-
Sarah F Andrews,
Qingzhao Zhang,
Samuel Lim,
Lie Li,
Jane-Hwei Lee,
Nai-Ying Zheng, Min Huang,
William M Taylor,
A Darise Farris,
Dongyao Ni,
Wenzhao Meng,
Eline T Luning Prak,
Patrick C Wilson
[show abstract]
[hide abstract]
ABSTRACT: The important subtleties of B cell tolerance are best understood in a diverse immunoglobulin (Ig) repertoire context encoding a full spectrum of autoreactivity. To achieve this, we used mice expressing Igκ transgenes that confer varying degrees of autoreactivity within a diverse heavy chain (HC) repertoire. These transgenes, coupled with a biomarker to identify receptor-edited cells and combined with expression cloning of B cell receptors, allowed us to analyze tolerance throughout B cell development. We found that both the nature of the autoantigen and the Ig HC versus light chain (LC) contribution to autoreactivity dictate the developmental stage and mechanism of tolerance. Furthermore, although selection begins in the bone marrow, over one third of primary tolerance occurs in the periphery at the late transitional developmental stage. Notably, we demonstrate that the LC has profound effects on tolerance and can lead to exacerbated autoantibody production.
Journal of Experimental Medicine 12/2012; · 13.85 Impact Factor
-
Gui-Mei Li,
Christopher Chiu,
Jens Wrammert,
Megan McCausland,
Sarah F Andrews,
Nai-Ying Zheng,
Jane-Hwei Lee, Min Huang,
Xinyan Qu,
Srilatha Edupuganti,
Mark Mulligan,
Suman R Das,
Jonathan W Yewdell,
Aneesh K Mehta,
Patrick C Wilson,
Rafi Ahmed
[show abstract]
[hide abstract]
ABSTRACT: We have previously shown that broadly neutralizing antibodies reactive to the conserved stem region of the influenza virus hemagglutinin (HA) were generated in people infected with the 2009 pandemic H1N1 strain. Such antibodies are rarely seen in humans following infection or vaccination with seasonal influenza virus strains. However, the important question remained whether the inactivated 2009 pandemic H1N1 vaccine, like the infection, could also induce these broadly neutralizing antibodies. To address this question, we analyzed B-cell responses in 24 healthy adults immunized with the pandemic vaccine in 2009. In all cases, we found a rapid, predominantly IgG-producing vaccine-specific plasmablast response. Strikingly, the majority (25 of 28) of HA-specific monoclonal antibodies generated from the vaccine-specific plasmablasts neutralized more than one influenza strain and exhibited high levels of somatic hypermutation, suggesting they were derived from recall of B-cell memory. Indeed, memory B cells that recognized the 2009 pandemic H1N1 HA were detectable before vaccination not only in this cohort but also in samples obtained before the emergence of the pandemic strain. Three antibodies demonstrated extremely broad cross-reactivity and were found to bind the HA stem. Furthermore, one stem-reactive antibody recognized not only H1 and H5, but also H3 influenza viruses. This exceptional cross-reactivity indicates that antibodies capable of neutralizing most influenza subtypes might indeed be elicited by vaccination. The challenge now is to improve upon this result and design influenza vaccines that can elicit these broadly cross-reactive antibodies at sufficiently high levels to provide heterosubtypic protection.
Proceedings of the National Academy of Sciences 05/2012; 109(23):9047-52. · 9.68 Impact Factor
-
Roberto Di Niro,
Luka Mesin,
Nai-Ying Zheng,
Jorunn Stamnaes,
Michael Morrissey,
Jane-Hwei Lee, Min Huang,
Rasmus Iversen,
M Fleur du Pré,
Shuo-Wang Qiao,
Knut E A Lundin,
Patrick C Wilson,
Ludvig M Sollid
[show abstract]
[hide abstract]
ABSTRACT: Celiac disease is an immune-mediated disorder in which mucosal autoantibodies to the enzyme transglutaminase 2 (TG2) are generated in response to the exogenous antigen gluten in individuals who express human leukocyte antigen HLA-DQ2 or HLA-DQ8 (ref. 3). We assessed in a comprehensive and nonbiased manner the IgA anti-TG2 response by expression cloning of the antibody repertoire of ex vivo-isolated intestinal antibody-secreting cells (ASCs). We found that TG2-specific plasma cells are markedly expanded within the duodenal mucosa in individuals with active celiac disease. TG2-specific antibodies were of high affinity yet showed little adaptation by somatic mutations. Unlike infection-induced peripheral blood plasmablasts, the TG2-specific ASCs had not recently proliferated and were not short-lived ex vivo. Altogether, these observations demonstrate that there is a germline repertoire with high affinity for TG2 that may favor massive generation of autoreactive B cells. TG2-specific antibodies did not block enzymatic activity and served as substrates for TG2-mediated crosslinking when expressed as IgD or IgM but not as IgA1 or IgG1. This could result in preferential recruitment of plasma cells from naive IgD- and IgM-expressing B cells, thus possibly explaining why the antibody response to TG2 bears signs of a primary immune response despite the disease chronicity.
Nature medicine 01/2012; 18(3):441-5. · 27.14 Impact Factor
-
Jens Wrammert,
Dimitrios Koutsonanos,
Gui-Mei Li,
Srilatha Edupuganti,
Jianhua Sui,
Michael Morrissey,
Megan McCausland,
Ioanna Skountzou,
Mady Hornig,
W Ian Lipkin, [......],
Youliang Wang,
Suman Ranjan Das,
Christopher David O'Donnell,
Jon W Yewdell,
Kanta Subbarao,
Wayne A Marasco,
Mark J Mulligan,
Richard Compans,
Rafi Ahmed,
Patrick C Wilson
[show abstract]
[hide abstract]
ABSTRACT: The 2009 pandemic H1N1 influenza pandemic demonstrated the global health threat of reassortant influenza strains. Herein, we report a detailed analysis of plasmablast and monoclonal antibody responses induced by pandemic H1N1 infection in humans. Unlike antibodies elicited by annual influenza vaccinations, most neutralizing antibodies induced by pandemic H1N1 infection were broadly cross-reactive against epitopes in the hemagglutinin (HA) stalk and head domain of multiple influenza strains. The antibodies were from cells that had undergone extensive affinity maturation. Based on these observations, we postulate that the plasmablasts producing these broadly neutralizing antibodies were predominantly derived from activated memory B cells specific for epitopes conserved in several influenza strains. Consequently, most neutralizing antibodies were broadly reactive against divergent H1N1 and H5N1 influenza strains. This suggests that a pan-influenza vaccine may be possible, given the right immunogen. Antibodies generated potently protected and rescued mice from lethal challenge with pandemic H1N1 or antigenically distinct influenza strains, making them excellent therapeutic candidates.
Journal of Experimental Medicine 01/2011; 208(1):181-93. · 13.85 Impact Factor
