Abstract
BackgroundIdeS, a proteinase from Streptococcus pyogenes, cleaves immunoglobulin (Ig)G antibodies with a unique degree of specificity. Pathogenic IgG antibodies constitute an important clinical problem contributing to the pathogenesis of a number of autoimmune conditions and acute transplant rejection. To be able to effectively remove such antibodies is therefore an important clinical challenge.Methodology/Principal FindingsIdeS was found to specifically and efficiently cleave IgG in human blood in vitro (20 µg of IdeS caused a complete degradation of IgG in one ml of human whole blood in 15 minutes) and to clear IgG from the blood stream of rabbits in vivo (no IgG was detected six hours following an intravenous injection of 5 mg of IdeS) without any side effects. In a mouse model of immune thrombocytopenic purpura (ITP), polyclonal IgG antibodies against platelet surface antigens were used to induce a lethal disease. These profoundly thrombocytopenic animals were treated and cured by a single injection of IdeS.Conclusions/SignificanceNovel information is provided concerning the IgG-cleaving activity of IdeS in vitro and in vivo. The highly specific and rapid elimination of IgG in vivo, the dramatic effect in a mouse model of ITP, and the lack of side effects in the treated animals, indicate that IdeS could also be used to treat IgG-driven diseases in humans.
Highlights
Antibodies play an important role in the defence against invading microorganisms
It is estimated that autoimmune diseases affect about five percent of people [1], and in many of these conditions (rheumatoid arthritis, systemic lupus, myasthenia gravis, immune thrombocytopenic purpura (ITP), Goodpasture’s syndrome, etc) IgG autoantibodies reacting with human molecules contribute to the pathogenesis
In these conditions removal of pathogenic IgG antibodies from the blood circulation represents a logical therapeutic strategy, and extracorporeal immunoadsorption where patient plasma is passed over columns that bind IgG, has proven to be beneficial in several autoimmune conditions [2,3,4,5,6,7]
Summary
Antibodies play an important role in the defence against invading microorganisms. Among the five classes of antibodies, immunoglobulin (Ig)G is the quantitatively dominating class, and apart from albumin the most abundant protein in human blood (7–16 mg/ml blood plasma). The results demonstrate that the enzyme in vitro efficiently cleaves IgG in human whole blood, removes IgG from the blood circulation of rabbits without any side effects, and cures mice from lethal IgGinduced thrombocytopenia. The results show that these antibodies do not inactivate the IgG-cleaving activity of IdeS when used at a concentration (20 mg IdeS/ml plasma) that completely cleaves IgG in human blood (Fig. 1B, lane 4).
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