45 results on '"Smith, Kenneth"'
Search Results
2. T-cell exhaustion: understanding the interface of chronic viral and autoinflammatory diseases.
- Author
-
McKinney EF and Smith KG
- Subjects
- Animals, Chronic Disease, Humans, Receptors, Immunologic metabolism, Autoimmunity immunology, Inflammation immunology, Inflammation pathology, T-Lymphocytes immunology, Virus Diseases immunology
- Abstract
During acute viral infection CD8 T cells rapidly expand before contracting down to a persistent memory population that confers long-lasting immunity. However when the antigen persists, such as during chronic viral infection, a dysfunctional process termed 'exhaustion' limits the antiviral response, facilitating ongoing viraemia and poor clinical outcome. CD8 T-cell exhaustion was originally identified in lymphocytic choriomeningitis virus infection of mice; however, new evidence has shown that exhaustion is associated with the control of a wide range of human chronic inflammatory states, including chronic viral infection, autoimmunity and cancer. Consequently, an understanding of the mechanisms controlling exhaustion during chronic infection may also indicate new strategies for controlling other chronic inflammatory diseases. In particular, the success of immune checkpoint blockade as a form of cancer immunotherapy has prompted renewed efforts to understand how T-cell immunity to chronic antigenic stimulation might similarly be measured or modulated in autoimmune diseases. Here we summarise the mechanisms controlling T-cell exhaustion and how they relate to the control of autoimmune responses, providing a future perspective on measuring or manipulating exhaustion to personalise therapy.
- Published
- 2016
- Full Text
- View/download PDF
3. A type I interferon transcriptional signature precedes autoimmunity in children genetically at risk for type 1 diabetes.
- Author
-
Ferreira RC, Guo H, Coulson RM, Smyth DJ, Pekalski ML, Burren OS, Cutler AJ, Doecke JD, Flint S, McKinney EF, Lyons PA, Smith KG, Achenbach P, Beyerlein A, Dunger DB, Clayton DG, Wicker LS, Todd JA, Bonifacio E, Wallace C, and Ziegler AG
- Subjects
- Adolescent, Adult, Child, Cohort Studies, Diabetes Mellitus, Type 1 immunology, Female, Gene Expression Regulation drug effects, Genetic Predisposition to Disease, Humans, Interferon Type I pharmacology, Male, Middle Aged, Risk, Transcriptome drug effects, Young Adult, Autoimmunity genetics, Diabetes Mellitus, Type 1 genetics, Interferon Type I immunology, Transcriptome immunology
- Abstract
Diagnosis of the autoimmune disease type 1 diabetes (T1D) is preceded by the appearance of circulating autoantibodies to pancreatic islets. However, almost nothing is known about events leading to this islet autoimmunity. Previous epidemiological and genetic data have associated viral infections and antiviral type I interferon (IFN) immune response genes with T1D. Here, we first used DNA microarray analysis to identify IFN-β-inducible genes in vitro and then used this set of genes to define an IFN-inducible transcriptional signature in peripheral blood mononuclear cells from a group of active systemic lupus erythematosus patients (n = 25). Using this predefined set of 225 IFN signature genes, we investigated the expression of the signature in cohorts of healthy controls (n = 87), patients with T1D (n = 64), and a large longitudinal birth cohort of children genetically predisposed to T1D (n = 109; 454 microarrayed samples). Expression of the IFN signature was increased in genetically predisposed children before the development of autoantibodies (P = 0.0012) but not in patients with established T1D. Upregulation of IFN-inducible genes was transient, temporally associated with a recent history of upper respiratory tract infections (P = 0.0064), and marked by increased expression of SIGLEC-1 (CD169), a lectin-like receptor expressed on CD14(+) monocytes. DNA variation in IFN-inducible genes altered T1D risk (P = 0.007), as exemplified by IFIH1, one of the genes in our IFN signature for which increased expression is a known risk factor for disease. These findings identify transient increased expression of type I IFN genes in preclinical diabetes as a risk factor for autoimmunity in children with a genetic predisposition to T1D., (© 2014 by the American Diabetes Association.)
- Published
- 2014
- Full Text
- View/download PDF
4. Analysis of a wild mouse promoter variant reveals a novel role for FcγRIIb in the control of the germinal center and autoimmunity.
- Author
-
Espéli M, Clatworthy MR, Bökers S, Lawlor KE, Cutler AJ, Köntgen F, Lyons PA, and Smith KG
- Subjects
- Animals, Autoantibodies biosynthesis, Autoimmunity genetics, Chromatin Immunoprecipitation, DNA Primers genetics, Enzyme-Linked Immunosorbent Assay, Enzyme-Linked Immunospot Assay, Flow Cytometry, Gene Knock-In Techniques, Germinal Center cytology, Luciferases, Mice, Mice, Inbred C57BL, Mutagenesis, Site-Directed, Promoter Regions, Genetic genetics, Receptors, IgG metabolism, Sequence Analysis, DNA, Statistics, Nonparametric, Transcription Factor AP-1 genetics, Transcription Factor AP-1 metabolism, Autoimmunity immunology, B-Lymphocytes metabolism, Gene Expression Regulation immunology, Genetic Variation, Germinal Center immunology, Receptors, IgG genetics
- Abstract
Genetic variants of the inhibitory Fc receptor FcγRIIb have been associated with systemic lupus erythematosus in humans and mice. The mechanism by which Fcgr2b variants contribute to the development of autoimmunity is unknown and was investigated by knocking in the most commonly conserved wild mouse Fcgr2b promoter haplotype, also associated with autoimmune-prone mouse strains, into the C57BL/6 background. We found that in the absence of an AP-1-binding site in its promoter, FcγRIIb failed to be up-regulated on activated and germinal center (GC) B cells. This resulted in enhanced GC responses, increased affinity maturation, and autoantibody production. Accordingly, in the absence of FcγRIIb activation-induced up-regulation, mice developed more severe collagen-induced arthritis and spontaneous glomerular immune complex deposition. Our data highlight how natural variation in Fcgr2b drives the development of autoimmune disease. They also show how the study of such variants using a knockin approach can provide insight into immune mechanisms not possible using conventional genetic manipulation, in this case demonstrating an unexpected critical role for the activation-induced up-regulation of FcγRIIb in controlling affinity maturation, autoantibody production, and autoimmunity.
- Published
- 2012
- Full Text
- View/download PDF
5. Genetic variation, Fcγ receptors, KIRs and infection: the evolution of autoimmunity.
- Author
-
Espeli M, Niederer HA, Traherne JA, Trowsdale J, and Smith KG
- Subjects
- Humans, Infections genetics, Receptors, IgG immunology, Receptors, KIR immunology, Autoimmunity genetics, Autoimmunity immunology, Genetic Variation genetics, Infections immunology, Receptors, IgG genetics, Receptors, KIR genetics
- Abstract
Recent work has emphasised the marked genetic variability that exists in the Fc receptor locus. This variation can contribute to the risk of autoimmune disease in both mice and humans, but can also have a profound impact on defence against infection. Using FcγRIIB and FcγRIIIB as examples, we demonstrate that variations associated with increased susceptibility to autoimmunity may be maintained in populations for their beneficial effect against infection. We examine the KIR locus from the same perspective and highlight similarities between the two loci. Intense selection pressure by pathogens presumably accounts for the marked variability within both regions and leads to susceptibility to autoimmunity for some alleles., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
6. Low-affinity Fcgamma receptors, autoimmunity and infection.
- Author
-
Willcocks LC, Smith KG, and Clatworthy MR
- Subjects
- Animals, Antibodies chemistry, Antibodies metabolism, Antibody Affinity immunology, Autoimmune Diseases therapy, Humans, Immunoglobulins, Intravenous therapeutic use, Mice, Receptors, IgG genetics, Receptors, IgG metabolism, Antibodies immunology, Autoimmune Diseases immunology, Autoimmunity immunology, Immunoglobulins, Intravenous immunology, Infections immunology, Receptors, IgG immunology
- Abstract
Low-affinity Fcgamma receptors (FcgammaRs) mediate the effects of immunoglobulin G (IgG) antibodies on leukocytes, including recruitment to inflammatory lesions, phagocytosis, antibody-dependent cellular cytotoxicity, release of inflammatory mediators and regulation of B cell activation. These functions are an important part of the mammalian response to infection, but if deployed inappropriately can cause autoimmune disease. Although most FcgammaRs are activatory, there is also an inhibitory FcgammaR that, when bound to IgG immune complexes, is able to downregulate the effects of both the activatory FcgammaRs and the B cell receptor. This review discusses the role of the low-affinity FcgammaRs in a balanced immune response and how perturbations in FcgammaR function result in susceptibility to infection or autoimmunity.
- Published
- 2009
- Full Text
- View/download PDF
7. Functional anergy in a subpopulation of naive B cells from healthy humans that express autoreactive immunoglobulin receptors.
- Author
-
Duty JA, Szodoray P, Zheng NY, Koelsch KA, Zhang Q, Swiatkowski M, Mathias M, Garman L, Helms C, Nakken B, Smith K, Farris AD, and Wilson PC
- Subjects
- Antibodies, Anti-Idiotypic pharmacology, Antibodies, Antinuclear genetics, Antibodies, Antinuclear immunology, Antibodies, Monoclonal genetics, Antibodies, Monoclonal immunology, Antigens, CD analysis, Antigens, CD metabolism, Autoantigens immunology, B-Lymphocyte Subsets drug effects, B-Lymphocyte Subsets metabolism, Calcium Signaling drug effects, Calcium Signaling immunology, Genes, Immunoglobulin genetics, Humans, Immunoglobulin D analysis, Immunoglobulin D immunology, Immunoglobulin M analysis, Immunoglobulin M immunology, Immunophenotyping, Ionomycin pharmacology, Kinetics, Lymphocyte Activation drug effects, Lymphocyte Activation immunology, Mutation immunology, Phosphorylation drug effects, Phosphorylation immunology, Tyrosine metabolism, Autoimmunity immunology, B-Lymphocyte Subsets immunology, Clonal Anergy immunology, Receptors, Antigen, B-Cell immunology
- Abstract
Self-reactive B cells not controlled by receptor editing or clonal deletion may become anergic. We report that fully mature human B cells negative for surface IgM and retaining only IgD are autoreactive and functionally attenuated (referred to as naive IgD(+)IgM(-) B cells [B(ND)]). These B(ND) cells typically make up 2.5% of B cells in the peripheral blood, have antibody variable region genes in germline (unmutated) configuration, and, by all current measures, are fully mature. Analysis of 95 recombinant antibodies expressed from the variable genes of single B(ND) cells demonstrated that they are predominantly autoreactive, binding to HEp-2 cell antigens and DNA. Upon B cell receptor cross-linkage, B(ND) cells have a reduced capacity to mobilize intracellular calcium or phosphorylate tyrosines, demonstrating that they are anergic. However, intense stimulation causes B(ND) cells to fully respond, suggesting that these cells could be the precursors of autoantibody secreting plasma cells in autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis. This is the first identification of a distinct mature human B cell subset that is naturally autoreactive and controlled by the tolerizing mechanism of functional anergy.
- Published
- 2009
- Full Text
- View/download PDF
8. Distinct cell-specific control of autoimmunity and infection by FcgammaRIIb.
- Author
-
Brownlie RJ, Lawlor KE, Niederer HA, Cutler AJ, Xiang Z, Clatworthy MR, Floto RA, Greaves DR, Lyons PA, and Smith KG
- Subjects
- Animals, Arthritis, Experimental, B-Lymphocytes cytology, B-Lymphocytes enzymology, B7-2 Antigen immunology, Bacterial Infections, Cell Proliferation, Extracellular Signal-Regulated MAP Kinases metabolism, Humans, Immunoglobulin G immunology, Lupus Erythematosus, Systemic immunology, Macrophages immunology, Mice, Mice, Transgenic, Organ Specificity, Phosphorylation, T-Lymphocytes immunology, Transgenes, Antigens, CD immunology, Autoimmunity immunology, Infections immunology, Receptors, IgG immunology
- Abstract
FcgammaRIIb is an inhibitory Fc receptor expressed on B cells and myeloid cells. It is important in controlling responses to infection, and reduced expression or function predisposes to autoimmunity. To determine if increased expression of FcgammaRIIb can modulate these processes, we created transgenic mice overexpressing FcgammaRIIb on B cells or macrophages. Overexpression of FcgammaRIIb on B cells reduced the immunoglobulin G component of T-dependent immune responses, led to early resolution of collagen-induced arthritis (CIA), and reduced spontaneous systemic lupus erythematosus (SLE). In contrast, overexpression on macrophages had no effect on immune responses, CIA, or SLE but increased mortality after Streptococcus pneumoniae infection. These results help define the role of FcgammaRIIb in immune responses, demonstrate the contrasting roles played by FcgammaRIIb on B cells and macrophages in the control of infection and autoimmunity, and emphasize the therapeutic potential for modulation of FcgammaRIIb expression on B cells in inflammatory and autoimmune disease.
- Published
- 2008
- Full Text
- View/download PDF
9. CD22: an inhibitory enigma.
- Author
-
Walker JA and Smith KG
- Subjects
- Animals, B-Lymphocytes immunology, Humans, Ligands, Lymphocyte Activation immunology, Mice, Receptors, Antigen, B-Cell metabolism, Self Tolerance immunology, Sialic Acid Binding Ig-like Lectin 2 chemistry, Structure-Activity Relationship, Autoimmunity immunology, Sialic Acid Binding Ig-like Lectin 2 immunology
- Abstract
CD22 is an inhibitory coreceptor of the B-cell receptor (BCR), and plays a critical role in establishing signalling thresholds for B-cell activation. Like other coreceptors, the ability of CD22 to modulate B-cell signalling is critically dependent upon its proximity to the BCR, and this in turn is governed by the binding of its extracellular domain to alpha2,6-linked sialic acid ligands. Manipulation of CD22 ligand binding in various experimental settings has profound effects on B-cell signalling, but as yet there is no complete model for how ligand binding in vivo controls normal CD22 function. Several elegant studies have recently shed light on this issue, although the results appear to suggest two mutually exclusive models for the role of ligand binding; in either promoting or inhibiting, CD22 function. We shall therefore discuss these results in detail, and suggest possible approaches by which these conflicting experimental findings might be reconciled. We shall also consider a second important issue in CD22 biology, which relates to the role that defects in this receptor might play in mediating autoimmune disease. We review the current evidence for this, and discuss the importance of genetic background in modifying CD22 function and predisposition to autoimmunity.
- Published
- 2008
- Full Text
- View/download PDF
10. Mature B cells class switched to IgD are autoreactive in healthy individuals.
- Author
-
Koelsch K, Zheng NY, Zhang Q, Duty A, Helms C, Mathias MD, Jared M, Smith K, Capra JD, and Wilson PC
- Subjects
- Adult, Antibodies, Antinuclear genetics, Antibodies, Antinuclear metabolism, Autoantibodies genetics, Autoantibodies metabolism, B-Lymphocytes cytology, Base Sequence, Cell Differentiation, Cell Line, Child, DNA Primers genetics, Humans, In Vitro Techniques, Palatine Tonsil cytology, Palatine Tonsil immunology, Autoimmunity genetics, B-Lymphocytes immunology, Immunoglobulin Class Switching, Immunoglobulin D genetics, Immunoglobulin D metabolism
- Abstract
Determination of the origin and fate of autoreactive B cells is critical to understanding and treating autoimmune diseases. We report that, despite being derived from healthy people, antibodies from B cells that have class switched to IgD via genetic recombination (and thus become class switched to C delta [C delta-CS] cells) are highly reactive to self antigens. Over half of the antibodies from C delta-CS B cells bind autoantigens on human epithelioma cell line 2 (HEp-2) cells or antinuclear antigens, and a quarter bind double-stranded DNA; both groups of antibodies are frequently polyreactive. Intriguingly, some C delta-CS B cells have accumulated basic residues in the antibody variable regions that mediate anti-DNA reactivity via somatic hypermutation and selection, while other C delta-CS B cells are naturally autoreactive. Though the total percentage was appreciably less than for C delta-CS cells, a surprising 31% of IgG memory cell antibodies were somewhat autoreactive, and as expected, about 24% of naive cell antibodies were autoreactive. We interpret these findings to indicate either that autoreactive B cells can be induced to class switch to IgD or that autoreactive B cells that use IgD as the B cell receptor are not effectively deleted. Determination of the mechanism by which the majority of C delta-CS B cells are autoreactive may be important in understanding peripheral tolerance mechanisms and may provide insight into the enigmatic function of the IgD antibody.
- Published
- 2007
- Full Text
- View/download PDF
11. B cell inhibitory receptors and autoimmunity.
- Author
-
Pritchard NR and Smith KG
- Subjects
- Animals, Antigens, CD immunology, Antigens, Differentiation, B-Lymphocyte immunology, Antigens, Surface immunology, Apoptosis Regulatory Proteins, Humans, Lectins immunology, Mice, Programmed Cell Death 1 Receptor, Receptors, IgG immunology, Self Tolerance immunology, Sialic Acid Binding Ig-like Lectin 2, Autoimmunity immunology, B-Lymphocytes immunology, Cell Adhesion Molecules, Receptors, Antigen, B-Cell immunology
- Published
- 2003
- Full Text
- View/download PDF
12. Identification of new risk loci shared across systemic vasculitides points towards potential target genes for drug repurposing
- Author
-
Ortiz-Fernández, Lourdes, Carmona, Elio G, Kerick, Martin, Lyons, Paul, Carmona, Francisco David, López Mejías, Raquel, Khor, Chiea Chuen, Grayson, Peter C, Tombetti, Enrico, Jiang, Lindi, Direskeneli, Haner, Saruhan-Direskeneli, Guher, Callejas-Rubio, José-Luis, Vaglio, Augusto, Salvarani, Carlo, Hernández-Rodríguez, Jose, Cid, Maria Cinta, Morgan, Ann W, Merkel, Peter A, Burgner, David, Smith, Kenneth Gc, Gonzalez-Gay, Miguel Angel, Sawalha, Amr H, Martin, Javier, Marquez, Ana, Ortiz-Fernández, Lourdes [0000-0002-0247-4280], Carmona, Francisco David [0000-0002-1427-7639], Grayson, Peter C [0000-0002-8269-9438], Salvarani, Carlo [0000-0003-3708-3148], Hernández-Rodríguez, Jose [0000-0002-2357-2015], Cid, Maria Cinta [0000-0002-4730-0938], Gonzalez-Gay, Miguel Angel [0000-0002-7924-7406], Martin, Javier [0000-0002-2202-0622], Marquez, Ana [0000-0001-9913-7688], Apollo - University of Cambridge Repository, and Ortiz-Fernandez L., Carmona E. G., Kerick M., Lyons P., Carmona F. D., Mejias R. L., Khor C. C., Grayson P. C., Tombetti E., Jiang L., et al.
- Subjects
Internal Diseases ,Vasculitis ,Immunology ,Autoimmunity ,SUSCEPTIBILITY ,VARIANTS ,Sağlık Bilimleri ,İmmünoloji ve Romatoloji ,İç Hastalıkları ,Clinical Medicine (MED) ,General Biochemistry, Genetics and Molecular Biology ,Immunology and Rheumatology ,ACTIVATION ,Genetic ,Rheumatology ,Health Sciences ,Humans ,Immunology and Allergy ,Klinik Tıp (MED) ,CTLA-4 Antigen ,Genetic Predisposition to Disease ,Polymorphism ,GENOME-WIDE ASSOCIATION ,ROMATOLOJİ ,Internal Medicine Sciences ,Polymorphism, Genetic ,Klinik Tıp ,Systemic Vasculitis ,Drug Repositioning ,Dahili Tıp Bilimleri ,CLINICAL MEDICINE ,Tıp ,Medicine ,Romatoloji ,Apoptosis Regulatory Proteins - Abstract
Objectives The number of susceptibility loci currently associated with vasculitis is lower than in other immune-mediated diseases due in part to small cohort sizes, a consequence of the low prevalence of vasculitides. This study aimed to identify new genetic risk loci for the main systemic vasculitides through a comprehensive analysis of their genetic overlap. Methods Genome-wide data from 8467 patients with any of the main forms of vasculitis and 29 795 healthy controls were meta-analysed using ASSET. Pleiotropic variants were functionally annotated and linked to their target genes. Prioritised genes were queried in DrugBank to identify potentially repositionable drugs for the treatment of vasculitis. Results Sixteen variants were independently associated with two or more vasculitides, 15 of them representing new shared risk loci. Two of these pleiotropic signals, located close to CTLA4 and CPLX1, emerged as novel genetic risk loci in vasculitis. Most of these polymorphisms appeared to affect vasculitis by regulating gene expression. In this regard, for some of these common signals, potential causal genes were prioritised based on functional annotation, including CTLA4, RNF145, IL12B, IL5, IRF1, IFNGR1, PTK2B, TRIM35, EGR2 and ETS2, each of which has key roles in inflammation. In addition, drug repositioning analysis showed that several drugs, including abatacept and ustekinumab, could be potentially repurposed in the management of the analysed vasculitides. Conclusions We identified new shared risk loci with functional impact in vasculitis and pinpointed potential causal genes, some of which could represent promising targets for the treatment of vasculitis., HELICAL Innovative Training Network, European Commission funded-under the Marie Sklodowska-Curie 813545, Cooperative Research Thematic Network programme RD16/0012/0013, Redes de Investigacion Cooperativa Orientadas a Resultados en Salud (RICORS) RD21/0002/0039, Instituto de Salud Carlos III PI18/00040, Juan de la Cierva Incorporacion fellowship IJC2019- 040746-I, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA, NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) R01 AR070148, National Health and Medical Research Council (NHMRC) of Australia GTN1175744, Victorian Government's Operational Infrastructure Support Program, Rare Diseases Clinical Research Network (RDCRN), initiative of the Office of Rare Diseases Research (ORDR), NIH National Center for Advancing Translational Sciences (NCATS), NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) U54 AR057319, NIH National Center for Research Resources (NCRR) U54 RR019497
- Published
- 2023
13. Transcriptional networks in at-risk individuals identify signatures of type 1 diabetes progression
- Author
-
Xhonneux, Louis-Pascal, Knight, Oliver, Lernmark, Åke, Bonifacio, Ezio, Hagopian, William A, Rewers, Marian J, She, Jin-Xiong, Toppari, Jorma, Parikh, Hemang, Smith, Kenneth GC, Ziegler, Anette-G, Akolkar, Beena, Krischer, Jeffrey P, McKinney, Eoin F, Xhonneux, Louis-Pascal [0000-0003-1990-4475], Knight, Oliver [0000-0002-0424-2379], Lernmark, Åke [0000-0003-1735-0499], Bonifacio, Ezio [0000-0002-8704-4713], Hagopian, William A [0000-0003-2979-0475], Rewers, Marian J [0000-0003-3829-9207], She, Jin-Xiong [0000-0002-0966-6381], Toppari, Jorma [0000-0003-2228-334X], Parikh, Hemang [0000-0002-9076-6709], Smith, Kenneth GC [0000-0003-3829-4326], Ziegler, Anette-G [0000-0002-6290-5548], Akolkar, Beena [0000-0002-2351-5942], McKinney, Eoin F [0000-0003-3516-3072], and Apollo - University of Cambridge Repository
- Subjects
endocrine system ,Islets of Langerhans ,Diabetes Mellitus, Type 1 ,endocrine system diseases ,Disease Progression ,Humans ,Autoimmunity ,Bayes Theorem ,Gene Regulatory Networks ,Genetic Predisposition to Disease ,Prospective Studies ,Autoantibodies - Abstract
Type 1 diabetes (T1D) is a disease of insulin deficiency that results from autoimmune destruction of pancreatic islet β cells. The exact cause of T1D remains unknown, although asymptomatic islet autoimmunity lasting from weeks to years before diagnosis raises the possibility of intervention before the onset of clinical disease. The number, type, and titer of islet autoantibodies are associated with long-term disease risk but do not cause disease, and robust early predictors of individual progression to T1D onset remain elusive. The Environmental Determinants of Diabetes in the Young (TEDDY) consortium is a prospective cohort study aiming to determine genetic and environmental interactions causing T1D. Here, we analyzed longitudinal blood transcriptomes of 2013 samples from 400 individuals in the TEDDY study before both T1D and islet autoimmunity. We identified and interpreted age-associated gene expression changes in healthy infancy and age-independent changes tracking with progression to both T1D and islet autoimmunity, beginning before other evidence of islet autoimmunity was present. We combined multivariate longitudinal data in a Bayesian joint model to predict individual risk of T1D onset and validated the association of a natural killer cell signature with progression and the model's predictive performance on an additional 356 samples from 56 individuals in the independent Type 1 Diabetes Prediction and Prevention study. Together, our results indicate that T1D is characterized by early and longitudinal changes in gene expression, informing the immunopathology of disease progression and facilitating prediction of its course.
- Published
- 2021
14. One Gene, Many Facets: Multiple Immune Pathway Dysregulation in SOCS1 Haploinsufficiency
- Author
-
Körholz, Julia, Gabrielyan, Anastasia, Sowerby, John M, Boschann, Felix, Chen, Lan-Sun, Paul, Diana, Brandt, David, Kleymann, Janina, Kolditz, Martin, Toepfner, Nicole, Knöfler, Ralf, Jacobsen, Eva-Maria, Wolf, Christine, Conrad, Karsten, Röber, Nadja, Lee-Kirsch, Min Ae, Smith, Kenneth GC, Mundlos, Stefan, Berner, Reinhard, Dalpke, Alexander H, Schuetz, Catharina, Rae, William, Smith, Kenneth [0000-0003-3829-4326], Rae, William [0000-0003-0095-2514], and Apollo - University of Cambridge Repository
- Subjects
Male ,Pleiotropie ,T-Lymphocytes ,Immunology ,genetic pleiotropy ,Autoimmunity ,Autoimmunität ,Haploinsufficiency ,Models, Biological ,Immundefekt ,Suppressor of Cytokine Signaling 1 Protein ,SOCS1 ,Humans ,ddc:610 ,Genetic pleiotropy ,Child ,Alleles ,Original Research ,inborn error of immunity (IEI) ,FOS: Clinical medicine ,autoimmunity ,Genetic Diseases, Inborn ,Immunologic deficiency syndromes ,Pedigree ,Hyper-IgE syndrome ,Case-Control Studies ,Child, Preschool ,Immune System ,Job syndrome ,Cytokines ,Female ,Job Syndrome ,Biomarkers ,Signal Transduction - Abstract
Background: Inborn errors of immunity (IEI) present with a large phenotypic spectrum of disease, which can pose diagnostic and therapeutic challenges. Suppressor of cytokine signaling 1 (SOCS1) is a key negative regulator of cytokine signaling, and has recently been associated with a novel IEI. Of patients described to date, it is apparent that SOCS1 haploinsufficiency has a pleiotropic effect in humans. Objective: We sought to investigate whether dysregulation of immune pathways, in addition to STAT1, play a role in the broad clinical manifestations of SOCS1 haploinsufficiency. Methods: We assessed impacts of reduced SOCS1 expression across multiple immune cell pathways utilizing patient cells and CRISPR/Cas9 edited primary human T cells. Results: SOCS1 haploinsufficiency phenotypes straddled across the International Union of Immunological Societies classifications of IEI. We found that reduced SOCS1 expression led to dysregulation of multiple intracellular pathways in immune cells. STAT1 phosphorylation is enhanced, comparably with STAT1 gain-of-function mutations, and STAT3 phosphorylation is similarly reduced with concurrent reduction of Th17 cells. Furthermore, reduced SOCS1 E3 ligase function was associated with increased FAK1 in immune cells, and increased AKT and p70 ribosomal protein S6 kinase phosphorylation. We also found Toll-like receptor responses are increased in SOCS1 haploinsufficiency patients. Conclusions: SOCS1 haploinsufficiency is a pleiotropic monogenic IEI. Dysregulation of multiple immune cell pathways may explain the variable clinical phenotype associated with this new condition. Knowledge of these additional dysregulated immune pathways is important when considering the optimum management for SOCS1 haploinsufficient patients.
- Published
- 2021
15. B cells in glomerulonephritis: focus on lupus nephritis
- Author
-
Clatworthy, Menna R. and Smith, Kenneth G. C.
- Published
- 2007
- Full Text
- View/download PDF
16. Targeted genomic analysis reveals widespread autoimmune disease association with regulatory variants in the TNF superfamily cytokine signalling network
- Author
-
Richard, Arianne C, Peters, James E, Lee, James C, Vahedi, Golnaz, Schäffer, Alejandro A, Siegel, Richard M, Lyons, Paul A, Smith, Kenneth GC, Richard, Arianne [0000-0002-8708-9997], Lee, James [0000-0001-5711-9385], Lyons, Paul [0000-0001-7035-8997], Smith, Kenneth [0000-0003-3829-4326], and Apollo - University of Cambridge Repository
- Subjects
Risk ,Quantitative Trait Loci ,Autoimmunity ,eQTL ,Receptors, Tumor Necrosis Factor ,Autoimmune Diseases ,Genetics ,GWAS ,Humans ,Protein Isoforms ,Genetics(clinical) ,Gene Regulatory Networks ,Genetic Predisposition to Disease ,Molecular Biology ,Alleles ,TNF superfamily ,0604 Genetics ,Genome, Human ,Tumor Necrosis Factor-alpha ,Research ,Hereditary Autoinflammatory Diseases ,1103 Clinical Sciences ,Genomics ,Chromatin ,Gene set analysis ,Gene Expression Regulation ,FOS: Biological sciences ,Autoinflammation ,Leukocytes, Mononuclear ,Molecular Medicine ,Genome-Wide Association Study ,Signal Transduction - Abstract
Background Tumour necrosis factor (TNF) superfamily cytokines and their receptors regulate diverse immune system functions through a common set of signalling pathways. Genetic variants in and expression of individual TNF superfamily cytokines, receptors and signalling proteins have been associated with autoimmune and inflammatory diseases, but their interconnected biology has been largely unexplored. Methods We took a hypothesis-driven approach using available genome-wide datasets to identify genetic variants regulating gene expression in the TNF superfamily cytokine signalling network and the association of these variants with autoimmune and autoinflammatory disease. Using paired gene expression and genetic data, we identified genetic variants associated with gene expression, expression quantitative trait loci (eQTLs), in four peripheral blood cell subsets. We then examined whether eQTLs were dependent on gene expression level or the presence of active enhancer chromatin marks. Using these eQTLs as genetic markers of the TNF superfamily signalling network, we performed targeted gene set association analysis in eight autoimmune and autoinflammatory disease genome-wide association studies. Results Comparison of TNF superfamily network gene expression and regulatory variants across four leucocyte subsets revealed patterns that differed between cell types. eQTLs for genes in this network were not dependent on absolute gene expression levels and were not enriched for chromatin marks of active enhancers. By examining autoimmune disease risk variants among our eQTLs, we found that risk alleles can be associated with either increased or decreased expression of co-stimulatory TNF superfamily cytokines, receptors or downstream signalling molecules. Gene set disease association analysis revealed that eQTLs for genes in the TNF superfamily pathway were associated with six of the eight autoimmune and autoinflammatory diseases examined, demonstrating associations beyond single genome-wide significant hits. Conclusions This systematic analysis of the influence of regulatory genetic variants in the TNF superfamily network reveals widespread and diverse roles for these cytokines in susceptibility to a number of immune-mediated diseases. Electronic supplementary material The online version of this article (doi:10.1186/s13073-016-0329-5) contains supplementary material, which is available to authorized users.
- Published
- 2016
17. Leucocyte subset-specific type 1 interferon signatures in SLE and other immune-mediated diseases
- Author
-
Flint, Shaun M, Jovanovic, Vojislav, Teo, Boon Wee, Mak, Anselm, Thumboo, Julian, McKinney, Eoin F, Lee, James C, MacAry, Paul, Kemeny, David M, Jayne, David Rw, Fong, Kok Yong, Lyons, Paul A, Smith, Kenneth Gc, Flint, Shaun M [0000-0002-5282-9334], and Apollo - University of Cambridge Repository
- Subjects
Cytokines ,Autoimmunity ,Systemic Lupus Erythematosus ,health care economics and organizations - Abstract
OBJECTIVES: Type 1 interferons (IFN-1) are implicated in the pathogenesis of systemic lupus erythematosus (SLE), but most studies have only reported the effect of IFN-1 on mixed cell populations. We aimed to define modules of IFN-1-associated genes in purified leucocyte populations and use these as a basis for a detailed comparative analysis. METHODS: CD4+ and CD8+ T cells, monocytes and neutrophils were purified from patients with SLE, other immune-mediated diseases and healthy volunteers and gene expression then determined by microarray. Modules of IFN-1-associated genes were defined using weighted gene coexpression network analysis. The composition and expression of these modules was analysed. RESULTS: 1150 of 1288 IFN-1-associated genes were specific to myeloid subsets, compared with 11 genes unique to T cells. IFN-1 genes were more highly expressed in myeloid subsets compared with T cells. A subset of neutrophil samples from healthy volunteers (HV) and conditions not classically associated with IFN-1 signatures displayed increased IFN-1 gene expression, whereas upregulation of IFN-1-associated genes in T cells was restricted to SLE. CONCLUSIONS: Given the broad upregulation of IFN-1 genes in neutrophils including in some HV, investigators reporting IFN-1 signatures on the basis of whole blood samples should be cautious about interpreting this as evidence of bona fide IFN-1-mediated pathology. Instead, specific upregulation of IFN-1-associated genes in T cells may be a useful biomarker and a further mechanism by which elevated IFN-1 contributes to autoimmunity in SLE.
- Published
- 2016
18. Antibody repertoire analysis in polygenic autoimmune diseases.
- Author
-
Bashford‐Rogers, Rachael J. M., Smith, Kenneth G. C., and Thomas, David C.
- Subjects
- *
NUCLEOTIDE sequencing , *RNA sequencing , *AUTOIMMUNE diseases , *GENETIC polymorphisms , *B cells - Abstract
Summary: High‐throughput sequencing of the DNA/RNA encoding antibody heavy‐ and light‐chains is rapidly transforming the field of adaptive immunity. It can address key questions, including: (i) how the B‐cell repertoire differs in health and disease; and (ii) if it does differ, the point(s) in B‐cell development at which this occurs. The advent of technologies, such as whole‐genome sequencing, offers the chance to link abnormalities in the B‐cell antibody repertoire to specific genomic variants and polymorphisms. Here, we discuss the current research using B‐cell antibody repertoire sequencing in three polygenic autoimmune diseases where there is good evidence for a pathological role for B‐cells, namely systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. These autoimmune diseases exhibit significantly skewed B‐cell receptor repertoires compared with healthy controls. Interestingly, some common repertoire defects are shared between diseases, such as elevated IGHV4‐34 gene usage. B‐cell clones have effectively been characterized and tracked between different tissues and blood in autoimmune disease. It has been hypothesized that these differences may signify differences in B‐cell tolerance; however, the mechanisms and implications of these defects are not clear. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
19. Fcγ RIIB and autoimmunity.
- Author
-
Espéli, Marion, Smith, Kenneth G. C., and Clatworthy, Menna R.
- Subjects
- *
FC receptors , *AUTOIMMUNITY , *AUTOIMMUNE diseases , *AUTOANTIGENS , *AUTOANTIBODIES , *NATURAL immunity - Abstract
Autoimmune diseases are characterized by adaptive immune responses against self-antigens, including humoral responses resulting in the production of autoantibodies. Autoantibodies generate inflammation by activating complement and engaging Fcγ receptors (FcγRs). The inhibitory receptor Fcγ RIIB plays a central role in regulating the generation of autoantibodies and their effector functions, which include activation of innate immune cells and the cellular arm of the adaptive immune system, via effects on antigen presentation to CD4 T cells. Polymorphisms in Fcγ RIIB have been associated with susceptibility to autoimmunity but protection against infections in humans and mice. In the last few years, new mechanisms by which Fcγ RIIB controls the adaptive immune response have been described. Notably, Fcγ RIIB has been shown to regulate germinal center B cells and dendritic cell migration, with potential impact on the development of autoimmune diseases. Recent work has also highlighted the implication of Fcγ RIIB on the regulation of the innate immune system, via inhibition of Toll-like receptor- and complement receptor-mediated activation. This review will provide an update on the role of Fcγ RIIB in adaptive immune responses in autoimmunity, and then focus on their emerging function in innate immunity. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
20. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection.
- Author
-
McKinney, Eoin F., Lee, James C., Jayne, David R. W., Lyons, Paul A., and Smith, Kenneth G. C.
- Subjects
T cells ,AUTOIMMUNITY ,AUTOIMMUNE diseases ,VIRUS diseases ,IMMUNOLOGY ,T cell receptors - Abstract
The clinical course of autoimmune and infectious disease varies greatly, even between individuals with the same condition. An understanding of the molecular basis for this heterogeneity could lead to significant improvements in both monitoring and treatment. During chronic infection the process of T-cell exhaustion inhibits the immune response, facilitating viral persistence. Here we show that a transcriptional signature reflecting CD8 T-cell exhaustion is associated with poor clearance of chronic viral infection, but conversely predicts better prognosis in multiple autoimmune diseases. The development of CD8 T-cell exhaustion during chronic infection is driven both by persistence of antigen and by a lack of accessory 'help' signals. In autoimmunity, we find that where evidence of CD4 T-cell co-stimulation is pronounced, that of CD8 T-cell exhaustion is reduced. We can reproduce the exhaustion signature by modifying the balance of persistent stimulation of T-cell antigen receptors and specific CD2-induced co-stimulation provided to human CD8 T cells in vitro, suggesting that each process plays a role in dictating outcome in autoimmune disease. The 'non-exhausted' T-cell state driven by CD2-induced co-stimulation is reduced by signals through the exhaustion-associated inhibitory receptor PD-1, suggesting that induction of exhaustion may be a therapeutic strategy in autoimmune and inflammatory disease. Using expression of optimal surrogate markers of co-stimulation/exhaustion signatures in independent data sets, we confirm an association with good clinical outcome or response to therapy in infection (hepatitis C virus) and vaccination (yellow fever, malaria, influenza), but poor outcome in autoimmune and inflammatory disease (type 1 diabetes, anti-neutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosus, idiopathic pulmonary fibrosis and dengue haemorrhagic fever). Thus, T-cell exhaustion plays a central role in determining outcome in autoimmune disease and targeted manipulation of this process could lead to new therapeutic opportunities. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
21. FcγRllb inhibits immune complex-induced VEGF-A production and intranodal lymphangiogenesis.
- Author
-
Clatworthy, Menna R., Harford, Sarah K., Mathews, Rebeccah J., and Smith, Kenneth G. C.
- Subjects
IMMUNE complexes ,VASCULAR endothelial growth factor receptors ,IMMUNOGLOBULIN G ,SYSTEMIC lupus erythematosus ,DENDRITIC cells ,ARTHRITIS ,GENETIC polymorphisms ,DISEASE risk factors ,IMMUNOLOGY - Abstract
IgG immune complexes (ICs) are generated during immune responses to infection and self-antigen and have been implicated in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Their role, and that of the fragment crystallizable (Fc) receptors that bind them, in driving local inflammation is not fully understood. Low affinity-activating Fey receptors (FcγRs) that bind immune complexes are controlled by a single inhibitory receptor, FcγRllb (CD32b). We investigated whether FcγR cross-linking by IC might induce VEGF-A and lymph node lymphangiogenesis. Murine macrophages and dendritic cells (DCs) stimulated with ICs produced VEGF-A, and this was inhibited by coligation of FcγRllb. Similarly, IC-induced VEGF-A production by B cells was inhibited by FcγRllb. In vivo, IC generation resulted in VEGF-A-dependent intranodal lymphangiogenesis and increased DC number. We sought to determine the relevance of these findings to autoimmunity because elevated serum VEGF-A has been observed in patients with SLE; we found that lymphangiogenesis and VEGF-A were increased in the lymph nodes of mice with collagen-induced arthritis and SLE. In humans, a SLE-associated polymorphism (rs1050501) results in a dysfunctional FcyRIIB7232 receptor. Monocyte-derived macrophages from subjects with the FcyRIIB77'232 genotype showed increased FcγR-mediated VEGF-A production, demonstrating a similar process is likely to occur in humans. Thus, ICs contribute to inflammation through VEGF-A-driven lymph node lymphangiogenesis, which is controlled by FcγRllb. These findings have implications for the pathogenesis, and perhaps future treatment, of autoimmune diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
22. Lipid Anti-Lipid Antibody Responses Correlate with Disease Activity in Systemic Lupus Erythematosus.
- Author
-
Jovanović, Vojislav, Abdul Aziz, Nurhuda, Lim, Yan Ting, Ng Ai Poh, Amanda, Jin Hui Chan, Sherlynn, Ho Xin Pei, Eliza, Lew, Fei Chuin, Shui, Guanghou, Jenner, Andrew M., Bowen, Li, McKinney, Eoin F., Lyons, Paul A., Kemeny, Michael D., Smith, Kenneth G. C., Wenk, Markus R., and MacAry, Paul A.
- Subjects
SYSTEMIC lupus erythematosus ,ANTIBODY formation ,LIPIDS ,AUTOIMMUNE diseases ,IMMUNE complexes ,PERIODIC diseases ,CARDIOLIPIN ,HYDROXYCHOLESTEROLS ,BIOMARKERS - Abstract
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disorder characterized by broad clinical manifestations including cardiovascular and renal complications with periodic disease flares and significant morbidity and mortality. One of the main contributing factors to the pathology of SLE is the accumulation and impaired clearance of immune complexes of which the principle components are host auto-antigens and antibodies. The contribution of host lipids to the formation of these autoimmune complexes remains poorly defined. The aim of the present study was to identify and analyze candidate lipid autoantigens and their corresponding anti–lipid antibody responses in a well-defined SLE patient cohort using a combination of immunological and biophysical techniques. Disease monitoring in the SLE cohort was undertaken with serial British Isles Lupus Assessment Group (BILAG) scoring. Correlations between specific lipid/anti-lipid responses were investigated as disease activity developed from active flares to quiescent during a follow up period. We report a significant negative correlation between anti-lipid antibodies for 24S-hydroxycholesterol, cardiolipin and phosphatidylserine with SLE disease activity. Taken together, these data suggest that lipid autoantigens represent a new family of biomarkers that can be employed to monitor disease activity plus the efficacy of therapeutic intervention in SLE. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
23. CD22 and Autoimmune Disease.
- Author
-
Dörner, Thomas, Shock, Anthony, and Smith, Kenneth G.C.
- Abstract
CD22 is a 140-kDa member of the Siglec family of cell surface proteins that is expressed by most mature B-cell lineages. As a co-receptor of the B-cell receptor (BCR), it is known to contribute to the sensitive control of the B-cell response to antigen. Cross-linking of CD22 and the BCR by antigen triggers the phosphorylation of CD22, which leads to activation of signaling molecules such as phosphatases. Signal transduction pathways involving CD22 have been explored in a number of mouse models, some of which have provided evidence that in the absence of functional CD22, B cells have a 'hyperactivated' phenotype, and suggest that loss of CD22 function could contribute to the pathogenesis of autoimmune diseases. Modulating CD22 activity has therefore been suggested as a possible therapeutic approach to such diseases. For example, the novel CD22-targeting monoclonal antibody epratuzumab is currently under investigation as a treatment for the connective tissue disorder systemic lupus erythematosus (SLE). [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
24. FcgammaRIIB in autoimmunity and infection: evolutionary and therapeutic implications.
- Author
-
Smith, Kenneth G. C. and Clatworthy, Menna R.
- Subjects
- *
AUTOIMMUNITY , *IMMUNOLOGIC diseases , *AUTOANTIBODIES , *AUTOIMMUNE diseases , *SYSTEMIC lupus erythematosus , *THERAPEUTIC use of immunoglobulins , *ANIMAL experimentation , *BACTERIAL diseases , *CELL receptors , *COMPARATIVE studies , *CYTOKINES , *DENDRITIC cells , *GENES , *GENETIC polymorphisms , *GENETICS , *MALARIA , *RESEARCH methodology , *MEDICAL cooperation , *RESEARCH , *EVALUATION research , *CELL physiology - Abstract
FcgammaRIIB is the only inhibitory Fc receptor. It controls many aspects of immune and inflammatory responses, and variation in the gene encoding this protein has long been associated with susceptibility to autoimmune disease, particularly systemic lupus erythematosus (SLE). FcgammaRIIB is also involved in the complex regulation of defence against infection. A loss-of-function polymorphism in FcgammaRIIB protects against severe malaria, the investigation of which is beginning to clarify the evolutionary pressures that drive ethnic variation in autoimmunity. Our increased understanding of the function of FcgammaRIIB also has potentially far-reaching therapeutic implications, being involved in the mechanism of action of intravenous immunoglobulin, controlling the efficacy of monoclonal antibody therapy and providing a direct therapeutic target. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
25. A CD8+ T cell transcription signature predicts prognosis in autoimmune disease.
- Author
-
McKinney, Eoin F., Lyons, Paul A., Carr, Edward J., Hollis, Jane L., Jayne, David R. W., Willcocks, Lisa C., Koukoulaki, Maria, Brazma, Alvis, Jovanovic, Vojislav, Kemeny, D. Michael, Pollard, Andrew J., MacAry, Paul A., Chaudhry, Afzal N., and Smith, Kenneth G. C.
- Subjects
T cells ,TRANSCRIPTION factors ,AUTOIMMUNE diseases ,IMMUNOLOGIC diseases ,AUTOIMMUNITY ,PROGNOSIS ,PHYSIOLOGY - Abstract
Autoimmune diseases are common and debilitating, but their severe manifestations could be reduced if biomarkers were available to allow individual tailoring of potentially toxic immunosuppressive therapy. Gene expression–based biomarkers facilitating such tailoring of chemotherapy in cancer, but not autoimmunity, have been identified and translated into clinical practice. We show that transcriptional profiling of purified CD8
+ T cells, which avoids the confounding influences of unseparated cells, identifies two distinct subject subgroups predicting long-term prognosis in two autoimmune diseases, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), a chronic, severe disease characterized by inflammation of medium-sized and small blood vessels, and systemic lupus erythematosus (SLE), characterized by autoantibodies, immune complex deposition and diverse clinical manifestations ranging from glomerulonephritis to neurological dysfunction. We show that the subset of genes defining the poor prognostic group is enriched for genes involved in the interleukin-7 receptor (IL-7R) pathway and T cell receptor (TCR) signaling and those expressed by memory T cells. Furthermore, the poor prognostic group is associated with an expanded CD8+ T cell memory population. These subgroups, which are also found in the normal population and can be identified by measuring expression of only three genes, raise the prospect of individualized therapy and suggest new potential therapeutic targets in autoimmunity. [ABSTRACT FROM AUTHOR]- Published
- 2010
- Full Text
- View/download PDF
26. A defunctioning polymorphism in FCGR2B is associated with protection against malaria but susceptibility to systemic lupus erythematosus.
- Author
-
Wilicocks, Lisa C., Carr, Edward J., Niederer, Heather A., Rayner, Tim F., WiIIiams, Thomas N., Wanling Yang, Scott, J. Anthony G., Urban, Britta C., Peshu, Norbert, Vyse, Timothy J., Yu Lung Lau, Lyons, Paul A., and Smith, Kenneth G. C.
- Subjects
SYSTEMIC lupus erythematosus ,FC receptors ,GENE frequency ,MALARIA prevention ,CAUCASIAN race ,SOUTHEAST Asians - Abstract
Systemic lupus erythematosus (SLE) is a muttisystem autoimmune disease more prevalent in people of African and Asian origin than Caucasian origin. FcγRllb is an inhibitory Fc receptor .with a critical role in immune regulation. Mouse data suggest that FcγRllb deficiency increases susceptibility to autoimmune disease but protects against infection. We show that a SNP in human FCGR2B that abrogates receptor function is strongly associated with susceptibility to SLE in both Caucasians and Southeast Asians. The minor allele of this SNP is more common in Southeast Asians and Africans. populations from areas where malaria is endemic, than in Caucasians. We show that homozygosity for the minor allele is associated with substantial protection against severe malaria in an East African population (odds ratio = 0.56; P = 7.1 x 10
-5 ). This protective effect against malaria may contribute to the higher frequency of this SNP and hence, SLE in Africans and Southeast Asians. [ABSTRACT FROM AUTHOR]- Published
- 2010
27. FcγRIIB, FcγRIIIB, and systemic lupus erythematosus.
- Author
-
Niederer, Heather A., Clatworthy, Menna R., Willcocks, Lisa C., and Smith, Kenneth G.C.
- Subjects
SKIN diseases ,IMMUNOGLOBULINS ,CUTANEOUS tuberculosis ,AUTOIMMUNE diseases ,AUTOIMMUNITY - Abstract
The autoimmune disease systemic lupus erythematosus (SLE) is characterized by the deposition of immune complexes in organs such as the kidney. This occurs as a result of multiple immunological abnormalities, including the production of high levels of autoantibody and dysregulated handling of immune complexes. Receptors for the Fc portion of IgG are critically involved in immune complex handling and clearance and in the regulation of B-cell activation. Polymorphisms in the low-affinity Fcγ receptors have been associated with susceptibility to a number of autoimmune diseases, including SLE. We review the role of two such receptors in the pathogenesis of lupus—the inhibitory receptor FcγRIIB and the glycosylphosphatidylinositol-linked activatory receptor FcγRIIIB. Recent work has enhanced our understanding of the mechanism of action of the FcγRIIB I232T polymorphism and the overall role of this receptor in SLE. The human neutrophil antigen-1 allotypes of FcγRIIIB and the role of the receptor in SLE are discussed with regard to the recent determination of copy number variation in FCGR3B and the association of low copy number with SLE. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
28. Systemic lupus erythematosus-associated defects in the inhibitory receptor FcγRIIb reduce susceptibility to malaria.
- Author
-
Clatworthy, Menna R., Willcocks, Lisa, Urban, Britta, Langhorne, Jean, Williams, Tom N., Peshu, Norbert, Watkins, Nicholas A., Floto, R. Andres, and Smith, Kenneth G. C.
- Subjects
MALARIA ,GENETIC polymorphisms ,PROTOZOAN diseases ,LUPUS erythematosus ,PATHOLOGY ,IMMUNOLOGY - Abstract
Polygenic autoimmune diseases, such as systemic lupus erythematosus (SLE), are a significant cause of morbidity and mortality worldwide. In recent years, functionally important genetic polymorphisms conferring susceptibility to SLE have been identified, but the evolutionary pressures driving their retention in the gene pool remain elusive. A defunctioning. SLE-associated polymorphism of the inhibitory receptor FcγRllb is found at an increased frequency in African and Asian populations, broadly corresponding to areas where malaria is endemic. Here, we show that FcγRllb deficient mice have increased clearance of malarial parasites (Plasmodium chabaudi chabaud,) and develop less severe disease. In vitro, the human lupus associated FcγRllb polymorphism enhances phagocytosis of Plasmodium falciparum-infected erythrocytes. These results demonstrate that FcγRllb is important in controlling the immune response to malarial parasites and suggests that the higher frequency of human FcγRllb polymorphisms predisposing to SLE in Asians and Africans may be maintained because these variants reduce susceptibility to malaria. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
29. Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake
- Author
-
Willcocks, Lisa C, Lyons, Paul A, Clatworthy, Menna R, Robinson, James I, Yang, Wanling, Newland, Stephen A, Plagnol, Vincent, McGovern, Naomi N, Condliffe, Alison M, Chilvers, Edwin R, Adu, Dwomoa, Jolly, Elaine C, Watts, Richard, Lau, Yu Lung, Morgan, Ann W, Nash, Gerard, and Smith, Kenneth GC
- Subjects
Male ,Vasculitis ,Neutrophils ,Receptors, IgG ,Gene Dosage ,Genetic Variation ,Autoimmunity ,Antigen-Antibody Complex ,GPI-Linked Proteins ,White People ,3. Good health ,Antibodies, Antineutrophil Cytoplasmic ,Gene Expression Regulation ,Humans ,Lupus Erythematosus, Systemic ,Female ,Genetic Predisposition to Disease - Abstract
Copy number (CN) variation (CNV) has been shown to be common in regions of the genome coding for immune-related genes, and thus impacts upon polygenic autoimmunity. Low CN of FCGR3B has recently been associated with systemic lupus erythematosus (SLE). FcgammaRIIIb is a glycosylphosphatidylinositol-linked, low affinity receptor for IgG found predominantly on human neutrophils. We present novel data demonstrating that both in a family with FcgammaRIIIb-deficiency and in the normal population, FCGR3B CNV correlates with protein expression, with neutrophil uptake of and adherence to immune complexes, and with soluble serum FcgammaRIIIb. Reduced FcgammaRIIIb expression is thus likely to contribute to the impaired clearance of immune complexes, which is a feature of SLE, explaining the association between low FCGR3B CNV and SLE that we have confirmed in a Caucasian population. In contrast, antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV), a disease not associated with immune complex deposition, is associated with high FCGR3B CN. Thus, we define a role for FCGR3B CNV in immune complex clearance, a function that may explain why low FCGR3B CNV is associated with SLE, but not AASV. This is the first report of an association between disease-related gene CNV and variation in protein expression and function that may contribute to autoimmune disease susceptibility.
30. A CD8+ T cell transcription signature predicts prognosis in autoimmune disease
- Author
-
McKinney, Eoin F, Lyons, Paul A, Carr, Edward J, Hollis, Jane L, Jayne, David RW, Willcocks, Lisa C, Koukoulaki, Maria, Brazma, Alvis, Jovanovic, Vojislav, Kemeny, D Michael, Pollard, Andrew J, Macary, Paul A, Chaudhry, Afzal N, and Smith, Kenneth GC
- Subjects
Inflammation ,Vasculitis ,Dose-Response Relationship, Drug ,Interleukin-7 ,T-Lymphocytes ,Receptors, Antigen, T-Cell ,Gene Expression ,Autoimmunity ,CD8-Positive T-Lymphocytes ,Prognosis ,3. Good health ,Antibodies, Antineutrophil Cytoplasmic ,Autoimmune Diseases ,Cohort Studies ,Humans ,Lupus Erythematosus, Systemic ,Immunosuppressive Agents ,Signal Transduction - Abstract
Autoimmune diseases are common and debilitating, but their severe manifestations could be reduced if biomarkers were available to allow individual tailoring of potentially toxic immunosuppressive therapy. Gene expression-based biomarkers facilitating such tailoring of chemotherapy in cancer, but not autoimmunity, have been identified and translated into clinical practice. We show that transcriptional profiling of purified CD8(+) T cells, which avoids the confounding influences of unseparated cells, identifies two distinct subject subgroups predicting long-term prognosis in two autoimmune diseases, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), a chronic, severe disease characterized by inflammation of medium-sized and small blood vessels, and systemic lupus erythematosus (SLE), characterized by autoantibodies, immune complex deposition and diverse clinical manifestations ranging from glomerulonephritis to neurological dysfunction. We show that the subset of genes defining the poor prognostic group is enriched for genes involved in the interleukin-7 receptor (IL-7R) pathway and T cell receptor (TCR) signaling and those expressed by memory T cells. Furthermore, the poor prognostic group is associated with an expanded CD8(+) T cell memory population. These subgroups, which are also found in the normal population and can be identified by measuring expression of only three genes, raise the prospect of individualized therapy and suggest new potential therapeutic targets in autoimmunity.
31. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection
- Author
-
McKinney, Eoin F, Lee, James C, Jayne, David RW, Lyons, Paul A, and Smith, Kenneth GC
- Subjects
CD4-Positive T-Lymphocytes ,Inflammation ,Receptors, Interleukin-7 ,Programmed Cell Death 1 Receptor ,CD2 Antigens ,Receptors, Antigen, T-Cell ,Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ,Autoimmunity ,CD8-Positive T-Lymphocytes ,Infections ,Inflammatory Bowel Diseases ,3. Good health ,Autoimmune Diseases ,Mice ,Phenotype ,Animals ,Humans ,Lupus Erythematosus, Systemic ,Transcriptome - Abstract
The clinical course of autoimmune and infectious disease varies greatly, even between individuals with the same condition. An understanding of the molecular basis for this heterogeneity could lead to significant improvements in both monitoring and treatment. During chronic infection the process of T-cell exhaustion inhibits the immune response, facilitating viral persistence. Here we show that a transcriptional signature reflecting CD8 T-cell exhaustion is associated with poor clearance of chronic viral infection, but conversely predicts better prognosis in multiple autoimmune diseases. The development of CD8 T-cell exhaustion during chronic infection is driven both by persistence of antigen and by a lack of accessory 'help' signals. In autoimmunity, we find that where evidence of CD4 T-cell co-stimulation is pronounced, that of CD8 T-cell exhaustion is reduced. We can reproduce the exhaustion signature by modifying the balance of persistent stimulation of T-cell antigen receptors and specific CD2-induced co-stimulation provided to human CD8 T cells in vitro, suggesting that each process plays a role in dictating outcome in autoimmune disease. The 'non-exhausted' T-cell state driven by CD2-induced co-stimulation is reduced by signals through the exhaustion-associated inhibitory receptor PD-1, suggesting that induction of exhaustion may be a therapeutic strategy in autoimmune and inflammatory disease. Using expression of optimal surrogate markers of co-stimulation/exhaustion signatures in independent data sets, we confirm an association with good clinical outcome or response to therapy in infection (hepatitis C virus) and vaccination (yellow fever, malaria, influenza), but poor outcome in autoimmune and inflammatory disease (type 1 diabetes, anti-neutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosus, idiopathic pulmonary fibrosis and dengue haemorrhagic fever). Thus, T-cell exhaustion plays a central role in determining outcome in autoimmune disease and targeted manipulation of this process could lead to new therapeutic opportunities.
32. Antibody repertoire analysis in polygenic autoimmune diseases
- Author
-
Bashford-Rogers, RJM, Smith, Kenneth, and Thomas, David
- Subjects
Multifactorial Inheritance ,autoantibodies ,B-cell receptors ,autoimmunity ,antibodies ,High-Throughput Nucleotide Sequencing ,Humans ,B-cell ,3. Good health ,Autoimmune Diseases - Abstract
High-throughput sequencing of the DNA/RNA encoding antibody heavy and light chains is rapidly transforming the field of adaptive immunity. It can address key questions including (i) how the B-cell repertoire differs in health and disease and (ii) if it does differ, the point(s) in B-cell development at which this occurs. The advent of technologies, such as whole genome sequencing, offers the chance to link abnormalities in the B-cell antibody repertoire to specific genomic variants and polymorphisms. Here, we discuss the current research using B-cell antibody repertoire sequencing in three polygenic autoimmune diseases where there is good evidence for a pathological role for B-cells, namely systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. These autoimmune diseases exhibit significantly skewed B-cell receptor repertoires compared to healthy controls. Interestingly, some common repertoire defects are shared between diseases, such as elevated IGHV4-34 gene usage. B-cell clones have effectively been characterised and tracked between different tissues and blood in autoimmune disease. It has been hypothesised that these differences may signify differences in B-cell tolerance, however, the mechanisms and implications of these defects are not clear.
33. Resolving mechanisms of immune-mediated disease in primary CD4 T cells
- Author
-
Bourges, Christophe, Groff, Abigail F, Burren, Oliver S, Gerhardinger, Chiara, Mattioli, Kaia, Hutchinson, Anna, Hu, Theodore, Anand, Tanmay, Epping, Madeline W, Wallace, Chris, Smith, Kenneth Gc, Rinn, John L, and Lee, James C
- Subjects
CD4-Positive T-Lymphocytes ,super-enhancer ,CD4 T cells ,NF-kappa B ,GWAS ,Humans ,Autoimmunity ,MPRA ,Polymorphism, Single Nucleotide ,TNFAIP3 ,3. Good health - Abstract
Deriving mechanisms of immune-mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by strong linkage disequilibrium. To determine whether causal variants could be identified from their functional effects, we adapted a massively parallel reporter assay for use in primary CD4 T cells, the cell type whose regulatory DNA is most enriched for immune-mediated disease SNPs. This enabled the effects of candidate SNPs to be examined in a relevant cellular context and generated testable hypotheses into disease mechanisms. To illustrate the power of this approach, we investigated a locus that has been linked to six immune-mediated diseases but cannot be fine-mapped. By studying the lead expression-modulating SNP, we uncovered an NF-κB-driven regulatory circuit which constrains T-cell activation through the dynamic formation of a super-enhancer that upregulates TNFAIP3 (A20), a key NF-κB inhibitor. In activated T cells, this feedback circuit is disrupted-and super-enhancer formation prevented-by the risk variant at the lead SNP, leading to unrestrained T-cell activation via a molecular mechanism that appears to broadly predispose to human autoimmunity.
34. Analysis of a wild mouse promoter variant reveals a novel role for FcγRIIb in the control of the germinal center and autoimmunity
- Author
-
Espéli, Marion, Clatworthy, Menna R, Bökers, Susanne, Lawlor, Kate E, Cutler, Antony J, Köntgen, Frank, Lyons, Paul A, and Smith, Kenneth GC
- Subjects
B-Lymphocytes ,Chromatin Immunoprecipitation ,Enzyme-Linked Immunospot Assay ,Receptors, IgG ,Genetic Variation ,Autoimmunity ,Enzyme-Linked Immunosorbent Assay ,Sequence Analysis, DNA ,Flow Cytometry ,Germinal Center ,Statistics, Nonparametric ,3. Good health ,Mice, Inbred C57BL ,Transcription Factor AP-1 ,Mice ,Gene Expression Regulation ,Mutagenesis, Site-Directed ,Animals ,Gene Knock-In Techniques ,Luciferases ,Promoter Regions, Genetic ,Autoantibodies ,DNA Primers - Abstract
Genetic variants of the inhibitory Fc receptor FcγRIIb have been associated with systemic lupus erythematosus in humans and mice. The mechanism by which Fcgr2b variants contribute to the development of autoimmunity is unknown and was investigated by knocking in the most commonly conserved wild mouse Fcgr2b promoter haplotype, also associated with autoimmune-prone mouse strains, into the C57BL/6 background. We found that in the absence of an AP-1-binding site in its promoter, FcγRIIb failed to be up-regulated on activated and germinal center (GC) B cells. This resulted in enhanced GC responses, increased affinity maturation, and autoantibody production. Accordingly, in the absence of FcγRIIb activation-induced up-regulation, mice developed more severe collagen-induced arthritis and spontaneous glomerular immune complex deposition. Our data highlight how natural variation in Fcgr2b drives the development of autoimmune disease. They also show how the study of such variants using a knockin approach can provide insight into immune mechanisms not possible using conventional genetic manipulation, in this case demonstrating an unexpected critical role for the activation-induced up-regulation of FcγRIIb in controlling affinity maturation, autoantibody production, and autoimmunity.
35. Human interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance
- Author
-
Zhang, Zinan, Gothe, Florian, Pennamen, Perrine, James, John R, McDonald, David, Mata, Carlos P, Modis, Yorgo, Alazami, Anas M, Acres, Meghan, Haller, Wolfram, Bowen, Claire, Döffinger, Rainer, Sinclair, Jan, Brothers, Shannon, Zhang, Yu, Matthews, Helen F, Naudion, Sophie, Pelluard, Fanny, Alajlan, Huda, Yamazaki, Yasuhiro, Notarangelo, Luigi D, Thaventhiran, James E, Engelhardt, Karin R, Al-Mousa, Hamoud, Hambleton, Sophie, Rooryck, Caroline, Smith, Kenneth GC, and Lenardo, Michael J
- Subjects
STAT3 Transcription Factor ,Genotype ,T-Lymphocytes ,Lentivirus ,Immunity ,Immunologic Deficiency Syndromes ,Mutation, Missense ,Autoimmunity ,3. Good health ,Interleukin-2 Receptor beta Subunit ,Killer Cells, Natural ,HEK293 Cells ,Phenotype ,Mutation ,Immune Tolerance ,STAT5 Transcription Factor ,Humans ,Phosphorylation ,Alleles ,Signal Transduction - Abstract
Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) β chain (IL2RB) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the IL2RB gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rβ and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rβ expression and function. IL-2Rβ loss of function was recapitulated in a recombinant system in which IL2RB mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2Rβ also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.
36. Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations
- Author
-
William Rae, John M. Sowerby, Dorit Verhoeven, Mariam Youssef, Prasanti Kotagiri, Natalia Savinykh, Eve L. Coomber, Alexis Boneparth, Angela Chan, Chun Gong, Machiel H. Jansen, Romy du Long, Giorgia Santilli, Ilenia Simeoni, Jonathan Stephens, Kejia Wu, Marta Zinicola, Hana Lango Allen, Helen Baxendale, Dinakantha Kumararatne, Effrossyni Gkrania-Klotsas, Selma C. Scheffler Mendoza, Marco Antonio Yamazaki-Nakashimada, Laura Berrón Ruiz, Cesar Mauricio Rojas-Maruri, Saul O. Lugo Reyes, Paul A. Lyons, Anthony P. Williams, Daniel J. Hodson, Gail A. Bishop, Adrian J. Thrasher, David C. Thomas, Michael P. Murphy, Timothy J. Vyse, Joshua D. Milner, Taco W. Kuijpers, Kenneth G. C. Smith, Pathology, Rae, William [0000-0003-0095-2514], Sowerby, John M [0000-0001-6119-6965], Youssef, Mariam [0000-0002-9616-2172], Savinykh, Natalia [0000-0003-3929-2760], Coomber, Eve L [0000-0002-7093-2263], du Long, Romy [0000-0001-9679-1182], Santilli, Giorgia [0000-0003-1776-1984], Simeoni, Ilenia [0000-0001-5039-2194], Stephens, Jonathan [0000-0003-2020-9330], Wu, Kejia [0000-0002-7700-2907], Zinicola, Marta [0000-0002-3546-3297], Allen, Hana Lango [0000-0002-7803-8688], Baxendale, Helen [0000-0003-3838-3900], Kumararatne, Dinakantha [0000-0001-8438-4686], Gkrania-Klotsas, Effrossyni [0000-0002-0930-8330], Scheffler Mendoza, Selma C [0000-0001-6548-5721], Yamazaki-Nakashimada, Marco Antonio [0000-0002-7609-3923], Ruiz, Laura Berrón [0000-0002-3290-8705], Lugo Reyes, Saul O [0000-0002-3730-4150], Lyons, Paul A [0000-0001-7035-8997], Hodson, Daniel J [0000-0001-6225-2033], Bishop, Gail A [0000-0002-1291-5078], Thrasher, Adrian J [0000-0002-6097-6115], Thomas, David C [0000-0002-9738-2329], Murphy, Michael P [0000-0003-1115-9618], Kuijpers, Taco W [0000-0002-7421-3370], Smith, Kenneth GC [0000-0003-3829-4326], Apollo - University of Cambridge Repository, Graduate School, Paediatrics, Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Inflammatory diseases, and ARD - Amsterdam Reproduction and Development
- Subjects
B-Lymphocytes ,TNF Receptor-Associated Factor 3 ,Neoplasms ,Immunology ,Mutation ,Humans ,Autoimmunity ,General Medicine - Abstract
Tumor necrosis factor receptor–associated factor 3 (TRAF3) is a central regulator of immunity. TRAF3 is often somatically mutated in B cell malignancies, but its role in human immunity is not defined. Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia. Affected individuals each had monoallelic mutations in TRAF3 that reduced TRAF3 expression. Immunophenotyping showed that patients’ B cells were dysregulated, exhibiting increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and heightened inflammatory responses. Patients had mild CD4 + T cell lymphopenia, with a reduced proportion of naïve T cells but increased regulatory T cells and circulating T follicular helper cells. Guided by this clinical phenotype, targeted analyses demonstrated that common genetic variants, which also reduce TRAF3 expression, are associated with an increased risk of B cell malignancies, systemic lupus erythematosus, higher immunoglobulin levels, and bacterial infections in the wider population. Reduced TRAF3 conveys disease risks by driving B cell hyperactivity via intrinsic activation of multiple intracellular proinflammatory pathways and increased mitochondrial respiration, with a likely contribution from dysregulated T cell help. Thus, we define monogenic TRAF3 haploinsufficiency syndrome and demonstrate how common TRAF3 variants affect a range of human diseases.
- Published
- 2022
37. Human interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance
- Author
-
Sophie Hambleton, Perrine Pennamen, John R. James, Meghan Acres, Wolfram Haller, Anas M. Alazami, Yasuhiro Yamazaki, James Thaventhiran, Jan Sinclair, Yu Zhang, Rainer Doffinger, Helen F. Matthews, David MacDonald, Zinan Zhang, Sophie Naudion, Kenneth G. C. Smith, Fanny Pelluard, Huda Alajlan, Yorgo Modis, Karin R. Engelhardt, Carlos P. Mata, Claire Bowen, Florian Gothe, Caroline Rooryck, Luigi D. Notarangelo, Hamoud Al-Mousa, Michael J. Lenardo, Zhang, Zinan [0000-0003-3831-2272], Mata, Carlos P [0000-0003-3381-7431], Modis, Yorgo [0000-0002-6084-0429], Haller, Wolfram [0000-0002-0518-7383], Sinclair, Jan [0000-0002-1188-0096], Pelluard, Fanny [0000-0003-1874-2742], Notarangelo, Luigi D [0000-0002-8335-0262], Thaventhiran, James E [0000-0001-8616-074X], Hambleton, Sophie [0000-0001-7954-3267], Smith, Kenneth GC [0000-0003-3829-4326], Lenardo, Michael J [0000-0003-1584-468X], and Apollo - University of Cambridge Repository
- Subjects
STAT3 Transcription Factor ,Interleukin 2 ,Genotype ,T-Lymphocytes ,Immunology ,Mutation, Missense ,Autoimmunity ,medicine.disease_cause ,Article ,03 medical and health sciences ,0302 clinical medicine ,Aldesleukin ,Immunity ,Immune Tolerance ,STAT5 Transcription Factor ,medicine ,Humans ,Immunology and Allergy ,Phosphorylation ,Receptor ,Alleles ,Research Articles ,030304 developmental biology ,0303 health sciences ,Mutation ,business.industry ,Lentivirus ,Immunologic Deficiency Syndromes ,Peripheral tolerance ,biochemical phenomena, metabolism, and nutrition ,Immune dysregulation ,3. Good health ,Interleukin-2 Receptor beta Subunit ,Killer Cells, Natural ,HEK293 Cells ,Phenotype ,IL2RB ,business ,Signal Transduction ,030215 immunology ,medicine.drug - Abstract
Zhang et al. identify human IL-2Rβ deficiency as a cause of severe immune dysregulation. The hypomorphic gene mutations reveal variable IL-2Rβ expression and function between different lymphocyte subsets as a means of selectively modulating immune responses., Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) β chain (IL2RB) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the IL2RB gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rβ and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rβ expression and function. IL-2Rβ loss of function was recapitulated in a recombinant system in which IL2RB mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2Rβ also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2–based therapeutics for immunological diseases and cancer.
- Published
- 2019
38. FcγRIIb differentially regulates pre-immune and germinal center B cell tolerance in mouse and human
- Author
-
Limy Wong, Kenneth G. C. Smith, John M. Sowerby, Rachael Bashford-Rogers, Nagham Alouche, Alice E. Denton, Michelle A. Linterman, Marion Espéli, Smith, Kenneth [0000-0003-3829-4326], Bashford-Rogers, Rachael [0000-0002-6838-0711], Denton, Alice [0000-0002-4580-3443], Linterman, Michelle [0000-0001-6047-1996], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Male ,PROMOTER HAPLOTYPE ,Central tolerance ,Fc receptor ,General Physics and Astronomy ,Autoimmunity ,02 engineering and technology ,SUSCEPTIBILITY ,Mice ,SYSTEMIC-LUPUS-ERYTHEMATOSUS ,Receptor ,lcsh:Science ,B-Lymphocytes ,Multidisciplinary ,biology ,Cell Differentiation ,ASSOCIATION ,021001 nanoscience & nanotechnology ,Flow Cytometry ,3. Good health ,Cell biology ,Multidisciplinary Sciences ,medicine.anatomical_structure ,Science & Technology - Other Topics ,Female ,0210 nano-technology ,Algorithms ,EXPRESSION ,Science ,Enzyme-Linked Immunosorbent Assay ,Article ,Antibodies ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Immune system ,Antigen ,RECEPTOR IIB ,medicine ,Immune Tolerance ,Animals ,Humans ,FCGR2B ,B cell ,Cell Proliferation ,Autoimmune disease ,B cells ,Science & Technology ,Receptors, IgG ,Autoantibody ,Germinal center ,General Chemistry ,medicine.disease ,Germinal Center ,GENE ,POLYMORPHISM ,030104 developmental biology ,biology.protein ,Leukocytes, Mononuclear ,AUTOANTIBODIES ,lcsh:Q ,Software - Abstract
Several tolerance checkpoints exist throughout B cell development to control autoreactive B cells and prevent the generation of pathogenic autoantibodies. FcγRIIb is an Fc receptor that inhibits B cell activation and, if defective, is associated with autoimmune disease, yet its impact on specific B cell tolerance checkpoints is unknown. Here we show that reduced expression of FcγRIIb enhances the deletion and anergy of autoreactive immature B cells, but in contrast promotes autoreactive B cell expansion in the germinal center and serum autoantibody production, even in response to exogenous, non-self antigens. Our data thus show that FcγRIIb has opposing effects on pre-immune and post-immune tolerance checkpoints, and suggest that B cell tolerance requires the control of bystander germinal center B cells with low or no affinity for the immunizing antigen., The inhibitory receptor, FcγRIIb, is reported to limit autoimmune B cell response. Here the authors show that FcγRIIb has a dual role in both human and mouse, with reduced FcγRIIb expression or function associated with enhanced pre-immune B cell tolerance, yet defective control of mature autoreactive B cells in the germinal center.
- Published
- 2019
39. Resolving mechanisms of immune-mediated disease in primary CD4 T cells
- Author
-
Chris Wallace, Kaia Mattioli, Madeline W Epping, Kenneth G. C. Smith, Theodore Hu, John L. Rinn, Anna Hutchinson, James Lee, Christophe Bourges, Chiara Gerhardinger, Tanmay Anand, Abigail F. Groff, Oliver S. Burren, Wallace, Chris [0000-0001-9755-1703], Smith, Kenneth [0000-0003-3829-4326], Lee, James [0000-0001-5711-9385], Apollo - University of Cambridge Repository, Rinn, John L [0000-0002-7231-7539], and Lee, James C [0000-0001-5711-9385]
- Subjects
CD4-Positive T-Lymphocytes ,Linkage disequilibrium ,Gwas data ,CD4 T cells ,Autoimmunity ,Locus (genetics) ,Disease ,Computational biology ,Biology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,0302 clinical medicine ,super-enhancer ,Humans ,GWAS ,TNFAIP3 ,030304 developmental biology ,0303 health sciences ,Immune mediated disease ,Reporter gene ,Effector ,Disease mechanisms ,NF-kappa B ,MPRA ,3. Good health ,030220 oncology & carcinogenesis - Abstract
Deriving mechanisms of immune-mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by strong linkage disequilibrium. To determine whether causal variants could be identified from their functional effects, we adapted a massively parallel reporter assay for use in primary CD4 T cells, the cell type whose regulatory DNA is most enriched for immune-mediated disease SNPs. This enabled the effects of candidate SNPs to be examined in a relevant cellular context and generated testable hypotheses into disease mechanisms. To illustrate the power of this approach, we investigated a locus that has been linked to six immune-mediated diseases but cannot be fine-mapped. By studying the lead expression-modulating SNP, we uncovered an NF-κB-driven regulatory circuit which constrains T-cell activation through the dynamic formation of a super-enhancer that upregulates TNFAIP3 (A20), a key NF-κB inhibitor. In activated T cells, this feedback circuit is disrupted-and super-enhancer formation prevented-by the risk variant at the lead SNP, leading to unrestrained T-cell activation via a molecular mechanism that appears to broadly predispose to human autoimmunity.
- Published
- 2020
- Full Text
- View/download PDF
40. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection
- Author
-
James Lee, David Jayne, Kenneth G. C. Smith, Paul A. Lyons, Eoin F. McKinney, McKinney, Eoin [0000-0003-3516-3072], Lee, James [0000-0001-5711-9385], Jayne, David [0000-0002-1712-0637], Lyons, Paul [0000-0001-7035-8997], Smith, Kenneth [0000-0003-3829-4326], and Apollo - University of Cambridge Repository
- Subjects
CD4-Positive T-Lymphocytes ,T cell ,Programmed Cell Death 1 Receptor ,CD2 Antigens ,Receptors, Antigen, T-Cell ,Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ,Autoimmunity ,Disease ,CD8-Positive T-Lymphocytes ,Infections ,medicine.disease_cause ,Autoimmune Diseases ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,medicine ,Animals ,Humans ,Lupus Erythematosus, Systemic ,030304 developmental biology ,Inflammation ,Autoimmune disease ,0303 health sciences ,Receptors, Interleukin-7 ,Multidisciplinary ,Lupus erythematosus ,business.industry ,Inflammatory Bowel Diseases ,medicine.disease ,3. Good health ,Chronic infection ,Phenotype ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Transcriptome ,business - Abstract
The clinical course of autoimmune and infectious disease varies greatly, even between individuals with the same condition. An understanding of the molecular basis for this heterogeneity could lead to significant improvements in both monitoring and treatment. During chronic infection the process of T-cell exhaustion inhibits the immune response, facilitating viral persistence. Here we show that a transcriptional signature reflecting CD8 T-cell exhaustion is associated with poor clearance of chronic viral infection, but conversely predicts better prognosis in multiple autoimmune diseases. The development of CD8 T-cell exhaustion during chronic infection is driven both by persistence of antigen and by a lack of accessory 'help' signals. In autoimmunity, we find that where evidence of CD4 T-cell co-stimulation is pronounced, that of CD8 T-cell exhaustion is reduced. We can reproduce the exhaustion signature by modifying the balance of persistent stimulation of T-cell antigen receptors and specific CD2-induced co-stimulation provided to human CD8 T cells in vitro, suggesting that each process plays a role in dictating outcome in autoimmune disease. The 'non-exhausted' T-cell state driven by CD2-induced co-stimulation is reduced by signals through the exhaustion-associated inhibitory receptor PD-1, suggesting that induction of exhaustion may be a therapeutic strategy in autoimmune and inflammatory disease. Using expression of optimal surrogate markers of co-stimulation/exhaustion signatures in independent data sets, we confirm an association with good clinical outcome or response to therapy in infection (hepatitis C virus) and vaccination (yellow fever, malaria, influenza), but poor outcome in autoimmune and inflammatory disease (type 1 diabetes, anti-neutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosus, idiopathic pulmonary fibrosis and dengue haemorrhagic fever). Thus, T-cell exhaustion plays a central role in determining outcome in autoimmune disease and targeted manipulation of this process could lead to new therapeutic opportunities.
- Published
- 2015
41. Analysis of a wild mouse promoter variant reveals a novel role for FcγRIIb in the control of the germinal center and autoimmunity
- Author
-
Paul A. Lyons, Susanne Bökers, Frank Köntgen, Menna R. Clatworthy, Kate E. Lawlor, Kenneth G. C. Smith, Marion Espéli, Antony J. Cutler, Clatworthy, Menna [0000-0002-3340-9828], Lyons, Paul [0000-0001-7035-8997], Smith, Kenneth [0000-0003-3829-4326], and Apollo - University of Cambridge Repository
- Subjects
Chromatin Immunoprecipitation ,Enzyme-Linked Immunospot Assay ,Immunology ,Fc receptor ,Autoimmunity ,Enzyme-Linked Immunosorbent Assay ,FCGR2B ,Biology ,medicine.disease_cause ,Statistics, Nonparametric ,Affinity maturation ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Immunology and Allergy ,Gene Knock-In Techniques ,Luciferases ,Promoter Regions, Genetic ,Receptor ,Autoantibodies ,DNA Primers ,030304 developmental biology ,Autoimmune disease ,B-Lymphocytes ,0303 health sciences ,Receptors, IgG ,Genetic Variation ,Germinal center ,Sequence Analysis, DNA ,Flow Cytometry ,Germinal Center ,medicine.disease ,3. Good health ,Mice, Inbred C57BL ,Transcription Factor AP-1 ,Gene Expression Regulation ,Mutagenesis, Site-Directed ,biology.protein ,Chromatin immunoprecipitation ,030215 immunology - Abstract
Genetic variants of the inhibitory Fc receptor FcγRIIb have been associated with systemic lupus erythematosus in humans and mice. The mechanism by which Fcgr2b variants contribute to the development of autoimmunity is unknown and was investigated by knocking in the most commonly conserved wild mouse Fcgr2b promoter haplotype, also associated with autoimmune-prone mouse strains, into the C57BL/6 background. We found that in the absence of an AP-1–binding site in its promoter, FcγRIIb failed to be up-regulated on activated and germinal center (GC) B cells. This resulted in enhanced GC responses, increased affinity maturation, and autoantibody production. Accordingly, in the absence of FcγRIIb activation–induced up-regulation, mice developed more severe collagen-induced arthritis and spontaneous glomerular immune complex deposition. Our data highlight how natural variation in Fcgr2b drives the development of autoimmune disease. They also show how the study of such variants using a knockin approach can provide insight into immune mechanisms not possible using conventional genetic manipulation, in this case demonstrating an unexpected critical role for the activation-induced up-regulation of FcγRIIb in controlling affinity maturation, autoantibody production, and autoimmunity.
- Published
- 2012
42. A type I interferon transcriptional signature precedes autoimmunity in children genetically at risk for type 1 diabetes
- Author
-
Shaun M. Flint, Anette-G. Ziegler, Paul A. Lyons, John A. Todd, Kenneth G. C. Smith, Eoin F. McKinney, Hui Guo, David B. Dunger, Marcin L. Pekalski, Antony J. Cutler, Peter Achenbach, Ricardo C. Ferreira, Oliver S. Burren, David Clayton, Linda S. Wicker, Andreas Beyerlein, Chris Wallace, Deborah J. Smyth, James D. Doecke, Ezio Bonifacio, Richard M.R. Coulson, Burren, Oliver [0000-0002-3388-5760], McKinney, Eoin [0000-0003-3516-3072], Lyons, Paul [0000-0001-7035-8997], Smith, Kenneth [0000-0003-3829-4326], Dunger, David [0000-0002-2566-9304], Wallace, Chris [0000-0001-9755-1703], and Apollo - University of Cambridge Repository
- Subjects
Adult ,Male ,Risk ,endocrine system diseases ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Autoimmunity ,Biology ,medicine.disease_cause ,Transcriptome ,Cohort Studies ,Young Adult ,Interferon ,Internal Medicine ,medicine ,Genetic predisposition ,HLA-DQ beta-Chains ,Humans ,Genetic Predisposition to Disease ,Child ,Autoimmune disease ,Type 1 diabetes ,Autoantibody ,Genetics/Genomes/Proteomics/Metabolomics ,Middle Aged ,medicine.disease ,Immunity, Innate ,Diabetes Mellitus, Type 1 ,Gene Expression Regulation ,Immunology ,Interferon Type I ,Female ,Interferon type I ,medicine.drug - Abstract
Diagnosis of the autoimmune disease type 1 diabetes (T1D) is preceded by the appearance of circulating autoantibodies to pancreatic islets. However, almost nothing is known about events leading to this islet autoimmunity. Previous epidemiological and genetic data have associated viral infections and antiviral type I interferon (IFN) immune response genes with T1D. Here, we first used DNA microarray analysis to identify IFN-β–inducible genes in vitro and then used this set of genes to define an IFN-inducible transcriptional signature in peripheral blood mononuclear cells from a group of active systemic lupus erythematosus patients (n = 25). Using this predefined set of 225 IFN signature genes, we investigated the expression of the signature in cohorts of healthy controls (n = 87), patients with T1D (n = 64), and a large longitudinal birth cohort of children genetically predisposed to T1D (n = 109; 454 microarrayed samples). Expression of the IFN signature was increased in genetically predisposed children before the development of autoantibodies (P = 0.0012) but not in patients with established T1D. Upregulation of IFN-inducible genes was transient, temporally associated with a recent history of upper respiratory tract infections (P = 0.0064), and marked by increased expression of SIGLEC-1 (CD169), a lectin-like receptor expressed on CD14+ monocytes. DNA variation in IFN-inducible genes altered T1D risk (P = 0.007), as exemplified by IFIH1, one of the genes in our IFN signature for which increased expression is a known risk factor for disease. These findings identify transient increased expression of type I IFN genes in preclinical diabetes as a risk factor for autoimmunity in children with a genetic predisposition to T1D.
- Published
- 2014
43. Lipid anti-lipid antibody responses correlate with disease activity in systemic lupus erythematosus
- Author
-
Nurhuda Abdul Aziz, Michael D. Kemeny, Sherlynn Jin Hui Chan, Eliza Ho Xin Pei, Paul A. Lyons, Markus R. Wenk, Andrew M. Jenner, Eoin F. McKinney, Amanda Ng Ai Poh, Paul A. MacAry, Guanghou Shui, Fei Chuin Lew, Li Bowen, Kenneth G. C. Smith, Yan Ting Lim, Vojislav Jovanovic, McKinney, Eoin [0000-0003-3516-3072], Lyons, Paul [0000-0001-7035-8997], Smith, Kenneth [0000-0003-3829-4326], and Apollo - University of Cambridge Repository
- Subjects
Autoimmunity ,Disease ,Biochemistry ,Immunoglobulin G ,Cohort Studies ,chemistry.chemical_compound ,0302 clinical medicine ,immune system diseases ,Pathology ,Cardiolipin ,Medicine ,Lupus Erythematosus, Systemic ,skin and connective tissue diseases ,Immune Response ,0303 health sciences ,Multidisciplinary ,Systemic lupus erythematosus ,biology ,Lipids ,3. Good health ,Cohort ,lipids (amino acids, peptides, and proteins) ,Antibody ,Research Article ,Test Evaluation ,Clinical Research Design ,Science ,Immunology ,Immunoglobulins ,Enzyme-Linked Immunosorbent Assay ,Systemic Lupus Erythematosus ,Gas Chromatography-Mass Spectrometry ,Autoimmune Diseases ,03 medical and health sciences ,Immune system ,Rheumatology ,Diagnostic Medicine ,Humans ,Biology ,030304 developmental biology ,Autoantibodies ,030203 arthritis & rheumatology ,business.industry ,Autoantibody ,medicine.disease ,chemistry ,biology.protein ,Clinical Immunology ,business ,Biomarkers ,General Pathology - Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by broad clinical manifestations including cardiovascular and renal complications with periodic disease flares and significant morbidity and mortality. One of the main contributing factors to the pathology of SLE is the accumulation and impaired clearance of immune complexes of which the principle components are host auto-antigens and antibodies. The contribution of host lipids to the formation of these autoimmune complexes remains poorly defined. The aim of the present study was to identify and analyze candidate lipid autoantigens and their corresponding anti-lipid antibody responses in a well-defined SLE patient cohort using a combination of immunological and biophysical techniques. Disease monitoring in the SLE cohort was undertaken with serial British Isles Lupus Assessment Group (BILAG) scoring. Correlations between specific lipid/anti-lipid responses were investigated as disease activity developed from active flares to quiescent during a follow up period. We report a significant negative correlation between anti-lipid antibodies for 24S-hydroxycholesterol, cardiolipin and phosphatidylserine with SLE disease activity. Taken together, these data suggest that lipid autoantigens represent a new family of biomarkers that can be employed to monitor disease activity plus the efficacy of therapeutic intervention in SLE.
- Published
- 2013
44. A CD8+ T cell transcription signature predicts prognosis in autoimmune disease
- Author
-
Kenneth G. C. Smith, Alvis Brazma, Andrew J. Pollard, D. Michael Kemeny, Eoin F. McKinney, Lisa C. Willcocks, Paul A. Lyons, Afzal N. Chaudhry, Edward J. Carr, Maria Koukoulaki, Vojislav Jovanovic, Jane L Hollis, Paul A. MacAry, David Jayne, McKinney, Eoin [0000-0003-3516-3072], Lyons, Paul [0000-0001-7035-8997], Carr, Edward [0000-0001-9343-4593], Jayne, David [0000-0002-1712-0637], Smith, Kenneth [0000-0003-3829-4326], and Apollo - University of Cambridge Repository
- Subjects
Vasculitis ,T-Lymphocytes ,T cell ,Population ,Receptors, Antigen, T-Cell ,Gene Expression ,Autoimmunity ,CD8-Positive T-Lymphocytes ,Biology ,medicine.disease_cause ,Article ,General Biochemistry, Genetics and Molecular Biology ,Antibodies, Antineutrophil Cytoplasmic ,Autoimmune Diseases ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Lupus Erythematosus, Systemic ,Cytotoxic T cell ,education ,030304 developmental biology ,Inflammation ,030203 arthritis & rheumatology ,Autoimmune disease ,0303 health sciences ,education.field_of_study ,Lupus erythematosus ,Dose-Response Relationship, Drug ,Interleukin-7 ,Autoantibody ,General Medicine ,Prognosis ,medicine.disease ,3. Good health ,medicine.anatomical_structure ,Immunology ,Immunosuppressive Agents ,CD8 ,Signal Transduction - Abstract
Autoimmune diseases are common and debilitating, but their severe manifestations could be reduced if biomarkers were available to allow individual tailoring of potentially toxic immunosuppressive therapy. Gene expression-based biomarkers facilitating such tailoring of chemotherapy in cancer, but not autoimmunity, have been identified and translated into clinical practice. We show that transcriptional profiling of purified CD8(+) T cells, which avoids the confounding influences of unseparated cells, identifies two distinct subject subgroups predicting long-term prognosis in two autoimmune diseases, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), a chronic, severe disease characterized by inflammation of medium-sized and small blood vessels, and systemic lupus erythematosus (SLE), characterized by autoantibodies, immune complex deposition and diverse clinical manifestations ranging from glomerulonephritis to neurological dysfunction. We show that the subset of genes defining the poor prognostic group is enriched for genes involved in the interleukin-7 receptor (IL-7R) pathway and T cell receptor (TCR) signaling and those expressed by memory T cells. Furthermore, the poor prognostic group is associated with an expanded CD8(+) T cell memory population. These subgroups, which are also found in the normal population and can be identified by measuring expression of only three genes, raise the prospect of individualized therapy and suggest new potential therapeutic targets in autoimmunity.
- Published
- 2010
45. Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake
- Author
-
Yu-Lung Lau, Menna R. Clatworthy, Wanling Yang, Edwin R. Chilvers, Vincent Plagnol, Elaine C. Jolly, James I. Robinson, Richard A. Watts, Paul A. Lyons, Naomi McGovern, Lisa C. Willcocks, Stephen A. Newland, Gerard B. Nash, Kenneth G. C. Smith, Alison M. Condliffe, Ann W. Morgan, Dwomoa Adu, Lyons, Paul [0000-0001-7035-8997], Clatworthy, Menna [0000-0002-3340-9828], McGovern, Naomi [0000-0001-5200-2698], Chilvers, Edwin [0000-0002-4230-9677], Smith, Kenneth [0000-0003-3829-4326], and Apollo - University of Cambridge Repository
- Subjects
Male ,Neutrophils ,Gene Dosage ,Autoimmunity ,Antigen-Antibody Complex ,Research & Experimental Medicine ,SUSCEPTIBILITY ,medicine.disease_cause ,DISEASE ,0302 clinical medicine ,Gene Dosage - genetics - immunology ,Immunology and Allergy ,Lupus Erythematosus, Systemic ,11 Medical and Health Sciences ,0303 health sciences ,HUMAN NEUTROPHILS ,FCGR3B ,Immune complex ,3. Good health ,Medicine, Research & Experimental ,030220 oncology & carcinogenesis ,Female ,Life Sciences & Biomedicine ,CD16 ,Systemic vasculitis ,Vasculitis ,Gene Expression Regulation - genetics - immunology ,Immunology ,European Continental Ancestry Group ,Biology ,FC-GAMMA-RIII ,GPI-Linked Proteins ,White People ,PHAGOCYTOSIS ,Antibodies, Antineutrophil Cytoplasmic ,03 medical and health sciences ,Immune system ,RECEPTOR IIB ,medicine ,Humans ,Antigen-Antibody Complex - genetics - immunology ,RESPIRATORY BURST ,Genetic Predisposition to Disease ,POLYMORPHISMS ,030304 developmental biology ,Autoimmune disease ,Science & Technology ,Immune complex clearance ,Receptors, IgG ,Brief Definitive Report ,Genetic Variation ,Genetic Variation - immunology ,medicine.disease ,GENE ,Gene Expression Regulation ,Brief Definitive Reports - Abstract
Copy number (CN) variation (CNV) has been shown to be common in regions of the genome coding for immune-related genes, and thus impacts upon polygenic autoimmunity. Low CN of FCGR3B has recently been associated with systemic lupus erythematosus (SLE). FcγRIIIb is a glycosylphosphatidylinositol-linked, low affinity receptor for IgG found predominantly on human neutrophils. We present novel data demonstrating that both in a family with FcγRIIIb- deficiency and in the normal population, FCGR3B CNV correlates with protein expression, with neutrophil uptake of and adherence to immune complexes, and with soluble serum FcγRIIIb. Reduced FcyRIIIb expression is thus likely to contribute to the impaired clearance of immune complexes, which is a feature of SLE, explaining the association between low FCGR3B CNV and SLE that we have confirmed in a Caucasian population. In contrast, antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV), a disease not associated with immune complex deposition, is associated with high FCGR3B CN. Thus, we define a role for FCGR3B CNV in immune complex clearance, a function that may explain why low FCGR3B CNV is associated with SLE, but not AASV. This is the first report of an association between disease-related gene CNV and variation in protein expression and function that may contribute to autoimmune disease susceptibility., published_or_final_version
- Published
- 2008
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.