Roles of Fc domain and exudation in L2 antibody-mediated protection against human papillomavirus

Joshua W. Wang, Wai Hong Wu, Tsui Chin Huang, Margaret Wong, Kihyuck Kwak, Keiko Ozato, Chien-Fu Hung, Richard S Roden

Research output: Contribution to journalArticle

Abstract

To address how L2-specific antibodies prevent human papillomavirus (HPV) infection of the genital tract, we generated neutralizing monoclonal antibodies (MAbs) WW1, a rat IgG2a that binds L2 residues 17 to 36 (like mouse MAb RG1), and JWW3, a mouse IgG2b derivative of Mab24 specific for L2 residues 58 to 64. By Western blotting, WW1 recognized L2 of 29/34 HPV genotypes tested, compared to only 13/34 for RG1 and 25/34 for JWW3. WW1 IgG and F(ab')2 bound HPV16 pseudovirions similarly; however, whole IgG provided better protection against HPV vaginal challenge. Passive transfer of WW1 IgG was similarly protective in wild-type and neonatal Fc receptor (FcRn)-deficient mice, suggesting that protection by WW1 IgG is not mediated by FcRn-dependent transcytosis. Rather, local epithelial disruption, required for genital infection and induced by either brushing or nonoxynol-9 treatment, released serum IgG in the genital tract, suggesting Fc-independent exudation. Depletion of neutrophils and macrophages reduced protection of mice upon passive transfer of whole WW1 or JWW3 IgGs. Similarly, IgG-mediated protection by L2 MAbs WW1, JWW3, and RG1 was reduced in Fc receptor knockout compared to wild-type mice. However, levels of in vitro neutralization by WW1 IgG were similar in TRIM21 knockout and wild-type cells, indicating that Fc does not contribute to antibody-dependent intracellular neutralization (ADIN). In conclusion, the Fc domain of L2-specific IgGs is not active for ADIN, but it opsonizes bound extracellular pseudovirions for phagocytes in protecting mice from intravaginal HPV challenge. Systemically administered neutralizing IgG can access the site of infection in an abrasion via exudation without the need for FcRn-mediated transcytosis.

Original languageEnglish (US)
Article numbere00572-18
JournalJournal of Virology
Volume92
Issue number15
DOIs
StatePublished - Aug 1 2018

Fingerprint

Papillomaviridae
exudation
Immunoglobulin G
neutralization
antibodies
Antibodies
mice
physiological transport
genitalia
Transcytosis
monoclonal antibodies
infection
receptors
Nonoxynol
phagocytes
Monoclonal Antibodies
neutralizing antibodies
Papillomavirus Infections
Fc Receptors
neutrophils

Keywords

  • Antibody-mediated protection
  • Cross-protection
  • Fc
  • FcRn
  • Human papillomavirus
  • Humoral immunity
  • L2 protein
  • Monoclonal antibody
  • Neutralizing antibodies
  • TRIM21

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Roles of Fc domain and exudation in L2 antibody-mediated protection against human papillomavirus. / Wang, Joshua W.; Wu, Wai Hong; Huang, Tsui Chin; Wong, Margaret; Kwak, Kihyuck; Ozato, Keiko; Hung, Chien-Fu; Roden, Richard S.

In: Journal of Virology, Vol. 92, No. 15, e00572-18, 01.08.2018.

Research output: Contribution to journalArticle

Wang, Joshua W. ; Wu, Wai Hong ; Huang, Tsui Chin ; Wong, Margaret ; Kwak, Kihyuck ; Ozato, Keiko ; Hung, Chien-Fu ; Roden, Richard S. / Roles of Fc domain and exudation in L2 antibody-mediated protection against human papillomavirus. In: Journal of Virology. 2018 ; Vol. 92, No. 15.
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abstract = "To address how L2-specific antibodies prevent human papillomavirus (HPV) infection of the genital tract, we generated neutralizing monoclonal antibodies (MAbs) WW1, a rat IgG2a that binds L2 residues 17 to 36 (like mouse MAb RG1), and JWW3, a mouse IgG2b derivative of Mab24 specific for L2 residues 58 to 64. By Western blotting, WW1 recognized L2 of 29/34 HPV genotypes tested, compared to only 13/34 for RG1 and 25/34 for JWW3. WW1 IgG and F(ab')2 bound HPV16 pseudovirions similarly; however, whole IgG provided better protection against HPV vaginal challenge. Passive transfer of WW1 IgG was similarly protective in wild-type and neonatal Fc receptor (FcRn)-deficient mice, suggesting that protection by WW1 IgG is not mediated by FcRn-dependent transcytosis. Rather, local epithelial disruption, required for genital infection and induced by either brushing or nonoxynol-9 treatment, released serum IgG in the genital tract, suggesting Fc-independent exudation. Depletion of neutrophils and macrophages reduced protection of mice upon passive transfer of whole WW1 or JWW3 IgGs. Similarly, IgG-mediated protection by L2 MAbs WW1, JWW3, and RG1 was reduced in Fc receptor knockout compared to wild-type mice. However, levels of in vitro neutralization by WW1 IgG were similar in TRIM21 knockout and wild-type cells, indicating that Fc does not contribute to antibody-dependent intracellular neutralization (ADIN). In conclusion, the Fc domain of L2-specific IgGs is not active for ADIN, but it opsonizes bound extracellular pseudovirions for phagocytes in protecting mice from intravaginal HPV challenge. Systemically administered neutralizing IgG can access the site of infection in an abrasion via exudation without the need for FcRn-mediated transcytosis.",
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