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Bruton's Tyrosine Kinase Deficiency Inhibits Autoimmune Arthritis in Mice but Fails to Block Immune Complex-Mediated Inflammatory Arthritis.
Nyhoff LE, Barron BL, Johnson EM, Bonami RH, Maseda D, Fensterheim BA, Han W, Blackwell TS, Crofford LJ, Kendall PL
(2016) Arthritis Rheumatol 68: 1856-68
MeSH Terms: Agammaglobulinaemia Tyrosine Kinase, Animals, Antigen-Antibody Complex, Arthritis, Autoimmune Diseases, Male, Mice, Protein-Tyrosine Kinases
Show Abstract · Added October 12, 2016
OBJECTIVE - Bruton's tyrosine kinase (BTK) is a B cell signaling protein that also contributes to innate immunity. BTK inhibitors prevent autoimmune arthritis but have off-target effects, and the mechanisms of protection remain unknown. We undertook these studies using genetic deletion to investigate the role of BTK in adaptive and innate immune responses that drive inflammatory arthritis.
METHODS - BTK-deficient K/BxN mice were generated to study the role of BTK in a spontaneous model that requires both adaptive and innate immunity. The K/BxN serum-transfer model was used to bypass the adaptive system and elucidate the role of BTK in innate immune contributions to arthritis.
RESULTS - BTK deficiency conferred disease protection to K/BxN mice, confirming outcomes of BTK inhibitors. B lymphocytes were profoundly reduced, more than in other models of BTK deficiency. Subset analysis revealed loss of B cells at all developmental stages. Germinal center B cells were also decreased, with downstream effects on numbers of follicular helper T cells and greatly reduced autoantibodies. In contrast, total IgG was only mildly decreased. Strikingly, and in contrast to small molecule inhibitors, BTK deficiency had no effect in the serum-transfer model of arthritis.
CONCLUSION - BTK contributes to autoimmune arthritis primarily through its role in B cell signaling and not through innate immune components.
© 2016, American College of Rheumatology.
1 Communities
3 Members
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8 MeSH Terms
Spleen Tyrosine Kinase (Syk) Mediates IL-1β Induction by Primary Human Monocytes during Antibody-enhanced Dengue Virus Infection.
Callaway JB, Smith SA, McKinnon KP, de Silva AM, Crowe JE, Ting JP
(2015) J Biol Chem 290: 17306-20
MeSH Terms: Antibodies, Viral, Antibody-Dependent Enhancement, Antigen-Antibody Complex, Carrier Proteins, Caspase 1, Cells, Cultured, Dengue, Dengue Virus, Glyburide, Humans, Interleukin-1beta, Intracellular Signaling Peptides and Proteins, MAP Kinase Signaling System, Monocytes, NLR Family, Pyrin Domain-Containing 3 Protein, Protein-Tyrosine Kinases, RNA, Messenger, RNA, Small Interfering, Syk Kinase, Virus Replication
Show Abstract · Added January 26, 2016
Approximately 500,000 people are hospitalized with severe dengue illness annually. Antibody-dependent enhancement (ADE) of dengue virus (DENV) infection is believed to contribute to the pathogenic cytokine storm described in severe dengue patients, but the precise signaling pathways contributing to elevated cytokine production are not elucidated. IL-1β is a potent inflammatory cytokine that is frequently elevated during severe dengue, and the unique dual regulation of IL-1β provides an informative model to study ADE-induced cytokines. This work utilizes patient-derived anti-DENV mAbs and primary human monocytes to study ADE-induced IL-1β and other cytokines. ADE of DENV serotype 2 (DENV-2) elevates mature IL-1β secretion by monocytes independent of DENV replication by 4 h postinoculation (hpi). Prior to this, DENV immune complexes activate spleen tyrosine kinase (Syk) within 1 hpi. Syk induces elevated IL1B, TNF, and IL6 mRNA by 2 hpi. Syk mediates elevated IL-1β secretion by activating ERK1/2, and both Syk and ERK1/2 inhibitors ablated ADE-induced IL-1β secretion. Maturation of pro-IL-1β during ADE requires caspase-1 and NLRP3, but caspase-1 is suboptimally increased by ADE and can be significantly enhanced by a typical inflammasome agonist, ATP. Importantly, this inflammatory Syk-ERK signaling axis requires DENV immune complexes, because DENV-2 in the presence of serotype-matched anti-DENV-2 mAb, but not anti-DENV-1 mAb, activates Syk, ERK, and IL-1β secretion. This study provides evidence that DENV-2 immune complexes activate Syk to mediate elevated expression of inflammatory cytokines. Syk and ERK may serve as new therapeutic targets for interfering with ADE-induced cytokine expression during severe dengue.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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1 Members
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20 MeSH Terms
Structural basis for Marburg virus neutralization by a cross-reactive human antibody.
Hashiguchi T, Fusco ML, Bornholdt ZA, Lee JE, Flyak AI, Matsuoka R, Kohda D, Yanagi Y, Hammel M, Crowe JE, Saphire EO
(2015) Cell 160: 904-912
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Antigen-Antibody Complex, Cell Line, Cross Reactions, Crystallography, X-Ray, Drosophila, Ebolavirus, Humans, Immunoglobulin Fab Fragments, Marburg Virus Disease, Marburgvirus, Models, Molecular, Molecular Sequence Data, Mucins, Sequence Alignment, Viral Envelope Proteins
Show Abstract · Added January 26, 2016
The filoviruses, including Marburg and Ebola, express a single glycoprotein on their surface, termed GP, which is responsible for attachment and entry of target cells. Filovirus GPs differ by up to 70% in protein sequence, and no antibodies are yet described that cross-react among them. Here, we present the 3.6 Å crystal structure of Marburg virus GP in complex with a cross-reactive antibody from a human survivor, and a lower resolution structure of the antibody bound to Ebola virus GP. The antibody, MR78, recognizes a GP1 epitope conserved across the filovirus family, which likely represents the binding site of their NPC1 receptor. Indeed, MR78 blocks binding of the essential NPC1 domain C. These structures and additional small-angle X-ray scattering of mucin-containing MARV and EBOV GPs suggest why such antibodies were not previously elicited in studies of Ebola virus, and provide critical templates for development of immunotherapeutics and inhibitors of entry.
Copyright © 2015 Elsevier Inc. All rights reserved.
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1 Members
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20 MeSH Terms
Mechanism of human antibody-mediated neutralization of Marburg virus.
Flyak AI, Ilinykh PA, Murin CD, Garron T, Shen X, Fusco ML, Hashiguchi T, Bornholdt ZA, Slaughter JC, Sapparapu G, Klages C, Ksiazek TG, Ward AB, Saphire EO, Bukreyev A, Crowe JE
(2015) Cell 160: 893-903
MeSH Terms: Adult, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Antigen-Antibody Complex, B-Lymphocytes, Female, Humans, Immunoglobulin Fab Fragments, Marburg Virus Disease, Marburgvirus, Models, Molecular, Mutation, Protein Structure, Tertiary, Viral Envelope Proteins
Show Abstract · Added January 26, 2016
The mechanisms by which neutralizing antibodies inhibit Marburg virus (MARV) are not known. We isolated a panel of neutralizing antibodies from a human MARV survivor that bind to MARV glycoprotein (GP) and compete for binding to a single major antigenic site. Remarkably, several of the antibodies also bind to Ebola virus (EBOV) GP. Single-particle EM structures of antibody-GP complexes reveal that all of the neutralizing antibodies bind to MARV GP at or near the predicted region of the receptor-binding site. The presence of the glycan cap or mucin-like domain blocks binding of neutralizing antibodies to EBOV GP, but not to MARV GP. The data suggest that MARV-neutralizing antibodies inhibit virus by binding to infectious virions at the exposed MARV receptor-binding site, revealing a mechanism of filovirus inhibition.
Copyright © 2015 Elsevier Inc. All rights reserved.
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1 Members
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16 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.
1 Communities
1 Members
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15 MeSH Terms
Human germline antibody gene segments encode polyspecific antibodies.
Willis JR, Briney BS, DeLuca SL, Crowe JE, Meiler J
(2013) PLoS Comput Biol 9: e1003045
MeSH Terms: Algorithms, Amino Acids, Antibodies, Antigen-Antibody Complex, Antigens, Computational Biology, Computer Simulation, Epitopes, Genes, Immunoglobulin, Humans, Mutation, Programming Languages, Protein Binding, Protein Conformation, Software
Show Abstract · Added March 7, 2014
Structural flexibility in germline gene-encoded antibodies allows promiscuous binding to diverse antigens. The binding affinity and specificity for a particular epitope typically increase as antibody genes acquire somatic mutations in antigen-stimulated B cells. In this work, we investigated whether germline gene-encoded antibodies are optimal for polyspecificity by determining the basis for recognition of diverse antigens by antibodies encoded by three VH gene segments. Panels of somatically mutated antibodies encoded by a common VH gene, but each binding to a different antigen, were computationally redesigned to predict antibodies that could engage multiple antigens at once. The Rosetta multi-state design process predicted antibody sequences for the entire heavy chain variable region, including framework, CDR1, and CDR2 mutations. The predicted sequences matched the germline gene sequences to a remarkable degree, revealing by computational design the residues that are predicted to enable polyspecificity, i.e., binding of many unrelated antigens with a common sequence. The process thereby reverses antibody maturation in silico. In contrast, when designing antibodies to bind a single antigen, a sequence similar to that of the mature antibody sequence was returned, mimicking natural antibody maturation in silico. We demonstrated that the Rosetta computational design algorithm captures important aspects of antibody/antigen recognition. While the hypervariable region CDR3 often mediates much of the specificity of mature antibodies, we identified key positions in the VH gene encoding CDR1, CDR2, and the immunoglobulin framework that are critical contributors for polyspecificity in germline antibodies. Computational design of antibodies capable of binding multiple antigens may allow the rational design of antibodies that retain polyspecificity for diverse epitope binding.
1 Communities
2 Members
0 Resources
15 MeSH Terms
A recurring motif for antibody recognition of the receptor-binding site of influenza hemagglutinin.
Xu R, Krause JC, McBride R, Paulson JC, Crowe JE, Wilson IA
(2013) Nat Struct Mol Biol 20: 363-70
MeSH Terms: Amino Acid Motifs, Amino Acid Sequence, Antibodies, Neutralizing, Antibodies, Viral, Antigen-Antibody Complex, Binding Sites, Crystallography, X-Ray, Epitopes, Hemagglutinin Glycoproteins, Influenza Virus, Humans, Immunoglobulin Fab Fragments, Influenza A Virus, H2N2 Subtype, Molecular Sequence Data, Mutation, Protein Conformation, Tryptophan, Tyrosine
Show Abstract · Added January 26, 2016
Influenza virus hemagglutinin (HA) mediates receptor binding and viral entry during influenza infection. The development of receptor analogs as viral-entry blockers has not been successful, which suggests that sialic acid may not be an ideal scaffold to obtain broad, potent HA inhibitors. Here, we report crystal structures of Fab fragments from three human antibodies that neutralize the 1957 pandemic H2N2 influenza virus in complex with H2 HA. All three antibodies use an aromatic residue to plug a conserved cavity in the HA receptor-binding site. Each antibody interacts with the absolutely conserved HA1 Trp153 at the cavity base through π-π stacking with the signature Phe54 of two VH1-69-encoded antibodies or a tyrosine from HCDR3 in the other antibody. This highly conserved interaction can be used as a starting point to design inhibitors targeting this conserved hydrophobic pocket in influenza viruses.
0 Communities
1 Members
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17 MeSH Terms
Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes.
Monsalvo AC, Batalle JP, Lopez MF, Krause JC, Klemenc J, Hernandez JZ, Maskin B, Bugna J, Rubinstein C, Aguilar L, Dalurzo L, Libster R, Savy V, Baumeister E, Aguilar L, Cabral G, Font J, Solari L, Weller KP, Johnson J, Echavarria M, Edwards KM, Chappell JD, Crowe JE, Williams JV, Melendi GA, Polack FP
(2011) Nat Med 17: 195-9
MeSH Terms: Adolescent, Adult, Age Factors, Antibodies, Viral, Antigen-Antibody Complex, Antigens, Viral, Complement C3, Cross Reactions, Cytokines, Humans, Influenza A Virus, H1N1 Subtype, Influenza, Human, Interferon-alpha, Interferon-beta, Lung, Middle Aged, Young Adult
Show Abstract · Added November 14, 2013
Pandemic influenza viruses often cause severe disease in middle-aged adults without preexisting comorbidities. The mechanism of illness associated with severe disease in this age group is not well understood. Here we find preexisting serum antibodies that cross-react with, but do not protect against, 2009 H1N1 influenza virus in middle-aged adults. Nonprotective antibody is associated with immune complex-mediated disease after infection. We detected high titers of serum antibody of low avidity for H1-2009 antigen, and low-avidity pulmonary immune complexes against the same protein, in severely ill individuals. Moreover, C4d deposition--a marker of complement activation mediated by immune complexes--was present in lung sections of fatal cases. Archived lung sections from middle-aged adults with confirmed fatal influenza 1957 H2N2 infection revealed a similar mechanism of illness. These observations provide a previously unknown biological mechanism for the unusual age distribution of severe cases during influenza pandemics.
0 Communities
2 Members
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17 MeSH Terms
Expansion of regulatory T cells via IL-2/anti-IL-2 mAb complexes suppresses experimental myasthenia.
Liu R, Zhou Q, La Cava A, Campagnolo DI, Van Kaer L, Shi FD
(2010) Eur J Immunol 40: 1577-89
MeSH Terms: Animals, Antibodies, Monoclonal, Antigen-Antibody Complex, B-Lymphocytes, Cell Separation, Cytokines, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Interleukin-2, Lymphocyte Activation, Mice, Myasthenia Gravis, Autoimmune, Experimental, T-Lymphocytes, Regulatory
Show Abstract · Added December 10, 2013
Human autoimmune diseases are often characterized by a relative deficiency in CD4(+)CD25(+) regulatory T cells (Treg). We therefore hypothesized that expansion of Treg can ameliorate autoimmune pathology. We tested this hypothesis in an experimental model for autoimmune myasthenia gravis (MG), a B-cell-mediated disease characterized by auto-Ab directed against the acetylcholine receptor within neuromuscular junctions. We showed that injection of immune complexes composed of the cytokine IL-2 and anti-IL-2 mAb (JES6-1A12) induced an effective and sustained expansion of Treg, via peripheral proliferation of CD4(+)CD25(+)Foxp3(+) cells and peripheral conversion of CD4(+)CD25(-)Foxp3(-) cells. The expanded Treg potently suppressed autoreactive T- and B-cell responses to acetylcholine receptor and attenuated the muscular weakness that is characteristic of MG. Thus, IL-2/anti-IL-2 mAb complexes can expand functional Treg in vivo, providing a potential clinical application of this modality for treatment of MG and other autoimmune disorders.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Sensitive and multiplexed detection of proteomic antigens via quantum dot aggregation.
Soman C, Giorgio T
(2009) Nanomedicine 5: 402-9
MeSH Terms: Angiopoietin-2, Antigen-Antibody Complex, Antigens, Flow Cytometry, Humans, Proteomics, Quantum Dots, Vascular Endothelial Growth Factor A
Show Abstract · Added March 20, 2014
UNLABELLED - A rapid, single-step, solution-phase method for quantifying multiple proteomic biomarkers is described. Nanoscale quantum dot-antibody conjugates self-assemble into microscale aggregates in the presence of a specific antigen through antibody-antigen molecular recognition. These aggregates are easily discriminated from the individual components by flow cytometry. Quantum dot (QD) aggregates can be quantified and correlated to the antigen concentration. Two QD populations with distinct emission spectra are used for detecting two proteomics antigens in a single reaction volume. Multiplexed detection of vascular endothelial growth factor A and angiopoietin-2 is demonstrated at the physiologically relevant, picomolar concentration range. Nonmultiplexed detection of the antigens is also demonstrated, with a femtomolar sensitivity limit. This technique may be optimized for low-cost early detection and frequent screening of cancers and other diseases as well as detection of the biological response to therapy.
FROM THE CLINICAL EDITOR - In this paper a rapid, single-step, solution-phase method is described with multiplexed detection at physiological relevant picomolar concentration range and nonmultiplexed detection with a femtomolar sensitivity limit. The technique may enable low-cost early detection of cancers and other diseases as well as detection of the biological response to therapy.
0 Communities
1 Members
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8 MeSH Terms