z. Hua, J. Wang, D. Chen, Kevin J. Tracey, A. F. Chen, +7 Additional Authors
Journal Articles
No abstract provided.
Integrative Neuroscience Approach To Neuropsychiatric Lupus,
2015
Zucker School of Medicine at Hofstra/Northwell
Integrative Neuroscience Approach To Neuropsychiatric Lupus, P. T. Huerta, E. L. Gibson, C. Rey, T. S. Huerta
Journal Articles
We present a succinct review of our approach to study the interactions between the DNA-reactive antibodies that cross-react with the GluN2A and GluN2B subunits of the N-methyl-D-aspartate receptor, denoted DNRABs, and their brain targets in subjects with neuropsychiatric systemic lupus erythematosus (NPSLE). We have analyzed the DNRAB-based brain symptomatology in mouse models of NPSLE by using an integrative neuroscience approach, which includes behavioral assessment coupled with electrophysiological studies of neural networks and synaptic connections in target brain regions, such as the CA1 region of the hippocampus. Our results suggest a framework for understanding the interactions between immune factors and neural …
Partitioning Heritability By Functional Annotation Using Genome-Wide Association Summary Statistics,
2015
Northwell Health
Partitioning Heritability By Functional Annotation Using Genome-Wide Association Summary Statistics, H. K. Finucane, B. Bulik-Sullivan, A. Gusev, G. Trynka, Y. Reshef, P. R. Loh, V. Anttila, S. Purcell, E. Stahl, A. L. Price, +12 Additional Authors
Journal Articles
Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here we analyze a broad set of functional elements, including cell type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits with an average sample size of 73,599. To enable this analysis, we introduce a new method, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers. This new method is computationally tractable at very large sample sizes and leverages genome-wide information. Our findings include …
