Lower IgG somatic hypermutation rates during acute dengue virus infection is compatible with a germinal center-independent B cell response.

Abstract

BACKGROUND:

The study of human B cell response to dengue virus (DENV) infection is critical to understand serotype-specific protection and the cross-reactive sub-neutralizing response. Whereas the first is beneficial and thus represents the ultimate goal of vaccination, the latter has been implicated in the development of severe disease, which occurs in a small, albeit significant, fraction of secondary DENV infections. Both primary and secondary infections are associated with the production of poly-reactive and cross-reactive IgG antibodies.

METHODS:

To gain insight into the effect of DENV infection on the B cell repertoire, we used VH region high-throughput cDNA sequencing of the peripheral blood IgG B cell compartment of 19 individuals during the acute phase of infection. For 11 individuals, a second sample obtained 6 months later was analyzed for comparison. Probabilities of sequencing antibody secreting cells or memory B cells were estimated using second-order Monte Carlo simulation.

RESULTS:

We found that in acute disease there is an increase in IgG B cell diversity and changes in the relative use of segments IGHV1-2, IGHV1-18, and IGHV1-69. Somewhat unexpectedly, an overall low proportion of somatic hypermutated antibody genes was observed during the acute phase plasmablasts, particularly in secondary infections and those cases with more severe disease.

CONCLUSIONS:

Our data are consistent with an innate-like antiviral recognition system mediated by B cells using defined germ-line coded B cell receptors, which could provide a rapid germinal center-independent antibody response during the early phase of infection. A model describing concurrent T-dependent and T-independent B cell responses in the context of DENV infection is proposed, which incorporates the selection of B cells using hypomutated IGHV segments and their potential role in poly/cross-reactivity. Its formal demonstration could lead to a definition of its potential implication in antibody-dependent enhancement, and may contribute to rational vaccine development efforts.

• Authors: Elizabeth Ernestina Godoy-Lozano, Juan Téllez-Sosa, Gilberto Sánchez-González, Hugo Sámano-Sánchez, Andrés Aguilar-Salgado, Aarón Salinas-Rodríguez, Bernardo Cortina-Ceballos, Héctor Vivanco-Cid, Karina Hernández-Flores, Jennifer M Pfaff, Kristen M Kahle, Benjamin J Doranz, Rosa Elena Gómez-Barreto, Humberto Valdovinos-Torres, Irma López-Martínez, Mario H Rodriguez, Jesús Martínez-Barnetche
• Journal: Genome medicine (Genome Med) Vol. 8 Issue 1 Pg. 23 (Feb 25 2016) ISSN: 1756-994X [Electronic] England
• PMID: 26917418 (Publication Type: Journal Article)

Chemical References

• Complementarity Determining Regions
• Immunoglobulin G
• Immunoglobulin Heavy Chains
• Immunoglobulin Variable Region

Topics

• Acute Disease
• Adolescent
• Adult
• Amino Acid Motifs
• B-Lymphocytes (immunology, metabolism)
• Cluster Analysis
• Complementarity Determining Regions (genetics)
• Computational Biology
• Dengue (diagnosis, genetics, immunology, virology)
• Dengue Virus (classification, genetics, immunology)
• Female
• Gene Expression Profiling
• Germinal Center (immunology)
• High-Throughput Nucleotide Sequencing
• Humans
• Immunoglobulin G (genetics, immunology)
• Immunoglobulin Heavy Chains (genetics)
• Immunoglobulin Variable Region (genetics)
• Male
• Middle Aged
• Mutation
• Position-Specific Scoring Matrices
• Serogroup
• Somatic Hypermutation, Immunoglobulin
• Young Adult