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Science. 2018 Jun 22;360(6395):1358-1362. doi: 10.1126/science.aar5304. Epub 2018 Jun 7.

Antihomotypic affinity maturation improves human B cell responses against a repetitive epitope.

Author information

1
B Cell Immunology, German Cancer Research Institute, Heidelberg, Germany.
2
Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
3
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, Canada.
4
Vector Biology Unit, Max Planck Institute for Infection Biology, Berlin, Germany.
5
Institute of Immunology, University Medical Center Ulm, Ulm, Germany.
6
Institute of Tropical Medicine and German Center for Infection Research, Partner Site Tübingen, University of Tübingen, Tübingen, Germany.
7
Sanaria, Rockville, MD, USA.
8
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, Canada. h.wardemann@dkfz.de jean-philippe.julien@sickkids.ca.
9
Departments of Biochemistry and Immunology, University of Toronto, Toronto, ON, Canada.
10
B Cell Immunology, German Cancer Research Institute, Heidelberg, Germany. h.wardemann@dkfz.de jean-philippe.julien@sickkids.ca.

Abstract

Affinity maturation selects B cells expressing somatically mutated antibody variants with improved antigen-binding properties to protect from invading pathogens. We determined the molecular mechanism underlying the clonal selection and affinity maturation of human B cells expressing protective antibodies against the circumsporozoite protein of the malaria parasite Plasmodium falciparum (PfCSP). We show in molecular detail that the repetitive nature of PfCSP facilitates direct homotypic interactions between two PfCSP repeat-bound monoclonal antibodies, thereby improving antigen affinity and B cell activation. These data provide a mechanistic explanation for the strong selection of somatic mutations that mediate homotypic antibody interactions after repeated parasite exposure in humans. Our findings demonstrate a different mode of antigen-mediated affinity maturation to improve antibody responses to PfCSP and presumably other repetitive antigens.

PMID:
29880723
PMCID:
PMC6420115
DOI:
10.1126/science.aar5304
[Indexed for MEDLINE]
Free PMC Article

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