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Title: Natural polyreactive IgA antibodies coat the intestinal microbiota

Abstract

Large quantities of immunoglobulin A (IgA) are constitutively secreted by intestinal plasma cells to coat and contain the commensal microbiota, yet the specificity of these antibodies remains elusive. In this paper, we profiled the reactivities of single murine IgA plasma cells by cloning and characterizing large numbers of monoclonal antibodies. IgAs were not specific to individual bacterial taxa but rather polyreactive, with broad reactivity to a diverse, but defined, subset of microbiota. These antibodies arose at low frequencies among naïve B cells and were selected into the IgA repertoire upon recirculation in Peyer’s patches. This selection process occurred independent of microbiota or dietary antigens. Furthermore, although some IgAs acquired somatic mutations, these did not substantially influence their reactivity. In conclusion, these findings reveal an endogenous mechanism driving homeostatic production of polyreactive IgAs with innate specificity to microbiota.

Authors:
ORCiD logo [1];  [1]; ORCiD logo [2];  [3];  [2];  [3]; ORCiD logo [3]; ORCiD logo [4]; ORCiD logo [3]; ORCiD logo [1]
  1. Univ. of Chicago, IL (United States). Committee on Immunology and Department of Pathology
  2. Argonne National Lab. (ANL), Argonne, IL (United States). Biosciences Division
  3. Univ. of Chicago, IL (United States). Committee on Immunology and Department of Medicine
  4. Argonne National Lab. (ANL), Argonne, IL (United States). Biosciences Division; Univ. of Chicago, IL (United States). Department of Medicine and Institute for Genomics and Systems Biology
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE; National Institutes of Health (NIH)
OSTI Identifier:
1425279
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Science
Additional Journal Information:
Journal Volume: 358; Journal Issue: 6361; Journal ID: ISSN 0036-8075
Publisher:
AAAS
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Bunker, Jeffrey J., Erickson, Steven A., Flynn, Theodore M., Henry, Carole, Koval, Jason C., Meisel, Marlies, Jabri, Bana, Antonopoulos, Dionysios A., Wilson, Patrick C., and Bendelac, Albert. Natural polyreactive IgA antibodies coat the intestinal microbiota. United States: N. p., 2017. Web. doi:10.1126/science.aan6619.
Bunker, Jeffrey J., Erickson, Steven A., Flynn, Theodore M., Henry, Carole, Koval, Jason C., Meisel, Marlies, Jabri, Bana, Antonopoulos, Dionysios A., Wilson, Patrick C., & Bendelac, Albert. Natural polyreactive IgA antibodies coat the intestinal microbiota. United States. doi:10.1126/science.aan6619.
Bunker, Jeffrey J., Erickson, Steven A., Flynn, Theodore M., Henry, Carole, Koval, Jason C., Meisel, Marlies, Jabri, Bana, Antonopoulos, Dionysios A., Wilson, Patrick C., and Bendelac, Albert. Thu . "Natural polyreactive IgA antibodies coat the intestinal microbiota". United States. doi:10.1126/science.aan6619. https://www.osti.gov/servlets/purl/1425279.
@article{osti_1425279,
title = {Natural polyreactive IgA antibodies coat the intestinal microbiota},
author = {Bunker, Jeffrey J. and Erickson, Steven A. and Flynn, Theodore M. and Henry, Carole and Koval, Jason C. and Meisel, Marlies and Jabri, Bana and Antonopoulos, Dionysios A. and Wilson, Patrick C. and Bendelac, Albert},
abstractNote = {Large quantities of immunoglobulin A (IgA) are constitutively secreted by intestinal plasma cells to coat and contain the commensal microbiota, yet the specificity of these antibodies remains elusive. In this paper, we profiled the reactivities of single murine IgA plasma cells by cloning and characterizing large numbers of monoclonal antibodies. IgAs were not specific to individual bacterial taxa but rather polyreactive, with broad reactivity to a diverse, but defined, subset of microbiota. These antibodies arose at low frequencies among naïve B cells and were selected into the IgA repertoire upon recirculation in Peyer’s patches. This selection process occurred independent of microbiota or dietary antigens. Furthermore, although some IgAs acquired somatic mutations, these did not substantially influence their reactivity. In conclusion, these findings reveal an endogenous mechanism driving homeostatic production of polyreactive IgAs with innate specificity to microbiota.},
doi = {10.1126/science.aan6619},
journal = {Science},
number = 6361,
volume = 358,
place = {United States},
year = {2017},
month = {9}
}

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Works referenced in this record:

Predominant Autoantibody Production by Early Human B Cell Precursors
journal, September 2003


Segmented Filamentous Bacterium Uses Secondary and Tertiary Lymphoid Tissues to Induce Gut IgA and Specific T Helper 17 Cell Responses
journal, April 2014


Diversification of memory B cells drives the continuous adaptation of secretory antibodies to gut microbiota
journal, June 2015

  • Lindner, Cornelia; Thomsen, Irene; Wahl, Benjamin
  • Nature Immunology, Vol. 16, Issue 8
  • DOI: 10.1038/ni.3213

Induction of group A Streptococcus virulence by a human antimicrobial peptide
journal, October 2008

  • Gryllos, I.; Tran-Winkler, H. J.; Cheng, M. -F.
  • Proceedings of the National Academy of Sciences, Vol. 105, Issue 43
  • DOI: 10.1073/pnas.0803815105

Reversible Microbial Colonization of Germ-Free Mice Reveals the Dynamics of IgA Immune Responses
journal, June 2010


Fortifying the barrier: the impact of lipid A remodelling on bacterial pathogenesis
journal, June 2013

  • Needham, Brittany D.; Trent, M. Stephen
  • Nature Reviews Microbiology, Vol. 11, Issue 7
  • DOI: 10.1038/nrmicro3047

Preexisting human antibodies neutralize recently emerged H7N9 influenza strains
journal, February 2015

  • Henry Dunand, Carole J.; Leon, Paul E.; Kaur, Kaval
  • Journal of Clinical Investigation, Vol. 125, Issue 3
  • DOI: 10.1172/JCI74374

Innate secretory antibodies protect against natural Salmonella typhimurium infection
journal, January 2006

  • Wijburg, Odilia L. C.; Uren, Tania K.; Simpfendorfer, Kim
  • The Journal of Experimental Medicine, Vol. 203, Issue 1
  • DOI: 10.1084/jem.20052093

PyNAST: a flexible tool for aligning sequences to a template alignment
journal, November 2009


Induction of Protective IgA by Intestinal Dendritic Cells Carrying Commensal Bacteria
journal, March 2004


Human Autoantibody Silencing by Immunoglobulin Light Chains
journal, July 2004

  • Wardemann, Hedda; Hammersen, Johanna; Nussenzweig, Michel C.
  • The Journal of Experimental Medicine, Vol. 200, Issue 2
  • DOI: 10.1084/jem.20040818

Improved Bacterial 16S rRNA Gene (V4 and V4-5) and Fungal Internal Transcribed Spacer Marker Gene Primers for Microbial Community Surveys
journal, December 2015


Proteobacteria-specific IgA regulates maturation of the intestinal microbiota
journal, September 2013

  • Mirpuri, Julie; Raetz, Megan; Sturge, Carolyn R.
  • Gut Microbes, Vol. 5, Issue 1
  • DOI: 10.4161/gmic.26489

Immune exclusion is a function of IgA
journal, June 1975

  • Stokes, C. R.; Soothill, J. F.; Turner, M. W.
  • Nature, Vol. 255, Issue 5511
  • DOI: 10.1038/255745a0

Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding
journal, July 2011


An improved Greengenes taxonomy with explicit ranks for ecological and evolutionary analyses of bacteria and archaea
journal, December 2011

  • McDonald, Daniel; Price, Morgan N.; Goodrich, Julia
  • The ISME Journal, Vol. 6, Issue 3
  • DOI: 10.1038/ismej.2011.139

Immunoglobulin A Coating Identifies Colitogenic Bacteria in Inflammatory Bowel Disease
journal, August 2014


Innate and Adaptive Immunity Cooperate Flexibly to Maintain Host-Microbiota Mutualism
journal, July 2009


The majority of intestinal IgA+ and IgG+ plasmablasts in the human gut are antigen-specific
journal, May 2011

  • Benckert, Julia; Schmolka, Nina; Kreschel, Cornelia
  • Journal of Clinical Investigation, Vol. 121, Issue 5
  • DOI: 10.1172/JCI44447

New concepts in the generation and functions of IgA
journal, October 2012

  • Pabst, Oliver
  • Nature Reviews Immunology, Vol. 12, Issue 12
  • DOI: 10.1038/nri3322

Cloning and expression of murine Ig genes from single B cells
journal, October 2009

  • Tiller, Thomas; Busse, Christian E.; Wardemann, Hedda
  • Journal of Immunological Methods, Vol. 350, Issue 1-2
  • DOI: 10.1016/j.jim.2009.08.009

Bacterial flagellin is a dominant antigen in Crohn disease
journal, May 2004

  • Lodes, Michael J.; Cong, Yingzi; Elson, Charles O.
  • Journal of Clinical Investigation, Vol. 113, Issue 9
  • DOI: 10.1172/JCI200420295

Identification of FcαRI as an Inhibitory Receptor that Controls Inflammation
journal, January 2005


Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine
journal, January 2016


IgT, a primitive immunoglobulin class specialized in mucosal immunity
journal, August 2010

  • Zhang, Yong-An; Salinas, Irene; Li, Jun
  • Nature Immunology, Vol. 11, Issue 9
  • DOI: 10.1038/ni.1913

Inhibition of Bacterial Adherence by Secretory Immunoglobulin A: A Mechanism of Antigen Disposal
journal, August 1972


Naive Bayesian Classifier for Rapid Assignment of rRNA Sequences into the New Bacterial Taxonomy
journal, June 2007

  • Wang, Q.; Garrity, G. M.; Tiedje, J. M.
  • Applied and Environmental Microbiology, Vol. 73, Issue 16
  • DOI: 10.1128/AEM.00062-07

MyD88 Signaling in T Cells Directs IgA-Mediated Control of the Microbiota to Promote Health
journal, February 2015


Entry Route of Salmonella typhimurium Directs the Type of Induced Immune Response
journal, December 2007


Defective B cell tolerance checkpoints in systemic lupus erythematosus
journal, February 2005

  • Yurasov, Sergey; Wardemann, Hedda; Hammersen, Johanna
  • The Journal of Experimental Medicine, Vol. 201, Issue 5
  • DOI: 10.1084/jem.20042251

Antigen Binding Properties of Purified Immunoglobulin A and Reconstituted Secretory Immunoglobulin A Antibodies
journal, July 1996

  • Lüllau, Elke; Heyse, Stephan; Vogel, Horst
  • Journal of Biological Chemistry, Vol. 271, Issue 27
  • DOI: 10.1074/jbc.271.27.16300

Flagellar glycosylation - a new component of the motility repertoire?
journal, May 2006


Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses
journal, February 2009

  • Sui, Jianhua; Hwang, William C.; Perez, Sandra
  • Nature Structural & Molecular Biology, Vol. 16, Issue 3
  • DOI: 10.1038/nsmb.1566

Functional characterization of IgA-targeted bacterial taxa from undernourished Malawian children that produce diet-dependent enteropathy
journal, February 2015


Development of the gut microbiota and mucosal IgA responses in twins and gnotobiotic mice
journal, May 2016

  • Planer, Joseph D.; Peng, Yangqing; Kau, Andrew L.
  • Nature, Vol. 534, Issue 7606
  • DOI: 10.1038/nature17940

IgA Response to Symbiotic Bacteria as a Mediator of Gut Homeostasis
journal, November 2007


Th17 Cell Induction by Adhesion of Microbes to Intestinal Epithelial Cells
journal, October 2015


Search and clustering orders of magnitude faster than BLAST
journal, August 2010


DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL
journal, August 2002

  • Litinskiy, Mikhail B.; Nardelli, Bernardetta; Hilbert, David M.
  • Nature Immunology, Vol. 3, Issue 9
  • DOI: 10.1038/ni829

Natural IgM Is Produced by CD5 Plasma Cells That Occupy a Distinct Survival Niche in Bone Marrow
journal, November 2014

  • Reynolds, Alexander E.; Kuraoka, Masayuki; Kelsoe, Garnett
  • The Journal of Immunology, Vol. 194, Issue 1
  • DOI: 10.4049/jimmunol.1401203

Adequacy of Chemically Defined, Water-Soluble Diet for Germfree BALB/c Mice Through Successive Generations and Litters
journal, October 1986

  • Pleasants, Julian R.; Johnson, Margaret H.; Wostmann, Bernard S.
  • The Journal of Nutrition, Vol. 116, Issue 10
  • DOI: 10.1093/jn/116.10.1949

IRAK-4- and MyD88-Dependent Pathways Are Essential for the Removal of Developing Autoreactive B Cells in Humans
journal, November 2008


Polyreactivity of antibody molecules
journal, April 2004


Innate and Adaptive Immunity Interact to Quench Microbiome Flagellar Motility in the Gut
journal, November 2013


Maternal IgG and IgA Antibodies Dampen Mucosal T Helper Cell Responses in Early Life
journal, May 2016


IMGT/V-QUEST: the highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysis
journal, May 2008

  • Brochet, X.; Lefranc, M. -P.; Giudicelli, V.
  • Nucleic Acids Research, Vol. 36, Issue Web Server
  • DOI: 10.1093/nar/gkn316

Critical Roles of Activation-Induced Cytidine Deaminase in the Homeostasis of Gut Flora
journal, November 2002


Innate and Adaptive Humoral Responses Coat Distinct Commensal Bacteria with Immunoglobulin A
journal, September 2015


Host interactions of probiotic bacterial surface molecules: comparison with commensals and pathogens
journal, March 2010

  • Lebeer, Sarah; Vanderleyden, Jos; De Keersmaecker, Sigrid C. J.
  • Nature Reviews Microbiology, Vol. 8, Issue 3
  • DOI: 10.1038/nrmicro2297

Polyreactive antibodies in adaptive immune responses to viruses
journal, November 2011

  • Mouquet, Hugo; Nussenzweig, Michel C.
  • Cellular and Molecular Life Sciences, Vol. 69, Issue 9
  • DOI: 10.1007/s00018-011-0872-6

Human Symbionts Use a Host-Like Pathway for Surface Fucosylation
journal, March 2005


Sequence-Intrinsic Mechanisms that Target AID Mutational Outcomes on Antibody Genes
journal, November 2015


Gastric MALT lymphoma B cells express polyreactive, somatically mutated immunoglobulins
journal, January 2010


The Inhibitory Receptor PD-1 Regulates IgA Selection and Bacterial Composition in the Gut
journal, April 2012


Immune history profoundly affects broadly protective B cell responses to influenza
journal, December 2015


IsXenopus IgX an analog of IgA?
journal, December 1996

  • Mußmann, Rainer; Du Pasquier, Louis; Hsu, Ellen
  • European Journal of Immunology, Vol. 26, Issue 12
  • DOI: 10.1002/eji.1830261205

Cardiolipin Polyspecific Autoreactivity in Two Broadly Neutralizing HIV-1 Antibodies
journal, June 2005


QIIME allows analysis of high-throughput community sequencing data
journal, April 2010

  • Caporaso, J. Gregory; Kuczynski, Justin; Stombaugh, Jesse
  • Nature Methods, Vol. 7, Issue 5
  • DOI: 10.1038/nmeth.f.303

Extensive surface diversity of a commensal microorganism by multiple DNA inversions
journal, November 2001

  • Krinos, Corinna M.; Coyne, Michael J.; Weinacht, Katja G.
  • Nature, Vol. 414, Issue 6863
  • DOI: 10.1038/35107092

Characterizing the Interactions between a Naturally Primed Immunoglobulin A and Its Conserved Bacteroides thetaiotaomicron Species-specific Epitope in Gnotobiotic Mice
journal, March 2015

  • Peterson, Daniel A.; Planer, Joseph D.; Guruge, Janaki L.
  • Journal of Biological Chemistry, Vol. 290, Issue 20
  • DOI: 10.1074/jbc.M114.633800

Generation of Gut-Homing IgA-Secreting B Cells by Intestinal Dendritic Cells
journal, November 2006


High-avidity IgA protects the intestine by enchaining growing bacteria
journal, April 2017

  • Moor, Kathrin; Diard, Médéric; Sellin, Mikael E.
  • Nature, Vol. 544, Issue 7651
  • DOI: 10.1038/nature22058

PEAR: a fast and accurate Illumina Paired-End reAd mergeR
journal, October 2013


IMGT/V-QUEST: IMGT Standardized Analysis of the Immunoglobulin (IG) and T Cell Receptor (TR) Nucleotide Sequences
journal, June 2011

  • Giudicelli, V.; Brochet, X.; Lefranc, M. -P.
  • Cold Spring Harbor Protocols, Vol. 2011, Issue 6
  • DOI: 10.1101/pdb.prot5633

Both Neutralizing and Non-Neutralizing Human H7N9 Influenza Vaccine-Induced Monoclonal Antibodies Confer Protection
journal, June 2016


A Neutralizing Antibody Selected from Plasma Cells That Binds to Group 1 and Group 2 Influenza A Hemagglutinins
journal, July 2011


Microbial glycan microarrays define key features of host-microbial interactions
journal, May 2014

  • Stowell, Sean R.; Arthur, Connie M.; McBride, Ryan
  • Nature Chemical Biology, Vol. 10, Issue 6
  • DOI: 10.1038/nchembio.1525

Rapid generation of fully human monoclonal antibodies specific to a vaccinating antigen
journal, February 2009

  • Smith, Kenneth; Garman, Lori; Wrammert, Jens
  • Nature Protocols, Vol. 4, Issue 3
  • DOI: 10.1038/nprot.2009.3

Autoreactivity in Human IgG+ Memory B Cells
journal, February 2007


Refined protocol for generating monoclonal antibodies from single human and murine B cells
journal, November 2016

  • Ho, Irvin Y.; Bunker, Jeffrey J.; Erickson, Steven A.
  • Journal of Immunological Methods, Vol. 438
  • DOI: 10.1016/j.jim.2016.09.001

The maternal microbiota drives early postnatal innate immune development
journal, March 2016

  • Gomez de Aguero, M.; Ganal-Vonarburg, S. C.; Fuhrer, T.
  • Science, Vol. 351, Issue 6279
  • DOI: 10.1126/science.aad2571

Evolutionary Ecology of Prokaryotic Immune Mechanisms
journal, July 2016

  • van Houte, Stineke; Buckling, Angus; Westra, Edze R.
  • Microbiology and Molecular Biology Reviews, Vol. 80, Issue 3
  • DOI: 10.1128/MMBR.00011-16

Half-life of polyreactive antibodies
journal, March 1994

  • Sigounas, George; Harindranath, Nagaradona; Donadel, Giulia
  • Journal of Clinical Immunology, Vol. 14, Issue 2
  • DOI: 10.1007/BF01541346

Highly Conserved Protective Epitopes on Influenza B Viruses
journal, August 2012


The metagenomics RAST server – a public resource for the automatic phylogenetic and functional analysis of metagenomes
journal, September 2008


Do antibodies select a healthy microbiota?
journal, November 2016

  • Kubinak, Jason L.; Round, June L.
  • Nature Reviews Immunology, Vol. 16, Issue 12
  • DOI: 10.1038/nri.2016.114

Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms
journal, March 2012

  • Caporaso, J. Gregory; Lauber, Christian L.; Walters, William A.
  • The ISME Journal, Vol. 6, Issue 8
  • DOI: 10.1038/ismej.2012.8

The microbiota in adaptive immune homeostasis and disease
journal, July 2016


Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation
journal, September 2010

  • Mouquet, Hugo; Scheid, Johannes F.; Zoller, Markus J.
  • Nature, Vol. 467, Issue 7315
  • DOI: 10.1038/nature09385

IgA production requires B cell interaction with subepithelial dendritic cells in Peyers patches
journal, May 2016


Elevated flagellin-specific immunoglobulins in Crohn's disease
journal, February 2005

  • Sitaraman, Shanthi V.; Klapproth, Jan-Michael; Moore, Daniel A.
  • American Journal of Physiology-Gastrointestinal and Liver Physiology, Vol. 288, Issue 2
  • DOI: 10.1152/ajpgi.00357.2004

A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota
journal, November 2009

  • Cong, Y.; Feng, T.; Fujihashi, K.
  • Proceedings of the National Academy of Sciences, Vol. 106, Issue 46
  • DOI: 10.1073/pnas.0812681106

Regulated Virulence Controls the Ability of a Pathogen to Compete with the Gut Microbiota
journal, May 2012


The regulation of IgA class switching
journal, June 2008

  • Cerutti, Andrea
  • Nature Reviews Immunology, Vol. 8, Issue 6
  • DOI: 10.1038/nri2322

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    • DOI: 10.7554/elife.40387