Fcγ receptor IIB (FcγRIIB) maintains humoral tolerance in the human immune system in vivo

Abstract

Maintenance of immunological tolerance is crucial to prevent development of autoimmune disease. The production of autoantibodies is a hallmark of many autoimmune diseases and studies in mouse model systems suggest that inhibitory signaling molecules may be important checkpoints of humoral tolerance. By generating humanized mice with normal and functionally impaired Fcγ receptor IIB (FcγRIIB) variants, we show that the inhibitory Fcγ-receptor is a checkpoint of humoral tolerance in the human immune system in vivo. Impaired human FcγRIIB function resulted in the generation of higher levels of serum immunoglobulins, the production of different autoantibody specificities, and a higher proportion of human plasmablasts and plasma cells in vivo. Our results suggest that the inhibitory FcγRIIB may be an important checkpoint of humoral tolerance in the human immune system.

Antagonistic Human FcγRIIB (CD32B) Antibodies Have Anti-Tumor Activity and Overcome Resistance to Antibody Therapy In Vivo

“…(E and F) Data analyzed using one-way ANOVA and (C, D, G, and H) a permutation statistical test. See also Figure S6 and Tables S3 and S4. as autoimmunity where FcgRIIB-expressing targets may be amenable to manipulation, for example in systemic light-chain amyloidosis where the target PCs express high levels of FcgRIIB (Zhou et al, 2008) and rheumatoid arthritis where B cell activation might be reduced through agonism of FcgRIIB (Baerenwaldt et al, 2011;Mauri and Jury, 2010). Clinical investigations in all of these areas are now warranted.…”

Molecular and Cellular Pathways of Immunoglobulin G Activity In Vivo

“…Underlining the importance of this activation threshold set by this receptor for B cell activation, Fc RIIB deficient mice start to develop autoantibodies and develop a SLE-like autoimmune disease on certain mouse genetic backgrounds [22][23][24][25][26]. In a similar manner nonfunctional Fc RIIB alleles or promoter polymorphisms causing a lower expression level have been associated with the development or severity of human and mouse autoimmune diseases and humanized mice transplanted with a human immune system carrying the nonfunctional Fc RIIB allele in a homozygous fashion start to develop autoantibodies [13,[26][27][28][29][30]. As this interesting gatekeeper function of Fc RIIB is not the main focus of this paper, the interested reader is directed to several excellent recent reviews covering this in greater detail [6,15,21].…”

Humanized mice: Current states and perspectives

“…These "memory" B cells also express IgM. This phenotype was associated with the presence of serum IgM levels, but nearly undetectable serum IgG levels; this indicates an absence of class-switching, which we will discuss below [8,22,[32][33][34]. It was also reported that the majority of HIS B cells expressed CD5 [32].…”