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Anti-Insulin B Cells Are Poised for Antigen Presentation in Type 1 Diabetes.
Felton JL, Maseda D, Bonami RH, Hulbert C, Thomas JW
(2018) J Immunol 201: 861-873
MeSH Terms: Animals, Antigen Presentation, Autoantibodies, Autoantigens, B-Lymphocyte Subsets, Diabetes Mellitus, Type 1, Female, Immune Tolerance, Inflammation, Insulin, Insulin Antibodies, Lymphocyte Activation, Male, Mice, Mice, Inbred NOD, Mice, Transgenic, Receptors, Antigen, B-Cell
Show Abstract · Added July 20, 2018
Early breaches in B cell tolerance are central to type 1 diabetes progression in mouse and man. Conventional BCR transgenic mouse models (VH125.Tg NOD) reveal the power of B cell specificity to drive disease as APCs. However, in conventional fixed IgM models, comprehensive assessment of B cell development is limited. To provide more accurate insight into the developmental and functional fates of anti-insulin B cells, we generated a new NOD model (V125NOD) in which anti-insulin VDJH125 is targeted to the IgH chain locus to generate a small (1-2%) population of class switch-competent insulin-binding B cells. Tracking of this rare population in a polyclonal repertoire reveals that anti-insulin B cells are preferentially skewed into marginal zone and late transitional subsets known to have increased sensitivity to proinflammatory signals. Additionally, IL-10 production, characteristic of regulatory B cell subsets, is increased. In contrast to conventional models, class switch-competent anti-insulin B cells proliferate normally in response to mitogenic stimuli but remain functionally silent for insulin autoantibody production. Diabetes development is accelerated, which demonstrates the power of anti-insulin B cells to exacerbate disease without differentiation into Ab-forming or plasma cells. Autoreactive T cell responses in V125NOD mice are not restricted to insulin autoantigens, as evidenced by increased IFN-γ production to a broad array of diabetes-associated epitopes. Together, these results independently validate the pathogenic role of anti-insulin B cells in type 1 diabetes, underscore their diverse developmental fates, and demonstrate the pathologic potential of coupling a critical β cell specificity to predominantly proinflammatory Ag-presenting B cell subsets.
Copyright © 2018 by The American Association of Immunologists, Inc.
1 Communities
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17 MeSH Terms
The susceptible HLA class II alleles and their presenting epitope(s) in Goodpasture's disease.
Xie LJ, Cui Z, Chen FJ, Pei ZY, Hu SY, Gu QH, Jia XY, Zhu L, Zhou XJ, Zhang H, Liao YH, Lai LH, Hudson BG, Zhao MH
(2017) Immunology 151: 395-404
MeSH Terms: Alleles, Anti-Glomerular Basement Membrane Disease, Autoantigens, China, Collagen Type IV, Computer Simulation, Epitope Mapping, Epitopes, T-Lymphocyte, Genetic Predisposition to Disease, Genotype, HLA-DRB1 Chains, Humans, Polymorphism, Genetic, Protein Binding, Protein Conformation, Receptors, Antigen, T-Cell, Risk, T-Lymphocytes
Show Abstract · Added May 12, 2017
Goodpasture's disease is closely associated with HLA, particularly DRB1*1501. Other susceptible or protective HLA alleles are not clearly elucidated. The presentation models of epitopes by susceptible HLA alleles are also unclear. We genotyped 140 Chinese patients and 599 controls for four-digit HLA II genes, and extracted the encoding sequences from the IMGT/HLA database. T-cell epitopes of α3(IV)NC1 were predicted and the structures of DR molecule-peptide-T-cell receptor were constructed. We confirmed DRB1*1501 (OR = 4·6, P = 5·7 × 10 ) to be a risk allele for Goodpasture's disease. Arginine at position 13 (ARG13) (OR = 4·0, P = 1·0 × 10 ) and proline at position 11 (PRO11) (OR = 4·0, P = 2·0 × 10 ) on DRβ1, encoded by DRB1*1501, were associated with disease susceptibility. α (HGWISLWKGFSFIMF) was predicted as a T-cell epitope presented by DRB1*1501. Isoleucine , tryptophan , glycine , phenylalanine and phenylalanine , were presented in peptide-binding pockets 1, 4, 6, 7 and 9 of DR2b, respectively. ARG13 in pocket 4 interacts with tryptophan and forms a hydrogen bond. In conclusion, we propose a mechanism for DRB1*1501 susceptibility for Goodpasture's disease through encoding ARG13 and PRO11 on MHC-DRβ1 chain and presenting T-cell epitope, α , with five critical residues.
© 2017 John Wiley & Sons Ltd.
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18 MeSH Terms
Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes.
Babon JA, DeNicola ME, Blodgett DM, Crèvecoeur I, Buttrick TS, Maehr R, Bottino R, Naji A, Kaddis J, Elyaman W, James EA, Haliyur R, Brissova M, Overbergh L, Mathieu C, Delong T, Haskins K, Pugliese A, Campbell-Thompson M, Mathews C, Atkinson MA, Powers AC, Harlan DM, Kent SC
(2016) Nat Med 22: 1482-1487
MeSH Terms: Adolescent, Adult, Autoantigens, Autoimmunity, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Child, Diabetes Mellitus, Type 1, Female, HLA-A2 Antigen, HLA-DQ Antigens, Humans, Islets of Langerhans, Male, T-Lymphocytes, Young Adult
Show Abstract · Added April 26, 2017
A major therapeutic goal for type 1 diabetes (T1D) is to induce autoantigen-specific tolerance of T cells. This could suppress autoimmunity in those at risk for the development of T1D, as well as in those with established disease who receive islet replacement or regeneration therapy. Because functional studies of human autoreactive T cell responses have been limited largely to peripheral blood-derived T cells, it is unclear how representative the peripheral T cell repertoire is of T cells infiltrating the islets. Our knowledge of the insulitic T cell repertoire is derived from histological and immunohistochemical analyses of insulitis, the identification of autoreactive CD8 T cells in situ, in islets of human leukocyte antigen (HLA)-A2 donors and isolation and identification of DQ8 and DQ2-DQ8 heterodimer-restricted, proinsulin-reactive CD4 T cells grown from islets of a single donor with T1D. Here we present an analysis of 50 of a total of 236 CD4 and CD8 T cell lines grown from individual handpicked islets or clones directly sorted from handpicked, dispersed islets from nine donors with T1D. Seventeen of these T cell lines and clones reacted to a broad range of studied native islet antigens and to post-translationally modified peptides. These studies demonstrate the existence of a variety of islet-infiltrating, islet-autoantigen reactive T cells in individuals with T1D, and these data have implications for the design of successful immunotherapies.
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16 MeSH Terms
Determinants of VH1-46 Cross-Reactivity to Pemphigus Vulgaris Autoantigen Desmoglein 3 and Rotavirus Antigen VP6.
Cho MJ, Ellebrecht CT, Hammers CM, Mukherjee EM, Sapparapu G, Boudreaux CE, McDonald SM, Crowe JE, Payne AS
(2016) J Immunol 197: 1065-73
MeSH Terms: Antigens, Viral, Autoantigens, Capsid Proteins, Cross Reactions, Desmoglein 3, Dual-Specificity Phosphatases, Enzyme-Linked Immunosorbent Assay, High-Throughput Screening Assays, Humans, Microscopy, Fluorescence, Pemphigus, Polymerase Chain Reaction, Rotavirus Infections
Show Abstract · Added April 13, 2017
Shared VH1-46 gene usage has been described in B cells reacting to desmoglein 3 (Dsg3) in the autoimmune disease pemphigus vulgaris (PV), as well as B cells responding to rotavirus capsid protein VP6. In both diseases, VH1-46 B cells bearing few to no somatic mutations can recognize the disease Ag. This intriguing connection between an autoimmune response to self-antigen and an immune response to foreign Ag prompted us to investigate whether VH1-46 B cells may be predisposed to Dsg3-VP6 cross-reactivity. Focused testing of VH1-46 mAbs previously isolated from PV and rotavirus-exposed individuals indicates that cross-reactivity is rare, found in only one of seven VH1-46 IgG clonotypes. High-throughput screening of IgG B cell repertoires from two PV patients identified no additional cross-reactive clonotypes. Screening of IgM B cell repertoires from one non-PV and three PV patients identified specific cross-reactive Abs in one PV patient, but notably all six cross-reactive clonotypes used VH1-46. Site-directed mutagenesis studies indicate that amino acid residues predisposing VH1-46 Abs to Dsg3 reactivity reside in CDR2. However, somatic mutations only rarely promote Dsg3-VP6 cross-reactivity; most mutations abolish VP6 and/or Dsg3 reactivity. Nevertheless, functional testing identified two cross-reactive VH1-46 Abs that both disrupt keratinocyte adhesion and inhibit rotavirus replication, indicating the potential for VH1-46 Abs to have both pathologic autoimmune and protective immune functions. Taken together, these studies suggest that certain VH1-46 B cell populations may be predisposed to Dsg3-VP6 cross-reactivity, but multiple mechanisms prevent the onset of autoimmunity after rotavirus exposure.
Copyright © 2016 by The American Association of Immunologists, Inc.
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13 MeSH Terms
Antibodies to α5 chain of collagen IV are pathogenic in Goodpasture's disease.
Cui Z, Zhao MH, Jia XY, Wang M, Hu SY, Wang SX, Yu F, Brown KL, Hudson BG, Pedchenko V
(2016) J Autoimmun 70: 1-11
MeSH Terms: Aged, Amino Acid Sequence, Animals, Anti-Glomerular Basement Membrane Disease, Autoantibodies, Autoantigens, Autoimmunity, Biopsy, Case-Control Studies, Cell Line, Tumor, Collagen Type IV, Disease Models, Animal, Epitope Mapping, Epitopes, Female, Humans, Kidney Glomerulus, Male, Models, Molecular, Protein Conformation, Protein Subunits, Rats, Rats, Inbred WKY
Show Abstract · Added June 14, 2016
Autoantibody against glomerular basement membrane (GBM) plays a direct role in the initiation and development of Goodpasture's (GP) disease. The principal autoantigen is the non-collagenous domain 1 (NC1) of α3 chain of collagen IV, with two immunodominant epitopes, EA-α3 and EB-α3. We recently demonstrated that antibodies targeting α5NC1 are bound to kidneys in GP patients, suggesting their pathogenic relevance. In the present study, we sought to assess the pathogenicity of the α5 autoantibody with clinical and animal studies. Herein, we present a special case of GP disease with circulating autoantibody reactive exclusively to the α5NC1 domain. This autoantibody reacted with conformational epitopes within GBM collagen IV hexamer and produced a linear IgG staining on frozen sections of human kidney. The antibody binds to the two regions within α5NC1 domain, EA and EB, and inhibition ELISA indicates that they are targeted by distinct sub-populations of autoantibodies. Sequence analysis highlights five residues that determine specificity of antibody targeting EA and EB epitopes of α5NC1 over homologous regions in α3NC1. Furthermore, immunization with recombinant α5NC1 domain induced crescentic glomerulonephritis and alveolar hemorrhage in Wistar-Kyoto rats. Thus, patient data and animal studies together reveal the pathogenicity of α5 antibodies. Given previously documented cases of GP disease with antibodies selectively targeting α3NC1 domain, our data presents a conundrum of why α3-specific antibodies developing in majority of GP patients, with α5-specific antibodies emerged in isolated cases, the answer for which is critical for understanding of etiology and progression of the GP disease.
Copyright © 2016 Elsevier Ltd. All rights reserved.
1 Communities
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23 MeSH Terms
Targeting Anti-Insulin B Cell Receptors Improves Receptor Editing in Type 1 Diabetes-Prone Mice.
Bonami RH, Thomas JW
(2015) J Immunol 195: 4730-41
MeSH Terms: Animals, Antibodies, Monoclonal, Autoantigens, Autoimmunity, B-Lymphocytes, DNA-Binding Proteins, Diabetes Mellitus, Type 1, Immune Tolerance, Immunoglobulin M, Immunoglobulin kappa-Chains, Immunomodulation, Insulin, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Molecular Sequence Data, Receptors, Antigen, B-Cell
Show Abstract · Added April 1, 2016
Autoreactive B lymphocytes that commonly arise in the developing repertoire can be salvaged by receptor editing, a central tolerance mechanism that alters BCR specificity through continued L chain rearrangement. It is unknown whether autoantigens with weak cross-linking potential, such as insulin, elicit receptor editing, or whether this process is dysregulated in related autoimmunity. To resolve these issues, we developed an editing-competent model in which anti-insulin Vκ125 was targeted to the Igκ locus and paired with anti-insulin VH125Tg. Physiologic, circulating insulin increased RAG-2 expression and was associated with BCR replacement that eliminated autoantigen recognition in a proportion of developing anti-insulin B lymphocytes. The proportion of anti-insulin B cells that underwent receptor editing was reduced in the type 1 diabetes-prone NOD strain relative to a nonautoimmune strain. Resistance to editing was associated with increased surface IgM expression on immature (but not transitional or mature) anti-insulin B cells in the NOD strain. The actions of mAb123 on central tolerance were also investigated, because selective targeting of insulin-occupied BCR by mAb123 eliminates anti-insulin B lymphocytes and prevents type 1 diabetes. Autoantigen targeting by mAb123 increased RAG-2 expression and dramatically enhanced BCR replacement in newly developed B lymphocytes. Administering F(ab')2123 induced IgM downregulation and reduced the frequency of anti-insulin B lymphocytes within the polyclonal repertoire of VH125Tg/NOD mice, suggesting enhanced central tolerance by direct BCR interaction. These findings indicate that weak or faulty checkpoints for central tolerance can be overcome by autoantigen-specific immunomodulatory therapy.
Copyright © 2015 by The American Association of Immunologists, Inc.
2 Communities
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17 MeSH Terms
Defective structural RNA processing in relapsing-remitting multiple sclerosis.
Spurlock CF, Tossberg JT, Guo Y, Sriram S, Crooke PS, Aune TM
(2015) Genome Biol 16: 58
MeSH Terms: Autoantigens, Gene Expression, Genomic Structural Variation, High-Throughput Nucleotide Sequencing, Humans, Leukocytes, Mononuclear, Multiple Sclerosis, Relapsing-Remitting, Phosphoproteins, Poly A, RNA Splicing, RNA Stability, RNA, Ribosomal, 18S, RNA, Ribosomal, 28S, RNA, Small Cytoplasmic, RNA, Small Interfering, Ribonucleoproteins
Show Abstract · Added April 18, 2017
BACKGROUND - Surveillance of integrity of the basic elements of the cell including DNA, RNA, and proteins is a critical element of cellular physiology. Mechanisms of surveillance of DNA and protein integrity are well understood. Surveillance of structural RNAs making up the vast majority of RNA in a cell is less well understood. Here, we sought to explore integrity of processing of structural RNAs in relapsing remitting multiple sclerosis (RRMS) and other inflammatory diseases.
RESULTS - We employed mononuclear cells obtained from subjects with RRMS and cell lines. We used quantitative-PCR and whole genome RNA sequencing to define defects in structural RNA surveillance and siRNAs to deplete target proteins. We report profound defects in surveillance of structural RNAs in RRMS exemplified by elevated levels of poly(A) + Y1-RNA, poly(A) + 18S rRNA and 28S rRNAs, elevated levels of misprocessed 18S and 28S rRNAs and levels of the U-class of small nuclear RNAs. Multiple sclerosis is also associated with genome-wide defects in mRNA splicing. Ro60 and La proteins, which exist in ribonucleoprotein particles and play different roles in quality control of structural RNAs, are also deficient in RRMS. In cell lines, silencing of the genes encoding Ro60 and La proteins gives rise to these same defects in surveillance of structural RNAs.
CONCLUSIONS - Our results establish that profound defects in structural RNA surveillance exist in RRMS and establish a causal link between Ro60 and La proteins and integrity of structural RNAs.
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16 MeSH Terms
Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways.
Gomez IG, MacKenna DA, Johnson BG, Kaimal V, Roach AM, Ren S, Nakagawa N, Xin C, Newitt R, Pandya S, Xia TH, Liu X, Borza DB, Grafals M, Shankland SJ, Himmelfarb J, Portilla D, Liu S, Chau BN, Duffield JS
(2015) J Clin Invest 125: 141-56
MeSH Terms: Animals, Autoantigens, Collagen Type IV, Disease Progression, Fibrosis, Kidney, Metabolic Networks and Pathways, Mice, 129 Strain, MicroRNAs, Nephritis, Hereditary, Oligoribonucleotides, Antisense, Reactive Oxygen Species, Transcriptome, Up-Regulation
Show Abstract · Added December 2, 2016
MicroRNA-21 (miR-21) contributes to the pathogenesis of fibrogenic diseases in multiple organs, including the kidneys, potentially by silencing metabolic pathways that are critical for cellular ATP generation, ROS production, and inflammatory signaling. Here, we developed highly specific oligonucleotides that distribute to the kidney and inhibit miR-21 function when administered subcutaneously and evaluated the therapeutic potential of these anti-miR-21 oligonucleotides in chronic kidney disease. In a murine model of Alport nephropathy, miR-21 silencing did not produce any adverse effects and resulted in substantially milder kidney disease, with minimal albuminuria and dysfunction, compared with vehicle-treated mice. miR-21 silencing dramatically improved survival of Alport mice and reduced histological end points, including glomerulosclerosis, interstitial fibrosis, tubular injury, and inflammation. Anti-miR-21 enhanced PPARα/retinoid X receptor (PPARα/RXR) activity and downstream signaling pathways in glomerular, tubular, and interstitial cells. Moreover, miR-21 silencing enhanced mitochondrial function, which reduced mitochondrial ROS production and thus preserved tubular functions. Inhibition of miR-21 was protective against TGF-β-induced fibrogenesis and inflammation in glomerular and interstitial cells, likely as the result of enhanced PPARα/RXR activity and improved mitochondrial function. Together, these results demonstrate that inhibition of miR-21 represents a potential therapeutic strategy for chronic kidney diseases including Alport nephropathy.
1 Communities
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14 MeSH Terms
Spatial control of Cdc42 signalling by a GM130-RasGRF complex regulates polarity and tumorigenesis.
Baschieri F, Confalonieri S, Bertalot G, Di Fiore PP, Dietmaier W, Leist M, Crespo P, Macara IG, Farhan H
(2014) Nat Commun 5: 4839
MeSH Terms: Antigens, CD, Autoantigens, Cadherins, Carcinogenesis, Cell Line, Tumor, Cell Polarity, Gene Expression Regulation, Neoplastic, Gene Silencing, Humans, MAP Kinase Signaling System, MCF-7 Cells, Membrane Proteins, Mitogen-Activated Protein Kinase 3, Rho Guanine Nucleotide Exchange Factors, Signal Transduction, cdc42 GTP-Binding Protein, ras Guanine Nucleotide Exchange Factors, ras-GRF1
Show Abstract · Added April 10, 2018
The small GTPase Cdc42 is a key regulator of polarity, but little is known in mammals about its spatial regulation and the relevance of spatial Cdc42 pools for polarity. Here we report the identification of a GM130-RasGRF complex as a regulator of Cdc42 at the Golgi. Silencing GM130 results in RasGRF-dependent inhibition of the Golgi pool of Cdc42, but does not affect Cdc42 at the cell surface. Furthermore, active Cdc42 at the Golgi is important to sustain asymmetric front-rear Cdc42-GTP distribution in directionally migrating cells. Concurrent to Cdc42 inhibition, silencing GM130 also results in RasGRF-dependent Ras-ERK pathway activation. Moreover, depletion of GM130 is sufficient to induce E-cadherin downregulation, indicative of a loss in cell polarity and epithelial identity. Accordingly, GM130 expression is frequently lost in colorectal and breast cancer patients. These findings establish a previously unrecognized role for a GM130-RasGRF-Cdc42 connection in regulating polarity and tumorigenesis.
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18 MeSH Terms
Neonatal Fc receptor promotes immune complex-mediated glomerular disease.
Olaru F, Luo W, Suleiman H, St John PL, Ge L, Mezo AR, Shaw AS, Abrahamson DR, Miner JH, Borza DB
(2014) J Am Soc Nephrol 25: 918-25
MeSH Terms: Albuminuria, Animals, Anti-Glomerular Basement Membrane Disease, Antigen-Antibody Complex, Autoantigens, Collagen Type IV, Glomerulonephritis, HEK293 Cells, Histocompatibility Antigens Class I, Humans, Immunoglobulin G, Male, Mice, Mice, Inbred C57BL, Receptors, Fc
Show Abstract · Added December 2, 2016
The neonatal Fc receptor (FcRn) is a major regulator of IgG and albumin homeostasis systemically and in the kidneys. We investigated the role of FcRn in the development of immune complex-mediated glomerular disease in mice. C57Bl/6 mice immunized with the noncollagenous domain of the α3 chain of type IV collagen (α3NC1) developed albuminuria associated with granular capillary loop deposition of exogenous antigen, mouse IgG, C3 and C5b-9, and podocyte injury. High-resolution imaging showed abundant IgG deposition in the expanded glomerular basement membrane, especially in regions corresponding to subepithelial electron dense deposits. FcRn-null and -humanized mice immunized with α3NC1 developed no albuminuria and had lower levels of serum IgG anti-α3NC1 antibodies and reduced glomerular deposition of IgG, antigen, and complement. Our results show that FcRn promotes the formation of subepithelial immune complexes and subsequent glomerular pathology leading to proteinuria, potentially by maintaining higher serum levels of pathogenic IgG antibodies. Therefore, reducing pathogenic IgG levels by pharmacologic inhibition of FcRn may provide a novel approach for the treatment of immune complex-mediated glomerular diseases. As proof of concept, we showed that a peptide inhibiting the interaction between human FcRn and human IgG accelerated the degradation of human IgG anti-α3NC1 autoantibodies injected into FCRN-humanized mice as effectively as genetic ablation of FcRn, thus preventing the glomerular deposition of immune complexes containing human IgG.
Copyright © 2014 by the American Society of Nephrology.
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15 MeSH Terms