IgG antibodies are the primary mediators of protective humoral immunity against pathogens, but they can also be pathogenic. Acting as cytotoxic molecules or as immune complexes, IgG autoantibodies are the principal mediators of autoimmune diseases such as immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AHA), and systemic lupus erythematosus (SLE), and may contribute to other autoimmune diseases, such as rheumatoid arthritis (RA), type I diabetes, and multiple sclerosis . IgG antibodies have been used therapeutically for over a century. They were first used as antitoxins for the treatment of infectious diseases in the preantibiotic era . Today, hyperimmune sera from human donors recovering from infection with specific viruses, such as hepatitis B, cytomegalovirus, and varicella zoster, are used to provide protective immunity to susceptible populations. In addition, pooled polyclonal IgG from the serum of thousands of donors is currently used to provide replacement IVIG therapy for patients lacking immunoglobulins . At high doses (1 g/kg), IVIG is also widely used as an antiinflammatory agent for the treatment of autoimmune diseases. This approach is based on an observation made in 1981 that administration of IVIG attenuated platelet clearance in a child with ITP . Since then, high dose IVIG has been widely used to treat patients with immune system disorders and is FDA approved for the treatment of ITP and Kawasaki's Disease, an acute vasculitic syndrome, in addition to humoral immunodeficiency and bone marrow transplantation. Off label uses include the treatment of RA, SLE, multiple sclerosis, and scleroderma. Demand for IVIG has been increasing in recent years, resulting in shortages and restrictions in its use. In the United States, over 4 million grams of IVIG was used in 2004 at a cost of $500 million, more than half of which was off label use.

The mechanisms by which high doses of pooled, monomeric IgG provide antiinflammatory activity have been the subject of much speculation, stemming from the fact that IgGs can form many different binding interactions through both their antigen binding and Fc domains. In this commentary, we will address the current models of IVIG antiinflammatory activity and review recent results that argue against these models and support an alternative, novel mechanism of action. This new model accounts for the high dose requirement for IVIG in inflammatory diseases and for the dominant role of the Fc portion of the molecule, and suggests ways to improve therapeutics for autoimmune diseases.

The observation that IVIG activity is caused by a limiting concentration of a sialic acid–bearing IgG glycoform provides the rationale for the preparation of a sialic acid–enriched IVIG product that would confer greater antiinflammatory activity at doses 1/10 to 1/100 currently required. It also suggests that a fully recombinant IVIG composed of hypersialylated IgG would be a potent antiinflammatory agent for use in autoimmune diseases. The identity of the macrophage receptor involved in the binding of sialylated IgG and the characterization of the inhibitory pathways induced by sialylated IgG will provide insights into the normal biological functions of sialylated IgG in vivo and the homeostatic pathways that regulate IgG effector activity.