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HCV Broadly Neutralizing Antibodies Use a CDRH3 Disulfide Motif to Recognize an E2 Glycoprotein Site that Can Be Targeted for Vaccine Design.
Flyak AI, Ruiz S, Colbert MD, Luong T, Crowe JE, Bailey JR, Bjorkman PJ
(2018) Cell Host Microbe 24: 703-716.e3
MeSH Terms: Antibodies, Neutralizing, Antibodies, Viral, Binding Sites, Disulfides, Drug Design, Epitopes, Hepacivirus, Hepatitis C, Hepatitis C Antibodies, Humans, Immunoglobulin G, Models, Molecular, Protein Conformation, Sequence Alignment, Viral Envelope Proteins, Viral Hepatitis Vaccines, X-Ray Diffraction
Show Abstract · Added March 31, 2019
Hepatitis C virus (HCV) vaccine efforts are hampered by the extensive genetic diversity of HCV envelope glycoproteins E1 and E2. Structures of broadly neutralizing antibodies (bNAbs) (e.g., HEPC3, HEPC74) isolated from individuals who spontaneously cleared HCV infection facilitate immunogen design to elicit antibodies against multiple HCV variants. However, challenges in expressing HCV glycoproteins previously limited bNAb-HCV structures to complexes with truncated E2 cores. Here we describe crystal structures of full-length E2 ectodomain complexes with HEPC3 and HEPC74, revealing lock-and-key antibody-antigen interactions, E2 regions (including a target of immunogen design) that were truncated or disordered in E2 cores, and an antibody CDRH3 disulfide motif that exhibits common interactions with a conserved epitope despite different bNAb-E2 binding orientations. The structures display unusual features relevant to common genetic signatures of HCV bNAbs and demonstrate extraordinary plasticity in antibody-antigen interactions. In addition, E2 variants that bind HEPC3/HEPC74-like germline precursors may represent candidate vaccine immunogens.
Copyright © 2018 Elsevier Inc. All rights reserved.
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17 MeSH Terms
Consider Changing the Horse for Your CAR-T?
Wilson MH
(2018) Mol Ther 26: 1873-1874
MeSH Terms: Animals, Antigens, CD19, Heterografts, Horses, Immunoglobulin G, Immunotherapy, Adoptive, T-Lymphocytes
Added December 13, 2018
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7 MeSH Terms
B Cell-Intrinsic mTORC1 Promotes Germinal Center-Defining Transcription Factor Gene Expression, Somatic Hypermutation, and Memory B Cell Generation in Humoral Immunity.
Raybuck AL, Cho SH, Li J, Rogers MC, Lee K, Williams CL, Shlomchik M, Thomas JW, Chen J, Williams JV, Boothby MR
(2018) J Immunol 200: 2627-2639
MeSH Terms: Animals, B-Lymphocytes, Cell Differentiation, Gene Expression, Germinal Center, Immunity, Humoral, Immunoglobulin G, Immunologic Memory, Lymphocyte Activation, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Mutation, Plasma Cells, Proto-Oncogene Proteins c-bcl-6, Signal Transduction, Transcription Factors
Show Abstract · Added March 14, 2018
B lymphocytes migrate among varied microenvironmental niches during diversification, selection, and conversion to memory or Ab-secreting plasma cells. Aspects of the nutrient milieu differ within these lymphoid microenvironments and can influence signaling molecules such as the mechanistic target of rapamycin (mTOR). However, much remains to be elucidated as to the B cell-intrinsic functions of nutrient-sensing signal transducers that modulate B cell differentiation or Ab affinity. We now show that the amino acid-sensing mTOR complex 1 (mTORC1) is vital for induction of Bcl6-a key transcriptional regulator of the germinal center (GC) fate-in activated B lymphocytes. Accordingly, disruption of mTORC1 after B cell development and activation led to reduced populations of Ag-specific memory B cells as well as plasma cells and GC B cells. In addition, induction of the germ line transcript that guides activation-induced deaminase in selection of the IgG1 H chain region during class switching required mTORC1. Expression of the somatic mutator activation-induced deaminase was reduced by a lack of mTORC1 in B cells, whereas point mutation frequencies in Ag-specific GC-phenotype B cells were only halved. These effects culminated in a B cell-intrinsic defect that impacted an antiviral Ab response and drastically impaired generation of high-affinity IgG1. Collectively, these data establish that mTORC1 governs critical B cell-intrinsic mechanisms essential for establishment of GC differentiation and effective Ab production.
Copyright © 2018 by The American Association of Immunologists, Inc.
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17 MeSH Terms
Application of C flux analysis to identify high-productivity CHO metabolic phenotypes.
Templeton N, Smith KD, McAtee-Pereira AG, Dorai H, Betenbaugh MJ, Lang SE, Young JD
(2017) Metab Eng 43: 218-225
MeSH Terms: Animals, Antibodies, Monoclonal, CHO Cells, Carbon Isotopes, Citric Acid Cycle, Cricetulus, Gene Expression, Immunoglobulin G, Isotope Labeling, Recombinant Proteins
Show Abstract · Added April 27, 2017
Industrial bioprocesses place high demands on the energy metabolism of host cells to meet biosynthetic requirements for maximal protein expression. Identifying metabolic phenotypes that promote high expression is therefore a major goal of the biotech industry. We conducted a series of C flux analysis studies to examine the metabolic response to IgG expression during early stationary phase of CHO cell cultures grown in 3L fed-batch bioreactors. We examined eight clones expressing four different IgGs and compared with three non-expressing host-cell controls. Some clones were genetically manipulated to be apoptosis-resistant by expressing Bcl-2Δ, which correlated with increased IgG production and elevated glucose metabolism. The metabolic phenotypes of the non-expressing, IgG-expressing, and Bcl-2Δ/IgG-expressing clones were fully segregated by hierarchical clustering analysis. Lactate consumption and citric acid cycle fluxes were most strongly associated with specific IgG productivity. These studies indicate that enhanced oxidative metabolism is a characteristic of high-producing CHO cell lines.
Copyright © 2017 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.
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10 MeSH Terms
Frequent Use of the IgA Isotype in Human B Cells Encoding Potent Norovirus-Specific Monoclonal Antibodies That Block HBGA Binding.
Sapparapu G, Czakó R, Alvarado G, Shanker S, Prasad BV, Atmar RL, Estes MK, Crowe JE
(2016) PLoS Pathog 12: e1005719
MeSH Terms: Antibodies, Monoclonal, B-Lymphocytes, Blood Group Antigens, Blotting, Western, Caliciviridae Infections, Cell Line, Enzyme-Linked Immunosorbent Assay, Gastroenteritis, Humans, Hybridomas, Immunoglobulin A, Immunoglobulin G, Norwalk virus, Polymerase Chain Reaction
Show Abstract · Added April 13, 2017
Noroviruses (NoV) are the most common cause of non-bacterial acute gastroenteritis and cause local outbreaks of illness, especially in confined situations. Despite being identified four decades ago, the correlates of protection against norovirus gastroenteritis are still being elucidated. Recent studies have shown an association of protection with NoV-specific serum histo-blood group antigen-blocking antibody and with serum IgA in patients vaccinated with NoV VLPs. Here, we describe the isolation and characterization of human monoclonal IgG and IgA antibodies against a GI.I NoV, Norwalk virus (NV). A higher proportion of the IgA antibodies blocked NV VLP binding to glycans than did IgG antibodies. We generated isotype-switched variants of IgG and IgA antibodies to study the effects of the constant domain on blocking and binding activities. The IgA form of antibodies appears to be more potent than the IgG form in blocking norovirus binding to histo-blood group antigens. These studies suggest a unique role for IgA antibodies in protection from NoV infections by blocking attachment to cell receptors.
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14 MeSH Terms
A peptide immunization approach to counteract a Staphylococcus aureus protease defense against host immunity.
Jordan RE, Fernandez J, Brezski RJ, Greenplate AR, Knight DM, Raju TS, Lynch AS
(2016) Immunol Lett 172: 29-39
MeSH Terms: Abscess, Animals, Bacterial Load, Disease Models, Animal, Drug Combinations, Freund's Adjuvant, Hemocyanins, Humans, Immune Evasion, Immunity, Humoral, Immunization, Immunoglobulin G, Peptide Fragments, Plant Extracts, Proteolysis, Rabbits, Recombinant Fusion Proteins, Staphylococcal Infections, Staphylococcus aureus
Show Abstract · Added April 22, 2016
Pathogens that induce acute and chronic infections, as well as certain cancers, employ numerous strategies to thwart host cellular and humoral immune defenses. One proposed evasion mechanism against humoral immunity is a localized expression of extracellular proteases that cleave the IgG hinge and disable host IgG functions. Host immunity appears to be prepared to counter such a proteolytic tactic by providing a group of autoantibodies, denoted anti-hinge antibodies that specifically bind to cleaved IgGs and provide compensating functional restoration in vitro. These respective counter-measures highlight the complex interrelationships among pathogens and host immunity and suggested to us a possible means for therapeutic intervention. In this study, we combined an investigation of pathogen-mediated proteolysis of host IgGs with an immunization strategy to boost host anti-hinge antibodies. In a Staphylococcus aureus infection model using an artificial tissue cage (wiffle ball) implanted into rabbits, cleaved rabbit IgGs were detected in abundance in the abscesses of untreated animals early after infection. However, in animals previously immunized with peptide analogs of the cleaved IgG hinge to generate substantial anti-hinge antibody titers, S. aureus colony formation was markedly reduced compared to control animals or those similarly immunized with a scrambled peptide sequence. The results of this study demonstrate that extensive local proteolysis of IgGs occurs in a test abscess setting and that immunization to increase host anti-hinge antibodies provided substantial acute protection against bacterial growth.
Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.
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19 MeSH Terms
Immunogenicity and efficacy of alphavirus-derived replicon vaccines for respiratory syncytial virus and human metapneumovirus in nonhuman primates.
Bates JT, Pickens JA, Schuster JE, Johnson M, Tollefson SJ, Williams JV, Davis NL, Johnston RE, Schultz-Darken N, Slaughter JC, Smith-House F, Crowe JE
(2016) Vaccine 34: 950-6
MeSH Terms: Alphavirus, Animals, Antibodies, Neutralizing, Antibodies, Viral, Bronchoalveolar Lavage Fluid, Cercopithecus aethiops, Encephalitis Virus, Venezuelan Equine, Immunoglobulin G, Metapneumovirus, Neutralization Tests, Nose, Paramyxoviridae Infections, Replicon, Respiratory Syncytial Virus Infections, Respiratory Syncytial Virus, Human, Viral Fusion Proteins, Viral Vaccines
Show Abstract · Added January 26, 2016
Human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV) are major causes of illness among children, the elderly, and the immunocompromised. No vaccine has been licensed for protection against either of these viruses. We tested the ability of two Venezuelan equine encephalitis virus-based viral replicon particle (VEE-VRP) vaccines that express the hRSV or hMPV fusion (F) protein to confer protection against hRSV or hMPV in African green monkeys. Animals immunized with VEE-VRP vaccines developed RSV or MPV F-specific antibodies and serum neutralizing activity. Compared to control animals, immunized animals were better able to control viral load in the respiratory mucosa following challenge and had lower levels of viral genome in nasopharyngeal and bronchoalveolar lavage fluids. The high level of immunogenicity and protective efficacy induced by these vaccine candidates in nonhuman primates suggest that they hold promise for further development.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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17 MeSH Terms
Evaluation of candidate vaccine approaches for MERS-CoV.
Wang L, Shi W, Joyce MG, Modjarrad K, Zhang Y, Leung K, Lees CR, Zhou T, Yassine HM, Kanekiyo M, Yang ZY, Chen X, Becker MM, Freeman M, Vogel L, Johnson JC, Olinger G, Todd JP, Bagci U, Solomon J, Mollura DJ, Hensley L, Jahrling P, Denison MR, Rao SS, Subbarao K, Kwong PD, Mascola JR, Kong WP, Graham BS
(2015) Nat Commun 6: 7712
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Coronavirus Infections, DNA, Viral, Female, HEK293 Cells, Humans, Immunoglobulin G, Macaca mulatta, Male, Mice, Mice, Inbred BALB C, Middle East Respiratory Syndrome Coronavirus, Spike Glycoprotein, Coronavirus, Vaccines, DNA, Viral Vaccines
Show Abstract · Added February 22, 2016
The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) as a cause of severe respiratory disease highlights the need for effective approaches to CoV vaccine development. Efforts focused solely on the receptor-binding domain (RBD) of the viral Spike (S) glycoprotein may not optimize neutralizing antibody (NAb) responses. Here we show that immunogens based on full-length S DNA and S1 subunit protein elicit robust serum-neutralizing activity against several MERS-CoV strains in mice and non-human primates. Serological analysis and isolation of murine monoclonal antibodies revealed that immunization elicits NAbs to RBD and, non-RBD portions of S1 and S2 subunit. Multiple neutralization mechanisms were demonstrated by solving the atomic structure of a NAb-RBD complex, through sequencing of neutralization escape viruses and by constructing MERS-CoV S variants for serological assays. Immunization of rhesus macaques confers protection against MERS-CoV-induced radiographic pneumonia, as assessed using computerized tomography, supporting this strategy as a promising approach for MERS-CoV vaccine development.
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18 MeSH Terms
Proteolytic cleavage and loss of function of biologic agents that neutralize tumor necrosis factor in the mucosa of patients with inflammatory bowel disease.
Biancheri P, Brezski RJ, Di Sabatino A, Greenplate AR, Soring KL, Corazza GR, Kok KB, Rovedatti L, Vossenkämper A, Ahmad N, Snoek SA, Vermeire S, Rutgeerts P, Jordan RE, MacDonald TT
(2015) Gastroenterology 149: 1564-1574.e3
MeSH Terms: Adalimumab, Antibodies, Monoclonal, Humanized, Biological Factors, Biopsy, Case-Control Studies, Colitis, Ulcerative, Colon, Crohn Disease, Epitopes, Etanercept, Female, Humans, Immunoblotting, Immunoglobulin G, Inflammatory Bowel Diseases, Infliximab, Intestinal Mucosa, Male, Matrix Metalloproteinase 12, Matrix Metalloproteinase 3, Middle Aged, Proteolysis, Tumor Necrosis Factor-alpha
Show Abstract · Added April 22, 2016
BACKGROUND & AIMS - Many patients with inflammatory bowel disease (IBD) fail to respond to anti-tumor necrosis factor (TNF) agents such as infliximab and adalimumab, and etanercept is not effective for treatment of Crohn's disease. Activated matrix metalloproteinase 3 (MMP3) and MMP12, which are increased in inflamed mucosa of patients with IBD, have a wide range of substrates, including IgG1. TNF-neutralizing agents act in inflamed tissues; we investigated the effects of MMP3, MMP12, and mucosal proteins from IBD patients on these drugs.
METHODS - Biopsy specimens from inflamed colon of 8 patients with Crohn's disease and 8 patients with ulcerative colitis, and from normal colon of 8 healthy individuals (controls), were analyzed histologically, or homogenized and proteins were extracted. We also analyzed sera from 29 patients with active Crohn's disease and 33 patients with active ulcerative colitis who were candidates to receive infliximab treatment. Infliximab, adalimumab, and etanercept were incubated with mucosal homogenates from patients with IBD or activated recombinant human MMP3 or MMP12 and analyzed on immunoblots or in luciferase reporter assays designed to measure TNF activity. IgG cleaved by MMP3 or MMP12 and antihinge autoantibodies against neo-epitopes on cleaved IgG were measured in sera from IBD patients who subsequently responded (clinical remission and complete mucosal healing) or did not respond to infliximab.
RESULTS - MMP3 and MMP12 cleaved infliximab, adalimumab, and etanercept, releasing a 32-kilodalton Fc monomer. After MMP degradation, infliximab and adalimumab functioned as F(ab')2 fragments, whereas cleaved etanercept lost its ability to neutralize TNF. Proteins from the mucosa of patients with IBD reduced the integrity and function of infliximab, adalimumab, and etanercept. TNF-neutralizing function was restored after incubation of the drugs with MMP inhibitors. Serum levels of endogenous IgG cleaved by MMP3 and MMP12, and antihinge autoantibodies against neo-epitopes of cleaved IgG, were higher in patients who did not respond to treatment vs responders.
CONCLUSIONS - Proteolytic degradation may contribute to the nonresponsiveness of patients with IBD to anti-TNF agents.
Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
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23 MeSH Terms
Reversing Tolerance in Isotype Switch-Competent Anti-Insulin B Lymphocytes.
Williams JM, Bonami RH, Hulbert C, Thomas JW
(2015) J Immunol 195: 853-64
MeSH Terms: Animals, Autoantibodies, Autoimmunity, B-Lymphocytes, CD40 Antigens, Diabetes Mellitus, Type 1, Immune Tolerance, Immunoglobulin G, Immunoglobulin M, Insulin, Insulin Antibodies, Lipopolysaccharides, Mice, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, VDJ Exons
Show Abstract · Added December 4, 2015
Autoreactive B lymphocytes that escape central tolerance and mature in the periphery are a liability for developing autoimmunity. IgG insulin autoantibodies that predict type 1 diabetes and complicate insulin therapies indicate that mechanisms for tolerance to insulin are flawed. To examine peripheral tolerance in anti-insulin B cells, we generated C57BL/6 mice that harbor anti-insulin VDJH-125 site directed to the native IgH locus (VH125(SD)). Class switch-competent anti-insulin B cells fail to produce IgG Abs following T cell-dependent immunization of VH125(SD) mice with heterologous insulin, and they exhibit markedly impaired proliferation to anti-CD40 plus insulin in vitro. In contrast, costimulation with LPS plus insulin drives robust anti-insulin B cell proliferation. Furthermore, VH125(SD) mice produce both IgM and IgG2a anti-insulin Abs following immunization with insulin conjugated to type 1 T cell-independent Brucella abortus ring test Ag (BRT). Anti-insulin B cells undergo clonal expansion in vivo and emerge as IgM(+) and IgM(-) GL7(+)Fas(+) germinal center (GC) B cells following immunization with insulin-BRT, but not BRT alone. Analysis of Igκ genes in VH125(SD) mice immunized with insulin-BRT reveals that anti-insulin Vκ from the preimmune repertoire is selected into GCs. These data demonstrate that class switch-competent anti-insulin B cells remain functionally silent in T cell-dependent immune responses, yet these B cells are vulnerable to reversal of anergy following combined BCR/TLR engagement that promotes Ag-specific GC responses and Ab production. Environmental factors that lead to infection and inflammation could play a critical yet underappreciated role in driving loss of tolerance and promoting autoimmune disease.
Copyright © 2015 by The American Association of Immunologists, Inc.
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17 MeSH Terms