Allelic-dependent expression of an activating Fc receptor on B cells enhances humoral immune responses.

Abstract

B cells are pivotal regulators of acquired immune responses, and recent work in both experimental murine models and humans has demonstrated that subtle changes in the regulation of B cell function can substantially alter immunological responses. The balance of negative and positive signals in maintaining an appropriate B cell activation threshold is critical in B lymphocyte immune tolerance and autoreactivity. FcγRIIb (CD32B), the only recognized Fcγ receptor on B cells, provides immunoglobulin G (IgG)-mediated negative modulation through a tyrosine-based inhibition motif, which down-regulates B cell receptor-initiated signaling. These properties make FcγRIIb a promising target for antibody-based therapy. We report the discovery of allele-dependent expression of the activating FcγRIIc on B cells. Identical to FcγRIIb in the extracellular domain, FcγRIIc has a tyrosine-based activation motif in its cytoplasmic domain. In both human B cells and B cells from mice transgenic for human FcγRIIc, FcγRIIc expression counterbalances the negative feedback of FcγRIIb and enhances humoral responses to immunization in mice and to BioThrax vaccination in a human anthrax vaccine trial. Moreover, the FCGR2C-ORF allele is associated with the risk of development of autoimmunity in humans. FcγRIIc expression on B cells challenges the prevailing paradigm of unidirectional negative feedback by IgG immune complexes via the inhibitory FcγRIIb, is a previously unrecognized determinant in human antibody/autoantibody responses, and opens the opportunity for more precise personalized use of B cell-targeted antibody-based therapy.

• Authors: Xinrui Li, Jianming Wu, Travis Ptacek, David T Redden, Elizabeth E Brown, Graciela S Alarcón, Rosalind Ramsey-Goldman, Michelle A Petri, John D Reveille, Richard A Kaslow, Robert P Kimberly, Jeffrey C Edberg
• Journal: Science translational medicine (Sci Transl Med) Vol. 5 Issue 216 Pg. 216ra175 (Dec 18 2013) ISSN: 1946-6242 [Electronic] United States
• PMID: 24353158 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anthrax Vaccines
• Codon, Terminator
• FCGR2B protein, human
• Fc gamma receptor IIC
• Receptors, Antigen, B-Cell
• Receptors, IgG

Topics

• Adult
• Alleles
• Animals
• Anthrax Vaccines (administration & dosage)
• Autoimmunity (genetics)
• B-Lymphocytes (immunology)
• Base Sequence
• Cell Line
• Codon, Terminator (genetics)
• Female
• Gene Expression
• Homozygote
• Humans
• Immunity, Humoral
• Male
• Mice
• Mice, Transgenic
• Middle Aged
• Open Reading Frames
• Polymorphism, Single Nucleotide
• Protein Structure, Tertiary
• Receptors, Antigen, B-Cell (metabolism)
• Receptors, IgG (chemistry, genetics, metabolism)
• Signal Transduction
• Translational Research, Biomedical