A Single Human VH-gene Allows for a Broad-Spectrum Antibody Response Targeting Bacterial Lipopolysaccharides in the Blood
Maya Sangesland,
Ashraf S. Yousif,
Larance Ronsard,
Samuel W. Kazer,
Alex Lee Zhu,
G. James Gatter,
Matthew R. Hayward,
Ralston M. Barnes,
Maricel Quirindongo-Crespo,
Daniel Rohrer,
Nils Lonberg,
Douglas Kwon,
Alex K. Shalek,
Daniel Lingwood
Affiliations
Maya Sangesland
The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA
Ashraf S. Yousif
The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA
Larance Ronsard
The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA
Samuel W. Kazer
The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA; Institute for Medical Engineering and Science (IMES), Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, 415 Main St., Cambridge, MA 02142, USA
Alex Lee Zhu
The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA
G. James Gatter
The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA; Institute for Medical Engineering and Science (IMES), Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, 415 Main St., Cambridge, MA 02142, USA
Matthew R. Hayward
The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA
Ralston M. Barnes
Bristol-Myers Squibb, 700 Bay Rd., Redwood City, CA 94063-2478, USA
Maricel Quirindongo-Crespo
Bristol-Myers Squibb, 700 Bay Rd., Redwood City, CA 94063-2478, USA
Daniel Rohrer
Broad Institute of Massachusetts Institute of Technology and Harvard, 415 Main St., Cambridge, MA 02142, USA
Nils Lonberg
Bristol-Myers Squibb, 700 Bay Rd., Redwood City, CA 94063-2478, USA
Douglas Kwon
The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA; Division of Infectious Diseases, Massachusetts General Hospital. 55 Fruit St., Boston, MA 02114, USA
Alex K. Shalek
The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA; Institute for Medical Engineering and Science (IMES), Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, 415 Main St., Cambridge, MA 02142, USA
Daniel Lingwood
The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA; Corresponding author
Summary: B cell receptors (BCRs) display a combination of variable (V)-gene-encoded complementarity determining regions (CDRs) and adaptive/hypervariable CDR3 loops to engage antigens. It has long been proposed that the former tune for recognition of pathogens or groups of pathogens. To experimentally evaluate this within the human antibody repertoire, we perform immune challenges in transgenic mice that bear diverse human CDR3 and light chains but are constrained to different human VH-genes. We find that, of six commonly deployed VH sequences, only those CDRs encoded by IGHV1-2∗02 enable polyclonal antibody responses against bacterial lipopolysaccharide (LPS) when introduced to the bloodstream. The LPS is from diverse strains of gram-negative bacteria, and the VH-gene-dependent responses are directed against the non-variable and universal saccrolipid substructure of this antigen. This reveals a broad-spectrum anti-LPS response in which germline-encoded CDRs naturally hardwire the human antibody repertoire for recognition of a conserved microbial target.
