title: 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.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Xinrui
authors.initials: X
authors.lastname: Li
authors.forename: Jianming
authors.initials: J
authors.lastname: Wu
authors.forename: Travis
authors.initials: T
authors.lastname: Ptacek
authors.forename: David T
authors.initials: DT
authors.lastname: Redden
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Brown
authors.forename: Graciela S
authors.initials: GS
authors.lastname: Alarcón
authors.forename: Rosalind
authors.initials: R
authors.lastname: Ramsey-Goldman
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Petri
authors.forename: John D
authors.initials: JD
authors.lastname: Reveille
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kaslow
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Edberg
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D022122:Anthrax Vaccines / Q000008:administration & dosage; D015551:Autoimmunity / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D002460:Cell Line; D018388:Codon, Terminator / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006720:Homozygote; D006801:Humans; D056724:Immunity, Humoral; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D016366:Open Reading Frames; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D017452:Receptors, IgG / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D057170:Translational Research, Biomedical
chemical_list: D022122:Anthrax Vaccines; D018388:Codon, Terminator; C499173:FCGR2B protein, human; C080572:Fc gamma receptor IIC; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG