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

被引：78

作者：

Imkeller, Katharina ^{[1
,2
]}

Scally, Stephen W. ^{[3
]}

Bosch, Alexandre ^{[3
]}

Marti, Gemma Pidelaserra ^{[1
,2
]}

Costa, Giulia ^{[4
]}

Triller, Gianna ^{[1
]}

Murugan, Rajagopal ^{[1
]}

Renna, Valerio ^{[5
]}

Jumaa, Hassan ^{[5
]}

Kremsner, Peter G. ^{[6
,7
]}

Sim, B. Kim Lee ^{[8
]}

Hoffman, Stephen L. ^{[8
]}

Mordmueller, Benjamin ^{[6
,7
]}

Levashina, Elena A. ^{[4
]}

Julien, Jean-Philippe ^{[3
,9
,10
]}

Wardemann, Hedda ^{[1
]}

机构：

[1] German Canc Res Inst, Cell Immunol B, Heidelberg, Germany

[2] Heidelberg Univ, Fac Biosci, Heidelberg, Germany

[3] Hosp Sick Children, Res Inst, Program Mol Med, Toronto, ON, Canada

[4] Max Planck Inst Infect Biol, Vector Biol Unit, Berlin, Germany

[5] Univ Med Ctr Ulm, Inst Immunol, Ulm, Germany

[6] Univ Tubingen, Inst Trop Med, Partner Site, Tubingen, Germany

[7] Univ Tubingen, German Ctr Infect Res, Partner Site, Tubingen, Germany

[8] Sanaria, Rockville, MD USA

[9] Univ Toronto, Dept Biochem, Toronto, ON, Canada

[10] Univ Toronto, Dept Immunol, Toronto, ON, Canada

来源：

SCIENCE | 2018年 / 360卷 / 6395期

基金：

比尔及梅琳达.盖茨基金会; 加拿大健康研究院; 加拿大自然科学与工程研究理事会; 加拿大创新基金会;

关键词：

PLASMODIUM-FALCIPARUM; MALARIA PARASITE; CIRCUMSPOROZOITE PROTEIN; MONOCLONAL-ANTIBODIES; SURFACE-ANTIGEN; INFECTION; SPOROZOITE; VACCINE; REPERTOIRE; SEQUENCE;

D O I：

10.1126/science.aar5304

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：1358 / 1362

页数：5

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