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Deacetylase activity of histone deacetylase 3 is required for productive recombination and B-cell development.
Stengel KR, Barnett KR, Wang J, Liu Q, Hodges E, Hiebert SW, Bhaskara S
(2017) Proc Natl Acad Sci U S A 114: 8608-8613
MeSH Terms: Animals, B-Lymphocytes, Histone Deacetylases, Immunoglobulin Heavy Chains, Immunoglobulin Variable Region, Mice, Mice, Transgenic, Point Mutation, V(D)J Recombination
Show Abstract · Added March 26, 2019
Histone deacetylase 3 (HDAC3) is the catalytic component of NCoR/SMRT corepressor complexes that mediate the actions of transcription factors implicated in the regulation of B-cell development and function. We crossed conditional knockout mice with knockin animals to delete in early progenitor B cells. The spleens of mice were virtually devoid of mature B cells, and B220CD43 B-cell progenitors accumulated within the bone marrow. Quantitative deep sequencing of the Ig heavy chain locus from B220CD43 populations identified a defect in recombination with a severe reduction in productive rearrangements, which directly corresponded to the loss of pre-B cells from bone marrow. For B cells that did show productive rearrangement, there was significant skewing toward the incorporation of proximal gene segments and a corresponding reduction in distal gene segment use. Although transcriptional effects within these loci were modest, progenitor cells displayed global changes in chromatin structure that likely hindered effective distal recombination. Reintroduction of wild-type Hdac3 restored normal B-cell development, whereas an Hdac3 point mutant lacking deacetylase activity failed to complement this defect. Thus, the deacetylase activity of Hdac3 is required for the generation of mature B cells.
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MeSH Terms
Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires.
Tian M, Cheng C, Chen X, Duan H, Cheng HL, Dao M, Sheng Z, Kimble M, Wang L, Lin S, Schmidt SD, Du Z, Joyce MG, Chen Y, DeKosky BJ, Chen Y, Normandin E, Cantor E, Chen RE, Doria-Rose NA, Zhang Y, Shi W, Kong WP, Choe M, Henry AR, Laboune F, Georgiev IS, Huang PY, Jain S, McGuire AT, Georgeson E, Menis S, Douek DC, Schief WR, Stamatatos L, Kwong PD, Shapiro L, Haynes BF, Mascola JR, Alt FW
(2016) Cell 166: 1471-1484.e18
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, B-Lymphocytes, Cell Line, Disease Models, Animal, Gene Expression Regulation, HIV-1, Immunization, Immunoglobulin Heavy Chains, Inhibitory Concentration 50, Mice, Precursor Cells, B-Lymphoid, Sequence Deletion, T-Lymphocytes
Show Abstract · Added May 3, 2017
The design of immunogens that elicit broadly reactive neutralizing antibodies (bnAbs) has been a major obstacle to HIV-1 vaccine development. One approach to assess potential immunogens is to use mice expressing precursors of human bnAbs as vaccination models. The bnAbs of the VRC01-class derive from the IGHV1-2 immunoglobulin heavy chain and neutralize a wide spectrum of HIV-1 strains via targeting the CD4 binding site of the envelope glycoprotein gp120. We now describe a mouse vaccination model that allows a germline human IGHV1-2(∗)02 segment to undergo normal V(D)J recombination and, thereby, leads to the generation of peripheral B cells that express a highly diverse repertoire of VRC01-related receptors. When sequentially immunized with modified gp120 glycoproteins designed to engage VRC01 germline and intermediate antibodies, IGHV1-2(∗)02-rearranging mice, which also express a VRC01-antibody precursor light chain, can support the affinity maturation of VRC01 precursor antibodies into HIV-neutralizing antibody lineages.
Copyright © 2016 Elsevier Inc. All rights reserved.
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15 MeSH Terms
Improving Loop Modeling of the Antibody Complementarity-Determining Region 3 Using Knowledge-Based Restraints.
Finn JA, Koehler Leman J, Willis JR, Cisneros A, Crowe JE, Meiler J
(2016) PLoS One 11: e0154811
MeSH Terms: Algorithms, Cluster Analysis, Complementarity Determining Regions, Immunoglobulin Heavy Chains, Immunoglobulin Variable Region, Models, Molecular, Protein Conformation, Structure-Activity Relationship
Show Abstract · Added April 8, 2017
Structural restrictions are present even in the most sequence diverse portions of antibodies, the complementary determining region (CDR) loops. Previous studies identified robust rules that define canonical structures for five of the six CDR loops, however the heavy chain CDR 3 (HCDR3) defies standard classification attempts. The HCDR3 loop can be subdivided into two domains referred to as the "torso" and the "head" domains and two major families of canonical torso structures have been identified; the more prevalent "bulged" and less frequent "non-bulged" torsos. In the present study, we found that Rosetta loop modeling of 28 benchmark bulged HCDR3 loops is improved with knowledge-based structural restraints developed from available antibody crystal structures in the PDB. These restraints restrict the sampling space Rosetta searches in the torso domain, limiting the φ and ψ angles of these residues to conformations that have been experimentally observed. The application of these restraints in Rosetta result in more native-like structure sampling and improved score-based differentiation of native-like HCDR3 models, significantly improving our ability to model antibody HCDR3 loops.
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8 MeSH Terms
Long antibody HCDR3s from HIV-naïve donors presented on a PG9 neutralizing antibody background mediate HIV neutralization.
Willis JR, Finn JA, Briney B, Sapparapu G, Singh V, King H, LaBranche CC, Montefiori DC, Meiler J, Crowe JE
(2016) Proc Natl Acad Sci U S A 113: 4446-51
MeSH Terms: Amino Acid Substitution, Antibodies, Neutralizing, Blood Donors, Complementarity Determining Regions, Female, HIV Antibodies, HIV Envelope Protein gp120, HIV-1, Humans, Immunoglobulin Heavy Chains, Male, Mutation, Missense
Show Abstract · Added May 4, 2016
Development of broadly neutralizing antibodies (bnAbs) against HIV-1 usually requires prolonged infection and induction of Abs with unusual features, such as long heavy-chain complementarity-determining region 3 (HCDR3) loops. Here we sought to determine whether the repertoires of HIV-1-naïve individuals contain Abs with long HCDR3 loops that could mediate HIV-1 neutralization. We interrogated at massive scale the structural properties of long Ab HCDR3 loops in HIV-1-naïve donors, searching for structured HCDR3s similar to those of the HIV-1 bnAb PG9. We determined the nucleotide sequences encoding 2.3 × 10(7)unique HCDR3 amino acid regions from 70 different HIV-1-naïve donors. Of the 26,917 HCDR3 loops with 30-amino acid length identified, we tested 30 for further study that were predicted to have PG9-like structure when chimerized onto PG9. Three of these 30 PG9 chimeras bound to the HIV-1 gp120 monomer, and two were neutralizing. In addition, we found 14 naturally occurring HCDR3 sequences that acquired the ability to bind to the HIV-1 gp120 monomer when adding 2- to 7-amino acid mutations via computational design. Of those 14 designed Abs, 8 neutralized HIV-1, with IC50values ranging from 0.7 to 98 µg/mL. These data suggest that the repertoire of HIV-1-naïve individuals contains rare B cells that encode HCDR3 loops that bind or neutralize HIV-1 when presented on a PG9 background with relatively few or no additional mutations. Long HCDR3 sequences are present in the HIV-naïve B-cell repertoire, suggesting that this class of bnAbs is a favorable target for rationally designed preventative vaccine efforts.
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12 MeSH Terms
Low frequency of broadly neutralizing HIV antibodies during chronic infection even in quaternary epitope targeting antibodies containing large numbers of somatic mutations.
Hicar MD, Chen X, Kalams SA, Sojar H, Landucci G, Forthal DN, Spearman P, Crowe JE
(2016) Mol Immunol 70: 94-103
MeSH Terms: Antibodies, Monoclonal, Antibodies, Neutralizing, B-Lymphocytes, Cell Separation, Enzyme-Linked Immunosorbent Assay, Epitopes, Flow Cytometry, Genes, Immunoglobulin, HIV Antibodies, HIV Infections, Humans, Immunoglobulin Heavy Chains, Immunoglobulin Variable Region, Mutation, env Gene Products, Human Immunodeficiency Virus
Show Abstract · Added January 26, 2016
Neutralizing antibodies (Abs) are thought to be a critical component of an appropriate HIV vaccine response. It has been proposed that Abs recognizing conformationally dependent quaternary epitopes on the HIV envelope (Env) trimer may be necessary to neutralize diverse HIV strains. A number of recently described broadly neutralizing monoclonal Abs (mAbs) recognize complex and quaternary epitopes. Generally, many such Abs exhibit extensive numbers of somatic mutations and unique structural characteristics. We sought to characterize the native antibody (Ab) response against circulating HIV focusing on such conformational responses, without a prior selection based on neutralization. Using a capture system based on VLPs incorporating cleaved envelope protein, we identified a selection of B cells that produce quaternary epitope targeting Abs (QtAbs). Similar to a number of broadly neutralizing Abs, the Ab genes encoding these QtAbs showed extensive numbers of somatic mutations. However, when expressed as recombinant molecules, these Abs failed to neutralize virus or mediate ADCVI activity. Molecular analysis showed unusually high numbers of mutations in the Ab heavy chain framework 3 region of the variable genes. The analysis suggests that large numbers of somatic mutations occur in Ab genes encoding HIV Abs in chronically infected individuals in a non-directed, stochastic, manner.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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15 MeSH Terms
Bruton's Tyrosine Kinase Synergizes with Notch2 To Govern Marginal Zone B Cells in Nonobese Diabetic Mice.
Case JB, Bonami RH, Nyhoff LE, Steinberg HE, Sullivan AM, Kendall PL
(2015) J Immunol 195: 61-70
MeSH Terms: Agammaglobulinaemia Tyrosine Kinase, Animals, Autoantibodies, Autoimmunity, B-Lymphocyte Subsets, Cell Differentiation, Cell Survival, Diabetes Mellitus, Experimental, Female, Gene Expression Regulation, Immunoglobulin Heavy Chains, Insulin, Male, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Protein-Tyrosine Kinases, Receptor, Notch2, Receptors, Antigen, B-Cell, Signal Transduction
Show Abstract · Added December 4, 2015
Expansion of autoimmune-prone marginal zone (MZ) B cells has been implicated in type 1 diabetes. To test disease contributions of MZ B cells in NOD mice, Notch2 haploinsufficiency (Notch2(+/-)) was introduced but failed to eliminate the MZ, as it does in C57BL/6 mice. Notch2(+/-)/NOD have MZ B cell numbers similar to those of wild-type C57BL/6, yet still develop diabetes. To test whether BCR signaling supports Notch2(+/-)/NOD MZ B cells, Bruton's tyrosine kinase (Btk) deficiency was introduced. Surprisingly, MZ B cells failed to develop in Btk-deficient Notch2(+/-)/NOD mice. Expression of Notch2 and its transcriptional target, Hes5, was increased in NOD MZ B cells compared with C57BL/6 MZ B cells. Btk deficiency reduced Notch2(+/-) signaling exclusively in NOD B cells, suggesting that BCR signaling enhances Notch2 signaling in this autoimmune model. The role of BCR signaling was further investigated using an anti-insulin transgenic (Tg) BCR (125Tg). Anti-insulin B cells in 125Tg/Notch2(+/-)/NOD mice populate an enlarged MZ, suggesting that low-level BCR signaling overcomes reliance on Notch2. Tracking clonotypes of anti-insulin B cells in H chain-only VH125Tg/NOD mice showed that BTK-dependent selection into the MZ depends on strength of antigenic binding, whereas Notch2-mediated selection does not. Importantly, anti-insulin B cell numbers were reduced by Btk deficiency, but not Notch2 haploinsufficiency. These studies show that 1) Notch2 haploinsufficiency limits NOD MZ B cell expansion without preventing type 1 diabetes, 2) BTK supports the Notch2 pathway in NOD MZ B cells, and 3) autoreactive NOD B cell survival relies on BTK more than Notch2, regardless of MZ location, which may have important implications for disease-intervention strategies.
Copyright © 2015 by The American Association of Immunologists, Inc.
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20 MeSH Terms
Influenza human monoclonal antibody 1F1 interacts with three major antigenic sites and residues mediating human receptor specificity in H1N1 viruses.
Tsibane T, Ekiert DC, Krause JC, Martinez O, Crowe JE, Wilson IA, Basler CF
(2012) PLoS Pathog 8: e1003067
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Viral, Antibody Affinity, Binding Sites, Antibody, Crystallography, X-Ray, Epitopes, Hemagglutinin Glycoproteins, Influenza Virus, Humans, Immunoglobulin Heavy Chains, Influenza A Virus, H1N1 Subtype, Mice, Mutagenesis, Site-Directed, Protein Structure, Quaternary
Show Abstract · Added January 26, 2016
Most monoclonal antibodies (mAbs) to the influenza A virus hemagglutinin (HA) head domain exhibit very limited breadth of inhibitory activity due to antigenic drift in field strains. However, mAb 1F1, isolated from a 1918 influenza pandemic survivor, inhibits select human H1 viruses (1918, 1943, 1947, and 1977 isolates). The crystal structure of 1F1 in complex with the 1918 HA shows that 1F1 contacts residues that are classically defined as belonging to three distinct antigenic sites, Sa, Sb and Ca(2). The 1F1 heavy chain also reaches into the receptor binding site (RBS) and interacts with residues that contact sialoglycan receptors and determine HA receptor specificity. The 1F1 epitope is remarkably similar to the previously described murine HC63 H3 epitope, despite significant sequence differences between H1 and H3 HAs. Both antibodies potently inhibit receptor binding, but only HC63 can block the pH-induced conformational changes in HA that drive membrane fusion. Contacts within the RBS suggested that 1F1 may be sensitive to changes that alter HA receptor binding activity. Affinity assays confirmed that sequence changes that switch the HA to avian receptor specificity affect binding of 1F1 and a mAb possessing a closely related heavy chain, 1I20. To characterize 1F1 cross-reactivity, additional escape mutant selection and site-directed mutagenesis were performed. Residues 190 and 227 in the 1F1 epitope were found to be critical for 1F1 reactivity towards 1918, 1943 and 1977 HAs, as well as for 1I20 reactivity towards the 1918 HA. Therefore, 1F1 heavy-chain interactions with conserved RBS residues likely contribute to its ability to inhibit divergent HAs.
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14 MeSH Terms
Human peripheral blood antibodies with long HCDR3s are established primarily at original recombination using a limited subset of germline genes.
Briney BS, Willis JR, Crowe JE
(2012) PLoS One 7: e36750
MeSH Terms: Complementarity Determining Regions, Female, HIV Antibodies, HIV-1, Humans, Immunoglobulin Heavy Chains, Immunoglobulin Joining Region, Male, Recombination, Genetic, Somatic Hypermutation, Immunoglobulin
Show Abstract · Added August 6, 2012
A number of antibodies that efficiently neutralize microbial targets contain long heavy chain complementarity determining region 3 (HCDR3) loops. For HIV, several of the most broad and potently neutralizing antibodies have exceptionally long HCDR3s. Two broad potently neutralizing HIV-specific antibodies, PG9 and PG16, exhibit secondary structure. Two other long HCDR3 antibodies, 2F5 and 4E10, protect against mucosal challenge with SHIV. Induction of such long HCDR3 antibodies may be critical to the design of an effective vaccine strategy for HIV and other pathogens, however it is unclear at present how to induce such antibodies. Here, we present genetic evidence that human peripheral blood antibodies containing long HCDR3s are not primarily generated by insertions introduced during the somatic hypermutation process. Instead, they are typically formed by processes occurring as part of the original recombination event. Thus, the response of B cells encoding antibodies with long HCDR3s results from selection of unusual clones from the naïve repertoire rather than through accumulation of insertions. These antibodies typically use a small subset of D and J gene segments that are particularly suited to encoding long HCDR3s, resulting in the incorporation of highly conserved genetic elements in the majority of antibody sequences encoding long HCDR3s.
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10 MeSH Terms
An insertion mutation that distorts antibody binding site architecture enhances function of a human antibody.
Krause JC, Ekiert DC, Tumpey TM, Smith PB, Wilson IA, Crowe JE
(2011) MBio 2: e00345-10
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Viral, Base Sequence, Binding Sites, Antibody, Cell Line, Female, Humans, Immunoglobulin Heavy Chains, Immunoglobulin Variable Region, Influenza A Virus, H1N1 Subtype, Influenza, Human, Mice, Mice, Inbred BALB C, Molecular Sequence Data, Mutagenesis, Insertional, Protein Binding, Protein Conformation
Show Abstract · Added August 6, 2012
The structural and functional significance of somatic insertions and deletions in antibody chains is unclear. Here, we demonstrate that a naturally occurring three-amino-acid insertion within the influenza virus-specific human monoclonal antibody 2D1 heavy-chain variable region reconfigures the antibody-combining site and contributes to its high potency against the 1918 and 2009 pandemic H1N1 influenza viruses. The insertion arose through a series of events, including a somatic point mutation in a predicted hot-spot motif, introduction of a new hot-spot motif, a molecular duplication due to polymerase slippage, a deletion due to misalignment, and additional somatic point mutations. Atomic resolution structures of the wild-type antibody and a variant in which the insertion was removed revealed that the three-amino-acid insertion near the base of heavy-chain complementarity-determining region (CDR) H2 resulted in a bulge in that loop. This enlarged CDR H2 loop impinges on adjacent regions, causing distortion of the CDR H1 architecture and its displacement away from the antigen-combining site. Removal of the insertion restores the canonical structure of CDR H1 and CDR H2, but binding, neutralization activity, and in vivo activity were reduced markedly because of steric conflict of CDR H1 with the hemagglutinin antigen.
Copyright © 2011 Krause et al.
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18 MeSH Terms
Reduced diabetes in btk-deficient nonobese diabetic mice and restoration of diabetes with provision of an anti-insulin IgH chain transgene.
Kendall PL, Moore DJ, Hulbert C, Hoek KL, Khan WN, Thomas JW
(2009) J Immunol 183: 6403-12
MeSH Terms: Agammaglobulinaemia Tyrosine Kinase, Animals, Autoantibodies, B-Lymphocyte Subsets, Diabetes Mellitus, Type 1, Immune Tolerance, Immunoglobulin Heavy Chains, Insulin, Insulin Antibodies, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Mutation, Protein-Tyrosine Kinases, Receptors, Antigen, B-Cell, Signal Transduction, T-Lymphocyte Subsets, Transgenes
Show Abstract · Added December 10, 2013
Type 1 diabetes results from T cell-mediated destruction of insulin-producing beta cells. Although elimination of B lymphocytes has proven successful at preventing disease, modulation of B cell function as a means to prevent type 1 diabetes has not been investigated. The development, fate, and function of B lymphocytes depend upon BCR signaling, which is mediated in part by Bruton's tyrosine kinase (BTK). When introduced into NOD mice, btk deficiency only modestly reduces B cell numbers, but dramatically protects against diabetes. In NOD, btk deficiency mirrors changes in B cell subsets seen in other strains, but also improves B cell-related tolerance, as indicated by failure to generate insulin autoantibodies. Introduction of an anti-insulin BCR H chain transgene restores diabetes in btk-deficient NOD mice, indicating that btk-deficient B cells are functionally capable of promoting autoimmune diabetes if they have a critical autoimmune specificity. This suggests that the disease-protective effect of btk deficiency may reflect a lack of autoreactive specificities in the B cell repertoire. Thus, signaling via BTK can be modulated to improve B cell tolerance, and prevent T cell-mediated autoimmune diabetes.
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19 MeSH Terms