Immune tolerance negatively regulates B cells in knock-in mice expressing broadly neutralizing HIV antibody 4E10
| Autor: | Anthony B. Cooper, Michael B. Zwick, William R. Schief, David Nemazee, Krystalyn E. Hudson, Patrick Skog, Colleen Doyle-Cooper, Phillip E. Dawson, Takayuki Ota, Dennis R. Burton |
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| Rok vydání: | 2013 |
| Předmět: |
HIV Antigens
Immunology Enzyme-Linked Immunosorbent Assay Mice Transgenic HIV Antibodies HIV Envelope Protein gp120 Epitope Recombination-activating gene Clonal deletion Article Immune tolerance Negative selection Mice medicine Immune Tolerance Immunology and Allergy Animals Gene Knock-In Techniques B cell AIDS Vaccines B-Lymphocytes biology Receptor editing Flow Cytometry Virology Antibodies Neutralizing HIV Envelope Protein gp41 Mice Inbred C57BL medicine.anatomical_structure biology.protein Immunoglobulin Light Chains Antibody Immunoglobulin Heavy Chains |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 191(6) |
| ISSN: | 1550-6606 |
| Popis: | A major goal of HIV research is to develop vaccines reproducibly eliciting broadly neutralizing Abs (bNAbs); however, this has proved to be challenging. One suggested explanation for this difficulty is that epitopes seen by bNAbs mimic self, leading to immune tolerance. We generated knock-in mice expressing bNAb 4E10, which recognizes the membrane proximal external region of gp41. Unlike b12 knock-in mice, described in the companion article (Ota et al. 2013. J. Immunol. 191: 3179–3185), 4E10HL mice were found to undergo profound negative selection of B cells, indicating that 4E10 is, to a physiologically significant extent, autoreactive. Negative selection occurred by various mechanisms, including receptor editing, clonal deletion, and receptor downregulation. Despite significant deletion, small amounts of IgM and IgG anti-gp41 were found in the sera of 4E10HL mice. On a Rag1−/− background, 4E10HL mice had virtually no serum Ig of any kind. These results are consistent with a model in which B cells with 4E10 specificity are counterselected, raising the question of how 4E10 was generated in the patient from whom it was isolated. This represents the second example of a membrane proximal external region–directed bNAb that is apparently autoreactive in a physiological setting. The relative conservation in HIV of the 4E10 epitope might reflect the fact that it is under less intense immunological selection as a result of B cell self-tolerance. The safety and desirability of targeting this epitope by a vaccine is discussed in light of the newly described bNAb 10E8. |
| Databáze: | OpenAIRE |
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