In retrospect, the therapeutic potential of immunoglobulins was first demonstrated by von Behring and Kitasato in the late nineteenth century by protecting mice from the lethal effects caused by tetanus and diphtheria toxin via injection of a hyperimmune serum generated in rabbits. Even today, hyperimmune sera generated from human donors with high serum titers against a certain pathogen are still in use as a means of providing passive protection. More importantly, therapeutic antibodies specific for malignant or autoreactive cells have become included in the standard of care in diseases such as breast cancer and malignant lymphoma. Despite this clinical success, we are only at the beginning of understanding the precise molecular and cellular pathways responsible for immunoglobulin G (IgG) activity in vivo. Since then, an enormous amount of information about the mechanism of IgG activity has been obtained in various model systems. The aim of this review is to provide a comprehensive overview of our current understanding of how IgG antibodies mediate their activity in vivo and how we can use this knowledge to enhance the activity of therapeutic antibodies or block the proinflammatory and tissue pathology inducing activity of autoantibodies. 1. Introduction Antibodies of the IgG isotype are an essential component of our armament against pathogenic microorganisms. IgG binding to invading microorganisms can block their binding to cellular receptors providing the basis for the so-called “sterile” immunity, which protects us from reinfection with highly cytopathic viruses such as influenza. On the other hand, IgG binding to bacteria makes them more visible for phagocytic cells, allowing removing them or their toxic products from the body. Apart from this protective function, autoantibodies directed against self-antigens are a major cause of tissue inflammation or removal of platelets and red blood cells resulting in autoimmune diseases such as systemic lupus erythematosus (SLE), chronic inflammatory demyelinating polyneuropathy (CIDP), skin blistering diseases, immunothrombocytopenia (ITP), and autoimmune hemolytic anemia (AIHA) [1–3]. Finally the potent cytotoxic function of IgG molecules having the capacity to find and destroy virtually any cell within the body is used therapeutically in the form of tumor-specific cytotoxic antibodies, exemplified by CD20, Her2/Neu, or CD52 specific antibodies [4, 5]. A detailed understanding of the molecular and cellular mechanisms underlying IgG activity are therefore of great importance as this may allow (1) improving
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