Abstract
A therapeutic preparation of polyclonal human IgG, i.e., intravenous immunoglobulin (IVIg), has been employed to treat several inflammatory and autoimmune disorders. B cells are supposed to be a target of IVIg, but the molecular mechanism is elusive because of the lack of a suitable experimental system. To gain an insight into the beneficial effect of IVIg on B cells, we first established an experimental setting in which IVIg modulates a murine B cell function in vitro, and then aimed at identifying the mechanistic features at the molecular level. Here we show that IVIg down-regulates IL-10 production by CpG-activated B cells in vitro. The responsible component of IVIg was identified as the F(ab’)2 portion, whose polyclonality is mandatory for the suppressive effect. IVIg, bound to the surface of activated B cells, was found to be co-localized with intracellular SHP-1 on confocal laser microscopy, suggesting that B cell-surface immunoreceptor tyrosine-based inhibitory motif-harboring receptors that recruit SHP-1 are target molecules for IVIg in our experimental setting. Overall, we postulate a scenario in which IVIg attenuates B cells by suppressing IL-10 production, a B cell growth factor, and thus down-regulates the production of pathogenic antibodies.
Highlights
Intravenous administration of a large quantity of polyclonal IgG antibodies purified from sera collected from a large number of healthy donors (IVIg) has been performed primarily for patients with antibody deficiencies, but nowadays is being utilized for the treatment of several inflammatory and autoimmune disorders, such as Kawasaki disease and idiotypic immune thrombocytopenic purpura, respectively [1,2]
Since the B cell population in a murine system can be subdivided into B1 and B2 cells, we isolated each population from peritoneal cavities or spleens, respectively, of C57BL/6 mice, and compared their responsiveness to CpG-B oligodeoxynucleotide (CpG), a tolllike receptor (TLR) 9 ligand, in the presence or absence of 10 mg/ml intravenous immunoglobulin (IVIg) or BSA as a control in vitro
That IL-10 production by both CpG-activated B1 and B2 cells was significantly reduced in the presence of IVIg (Figure 1(c))
Summary
Intravenous administration of a large quantity of polyclonal IgG antibodies purified from sera collected from a large number of healthy donors (IVIg) has been performed primarily for patients with antibody deficiencies, but nowadays is being utilized for the treatment of several inflammatory and autoimmune disorders, such as Kawasaki disease and idiotypic immune thrombocytopenic purpura, respectively [1,2]. Considering the pluripotential nature of IgG and the related molecules with which IgG molecules interact, it is reasonable to speculate that the IVIg mechanisms involve multiple scenarios for alleviation of diseases. While IVIg can directly neutralize pathogenic antibodies including autoantibodies via its anti-idiotypic activity in the preparation [5], the idea that activated B cells might be a direct target for IVIg is attractive and has been examined rigorously [1,6]. In support of this notion, autoimmune patients such as one with systemic lupus erythematosus administered IVIg often show rapid and even sustained reduction of anti-nuclear autoantibodies in their serum [7,8]. It has not been established yet whether or not this is the case for humans, because a human
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