[Mechanisms of immunoglobulins activity]

Intravenous immunoglobulin (IVIG) products are derived from plasma pools of thousands of healthy donors. These immunoglobulin concentrates contain large number of antibodies as well trace levels various other immunologically active molecules. Therapeutic Ig formulations contain intact IgG molecules, with variable amounts of monomeric and dimeric form existing in a dynamic equilibrium. Paradoxically, IgG can exert both pro-and anti-inflammatory activities, depending on its concentration. IVIG have been used for the treatment of primary immunodeficiency disorders for more than 25 years. IVIG products are also effective in the treatment of autoimmune and inflammatory disorders; however, the precise mechanism (s) of action is not known. Clinical and laboratory studies have documented various mechanisms of action of IVIG. The complex network of immunological reactions resulting from the infusion of IVIG includes changes in several cytokines, interactions with dendritic cells, T-and B-cell effects, macrophage effects, mediated by distinct Fc-gamma receptors. IVIG is also a recently recognized modifier of complement activation and injury. The complement--scavenging ability of Ig implies expansion of the use of IVIG to all disease in which generation of complement fragments plays a crucial role in pathogenesis. Recent studies showed that the anti-inflammatory activity of IVIG result from a minor population of the pooled IgG molecules that contains terminal a-2,6 sialic acid linkages on their Fc-linked glycans. This fully processed glycan is found in 1-3% of IgG in IVIG, which may explain the requirement for a high dose of IVIG. Recent data demonstrate, that the anti-inflammatory properties of IVIG can be recapitulated with fully recombinant preparation of appropriately sialylated IgG Fc fragments. This recombinant preparation had a 35 fold enhanced activity and potentially could be used at much lower doses than IVIG preparation in the treatment of autoimmune disorders.