Research Highlights

Intravenous immunoglobulin (IVIG): Straight from bench to bedside

Proposed mechanisms of action of intravenous immunoglobulin. Detail of Fig. 3 from Bayry, J. et al. Monoclonal antibody and intravenous immunoglobulin therapy for rheumatic diseases. Nat Clin Pract Rheumatol 3, 262-272 (2007)

IVIG is prepared by purifying IgG derived from the pooled blood plasma of several thousand donors. When injected in high doses it has an anti-inflammatory effect on autoimmune conditions such as immune thrombocytopenia. IVIG can also attenuate the cytotoxic effects on platelets that are induced by monoclonal IgG antibodies. It is known that the effect of IVIG derives from its sialylated Fc (fragment, crystallable) component. Sialylated Fc binds to a lectin found on regulatory myeloid cells, such as a subset of splenic macrophages in the mouse, which in turn modulate effector inflammatory macrophages by upregulating their inhibitory Fc receptors (FcRs). However, the role of the Fc glycan structure in this process has not yet been determined. IgG Fc carries a biantennary, complex N-glycan at Asn 297 that is terminated by the sialic acid N-acetylneuraminic acid (NeuAc), which is attached in an 2,3- or 2,6-linkage to the penultimate galactose. Now, in Science, Anthony et al. show that it is the type of sialic acid linkage that is responsible for the anti-inflammatory potency of IVIG.

Anthony et al. injected sialidase-treated IVIG into mice treated with K/BxN serum, which is a murine model for arthritis. They found that any anti-inflammatory activity was lost upon removal of 2,6-linked NeuAc, but was retained after 2,3-sialidase treatment. Similarly, in vitro galactosylation and sialylation of unglycosylated IVIG Fcs gave rise to anti-inflammatory molecules only upon the presence of 2,6-sialyltransferase. These findings show that the anti-inflammatory effects of IVIG are solely dependent upon the presence of an 2,6-linked sialic acid. Furthermore, recombinantly generated, galactosylated and sialylated IgG Fc was found to be active at concentrations 30 times less than that of donor-pooled IVIG.

In contrast to the anti-inflammatory effects of IVIG, the authors found that both 2,3- and 2,6-sialylated IgG Fcs reduced the toxic effects of monoclonal IgG antibodies on platelets. The authors conclude that the anti-inflammatory and anti-cytotoxic effects of IVIG are mediated by different Fc binding receptors. They hypothesize that a non-canonical FcR with lectin activity is involved in these anti-inflammatory effects.

The results of Anthony et al. illustrate the remarkable specificity of glycan-receptor interactions, as not only the carbohydrate type, but also its linkage to the penultimate carbohydrate determines the interaction of IVIG and its cognate receptor. In clinical practice, the use of native IVIG may eventually be entirely replaced by recombinant diglycosylated IVIG Fc, thus eliminating the dependency on large amounts of human blood plasma for the generation of IVIG.

Author: Mirko von Elstermann