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| Open AccessIgD attenuates the IgM-induced anergy response in transitional and mature B cells
Self-reactive B cells that are anergic express mainly IgD, yet the function of IgD is not clear. Here the authors analyse primary B cells from mice to show that IgD signalling attenuates self-antigen induced gene expression and promotes survival of anergic B cells that might go on to reactivate to foreign antigens and mutate away from self-reactivity.
- Zahra Sabouri
- , Samuel Perotti
- & Christopher C. Goodnow
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| Open AccessLong-lived antigen-induced IgM plasma cells demonstrate somatic mutations and contribute to long-term protection
Long-lived IgG plasma cells develop in germinal centres and then home to the bone marrow and persist for a lifetime. Here the authors identify long-lived IgM plasma cells in the murine spleen, which carry IgH mutations but can develop independently of germinal centres, and confer protective antiviral immunity.
- Caitlin Bohannon
- , Ryan Powers
- & Joshy Jacob
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| Open AccessSpecifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice
The induction of broadly neutralizing antibodies (bNAbs) is a goal of HIV-1 vaccine research. Here the authors demonstrate the ability of an HIV Env-derived immunogen to bind germline precursors of a class of bNAbs and to activate the corresponding B cells in a knock-in mouse model
- Andrew T. McGuire
- , Matthew D. Gray
- & Leonidas Stamatatos
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| Open AccessDeciphering the importance of the palindromic architecture of the immunoglobulin heavy-chain 3’ regulatory region
The IgH3’ regulatory region contains an evolutionarily conserved palindromic sequence flanking important enhancer elements. Here the authors show that the palindrome is required for generating antibody diversity.
- Alexis Saintamand
- , Christelle Vincent-Fabert
- & Yves Denizot
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| Open AccessMucosal immunoglobulins at respiratory surfaces mark an ancient association that predates the emergence of tetrapods
In teleost fish the gills perform—in addition to respiration—functions such as immune defence. Here the authors show that IgT, a teleost specific Ig previously shown to be involved in gut and skin mucosal immunity, is locally induced in the gill, where it plays a key role in immunity in rainbow trout.
- Zhen Xu
- , Fumio Takizawa
- & J. Oriol Sunyer
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| Open AccessComprehensive analysis of antibody recognition in convalescent humans from highly pathogenic avian influenza H5N1 infection
Unravelling the mechanism of the recognition of the highly pathogenic influenza A viruses by antibodies is important for understanding their protective function. Zuo et al. characterise the mechanism of recognition of the H5N1 influenza virus by human monoclonal antibodies isolated from convalescent individuals.
- Teng Zuo
- , Jianfeng Sun
- & Linqi Zhang
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| Open AccessSTAT3-mediated IGF-2 secretion in the tumour microenvironment elicits innate resistance to anti-IGF-1R antibody
Cixutumumab is an anti-IGF-1R monoclonal antibody and is used to treat cancer; however, tumours can develop resistance to the therapy. Here, the authors show that the resistance is mediated by activation of STAT3 that results in an IGF2/IGF-2R signalling loop and recruitment of macrophages.
- Ji-Sun Lee
- , Ju-Hee Kang
- & Ho-Young Lee
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| Open AccessReactivation of IgG-switched memory B cells by BCR-intrinsic signal amplification promotes IgG antibody production
Antigen receptors on memory B cells enhance their signaling strength by recruiting the cytosolic Grb2 adaptor to their ITT phosphorylation motifs. Here the authors show that inactivating the ITT motif of mouse mIgG1 impairs IgG1 production and T-cell independent reactivation of memory B cells.
- Johannes Lutz
- , Kai Dittmann
- & Niklas Engels
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| Open AccessDose–response curve slope helps predict therapeutic potency and breadth of HIV broadly neutralizing antibodies
Potencies of HIV broadly neutralizing antibodies are usually defined by theirin vitro IC50 and IC80 values, but much higher levels will be required for successful immunotherapies. Here, Webb et al. predict antibody potency at therapeutic levels by analyzing dose–response curve slopes, which correlate with epitope class.
- Nicholas E. Webb
- , David C. Montefiori
- & Benhur Lee
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| Open AccessAntibodies to a conformational epitope on gp41 neutralize HIV-1 by destabilizing the Env spike
The envelope glycoprotein (Env) trimer is the only antigenic target for broadly neutralizing antibodies on the surface of the HIV-1 virus. Here the authors show that two related monoclonal antibodies bind between gp41 protomers and neutralize HIV-1 by accelerating Env trimer decay.
- Jeong Hyun Lee
- , Daniel P. Leaman
- & Andrew B. Ward
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| Open AccessEvaluation of candidate vaccine approaches for MERS-CoV
Unmet need exists for a vaccine against Middle East respiratory syndrome coronavirus (MERS-CoV). Here the authors report the establishment and evaluation, in mice and primates, of a series of MERS-CoV immunogens and show that they can serve as promising leads for vaccine development.
- Lingshu Wang
- , Wei Shi
- & Barney S. Graham
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| Open AccessA potent broad-spectrum protective human monoclonal antibody crosslinking two haemagglutinin monomers of influenza A virus
Monoclonal antibodies with broadly neutralizing activity are being developed as potential treatment of influenza infections. Here, the authors describe a broadly neutralizing antibody with an unusual mode of binding to viral haemagglutinin, which has been isolated from patients convalescent from pandemic H1N1 influenza infection.
- Ying Wu
- , MyungSam Cho
- & Ruben O. Donis
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Glycan clustering stabilizes the mannose patch of HIV-1 and preserves vulnerability to broadly neutralizing antibodies
The glycan patch that covers the HIV-1 envelope protein gp120 can be targeted by broadly neutralizing antibodies. Here, Pritchard et al.show that structural changes in the glycans do not significantly hamper antibody recognition, supporting the glycan patch as a stable target for vaccine design.
- Laura K. Pritchard
- , Daniel I.R. Spencer
- & Max Crispin
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| Open AccessStructural basis for binding of human IgG1 to its high-affinity human receptor FcγRI
FcγRs are cell-surface receptors for IgGs that play key roles in the humoral and cellular immune response to infection. Here, the authors present a high-resolution crystal structure of the hFcγRI-Fc complex to reveal the molecular mechanisms underlying the high specificity of this important immunological interaction.
- Masato Kiyoshi
- , Jose M.M. Caaveiro
- & Kouhei Tsumoto
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Mir-17–92 regulates bone marrow homing of plasma cells and production of immunoglobulin G2c
After activation and selection, plasma cells home to the bone marrow where they persist and continue to make antibodies. Here the authors show that the mir-17–92cluster coordinates the process by regulating the homing receptor S1PR1 and the transcription factor IKAROS that controls IgG2c production.
- Shengli Xu
- , Xijun Ou
- & Kong-Peng Lam
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| Open AccessGlycosylation of immunoglobulin G determines osteoclast differentiation and bone loss
The IgG sugar moiety modulates the binding of immune complexes to their Fcγ receptors resulting in pro- or anti-inflammatory response. This study shows that IgG sialylation also affects osteoclastogenesis and bone mass in mice and humans, identifying a new link between bone and the immune system.
- Ulrike Harre
- , Stefanie C. Lang
- & Georg Schett
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| Open AccessMicroRNA-146a regulates ICOS–ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres
Maturation of antibody-producing B cells in germinal centers is orchestrated by T follicular helper cells. Here Pratama et al. show that miR-146a negatively regulates T follicular helper cells by targeting ICOS-ICOS ligand signaling in germinal centers.
- Alvin Pratama
- , Monika Srivastava
- & Carola G. Vinuesa
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| Open AccessTGF-β3-expressing CD4+CD25−LAG3+ regulatory T cells control humoral immune responses
B cells reactive against self antigens can cause autoimmune disease, but are normally suppressed by regulatory T cells (Tregs). Here the authors show that a subset of Tregs can suppress lupus in a mouse model by making TGF-β3 cytokine and by engaging an inhibitory PD-1 receptor on B cells.
- Tomohisa Okamura
- , Shuji Sumitomo
- & Kazuhiko Yamamoto
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| Open AccessCEACAM1 induces B-cell survival and is essential for protective antiviral antibody production
Antibody responses are regulated by selective survival of B cells with proper antigen specificity. Here the authors show that CEACAM1 is critical for B-cell survival during homeostasis and antiviral responses.
- Vishal Khairnar
- , Vikas Duhan
- & Karl S. Lang
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PD-L1hi B cells are critical regulators of humoral immunity
Follicular helper T cells promote antibody production by B cells, and regulatory B cells, in turn, can restrain T cell activation. Here, Khan et al. show that PD-L1 plays a critical role in regulatory B cell function, curbing excessive immune responses by engaging the PD-1 receptor on follicular helper T cells.
- Adnan R. Khan
- , Emily Hams
- & Padraic G. Fallon
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| Open AccessThe immunoglobulin tail tyrosine motif upgrades memory-type BCRs by incorporating a Grb2-Btk signalling module
How class-switched memory B cells signal to respond robustly to recurring pathogens is incompletely understood. Here the authors show that immunoglobulin tail tyrosine motifs in membrane-bound immunoglobulin isotypes of class-switched cells amplify signalling in memory B cells, in a mechanism that includes distinct kinases and adaptor proteins.
- Niklas Engels
- , Lars M. König
- & Jürgen Wienands
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Switching between humoral and cellular immune responses in Drosophila is guided by the cytokine GBP
Insects combat infection using humoral and cellular immunity but it is not fully understood how these mechanisms are coordinated. Here, using Drosophilaas a model, the authors show that the PDGF- and VEGF-receptor homologue (Pvr) can direct the nature of innate immune responses expressed by hematocytes.
- Seiji Tsuzuki
- , Hitoshi Matsumoto
- & Yoichi Hayakawa
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IgGs are made for walking on bacterial and viral surfaces
Antibody–antigen recognition is one of the important aspects of immunity, but the nanomechanical process of this recognition is not fully understood. Here, using high-speed atomic force microscopy, the authors observe that on membranes containing a high density of immobile antigens antibodies move in a ‘random walking’ motion.
- Johannes Preiner
- , Noriyuki Kodera
- & Peter Hinterdorfer
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| Open AccessShp1 signalling is required to establish the long-lived bone marrow plasma cell pool
SHP-1 signalling is required for the normal development of B lymphocytes but its role in the terminal differentiation of these cells has not been fully established. Here, the authors show that SHP-1 ablation impairs the establishment of long-lived bone marrow-resident plasma cells due to aberrant integrin activation.
- Yan-Feng Li
- , Shengli Xu
- & Kong-Peng Lam
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Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients
Pemphingus vulgaris is known to be caused by anti-desmoglein 3 autoantibodies, but how these antibodies arise is not clear. Here, the authors show that VH gene usage is shared among patients and that few or no somatic mutations are required for these autoantibodies to acquire autoreactivity.
- Michael Jeffrey Cho
- , Agnes S.Y. Lo
- & Aimee S. Payne
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Receptor mimicry by antibody F045–092 facilitates universal binding to the H3 subtype of influenza virus
Influenza A H3 viruses circulate in humans and bind host cells using the haemagglutinin (HA) glycoprotein. Here, Lee et al.perform a structural analysis of antibody F045–092 with broadly neutralizing activity against the H3 subtype and reveal its interaction with the HA receptor binding site.
- Peter S. Lee
- , Nobuko Ohshima
- & Ian A. Wilson
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Regulation of asymmetric cell division and polarity by Scribble is not required for humoral immunity
B cells are thought to divide asymmetrically to generate distinct lineages required for adaptive immunity. Hawkins et al. find that surprisingly, mice lacking components of a complex required for asymmetric cell division display normal responses to vaccination and viral infection.
- Edwin D. Hawkins
- , Jane Oliaro
- & Sarah M. Russell
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| Open AccessMicrobe-dependent CD11b+ IgA+ plasma cells mediate robust early-phase intestinal IgA responses in mice
Intestinal plasma cells contribute to the delicate balance between immunity against pathogens and tolerance of intestinal microflora. Kunisawa et al. identify a subpopulation of plasma cells whose proliferation depends on stimulation by microbes and IL-10, and which mediate early-phase responses to oral antigens.
- Jun Kunisawa
- , Masashi Gohda
- & Hiroshi Kiyono
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Germinal centre protein HGAL promotes lymphoid hyperplasia and amyloidosis via BCR-mediated Syk activation
The human germinal centre-associated lymphoma gene is expressed in germinal centre B-lymphocytes; however, its function is unknown. Here the authors show that human germinal centre-associated lymphoma activates Syk kinase, leading to lymphoid hyperplasia and systemic reactive amyloid A amyloidosis in transgenic mice.
- Isabel Romero-Camarero
- , Xiaoyu Jiang
- & Izidore S Lossos
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| Open AccessCompetition for FcRn-mediated transport gives rise to short half-life of human IgG3 and offers therapeutic potential
The half-life of IgG is regulated by binding to the neonatal Fc receptor and, in the case of IgG3, is reduced compared to other IgG proteins. In this study, a mutation in IgG3 is shown to reduce binding to the neonatal Fc receptor, which can be competitively blocked by IgG1.
- Nigel M. Stapleton
- , Jan Terje Andersen
- & Gestur Vidarsson
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| Open AccessB-cell depletion reveals a role for antibodies in the control of chronic HIV-1 infection
HIV infection can be partially regulated by the host immune system; however whether B cells contribute to this response is unclear. Huanget al. show that transient depletion of B cells can result in an increase in HIV viral load suggesting that these immune cells do participate in the control of HIV infection.
- Kuan-Hsiang G. Huang
- , David Bonsall
- & Paul Klenerman