Removing a sugar turns protective antibodies into attackers

In autoimmune diseases like arthritis and lupus, proteins whose job it is to recognize and fight foreign invaders somehow stop recognizing the body as “self” and begin to attack. But exactly what happens to these antibody proteins to transform them into pathological “autoantibodies” capable of causing tissue damage and disease has remained a puzzle to immunologists. New research from Rockefeller University is slowly putting some of the pieces in place.

In a paper in the Proceedings of the National Academy of Sciences, Jeffrey Ravetch — Theresa and Eugene M. Lang Professor and head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology — shows that the ability of the IgG family of antibodies to efficiently trigger inflammation depends on a specific sugar molecule at the stem of the Y-shaped antibody structure. Years of prior research have confirmed that patients with autoimmune diseases have variations in the sugar patterns on their antibodies. Now, Ravetch and postdocs Falk Nimmerjahn and Robert Anthony investigate how these sugar modifications might be responsible for altering antibody activity to make them more pathogenic.

Earlier work by Ravetch has shown that, in a pooled solution of antibodies called intravenous immunoglobulin (IVIG), the presence of the sialic acid sugar on IgG antibodies confers protective, anti-inflammatory properties. Now, the researchers show that, in mice, antibodies associated with more destructive autoimmune diseases appear to be lacking this sialic acid. “The differences in sugar pattern that have been seen in the past, the ones that are associated with more pathogenic autoantibodies, result from this sialic acid effect,” Ravetch says. “This research offers a further confirmation of our previous studies, showing that it’s relevant for autoimmune diseases and giving us a greater basis for saying that as we modify antibodies, the modification of sialic acid is key for changing their activity.”

Now that they have homed in on the importance of sialic acid in determining whether an IgG antibody is pro-inflammatory or anti-inflammatory, Ravetch now plans to look at patients in different stages of multiple autoimmune diseases, as well as healthy individuals who’ve just been vaccinated, in order to determine how the addition of sialic acid to IgG antibodies is regulated in healthy and disease states. He believes that unraveling the mechanisms that regulate this “sialic acid switch” will ultimately lead to new opportunities for vaccine design and treatment of autoimmune diseases.

Proceedings of the National Academy of Sciences 104(20): 8433-8437 (May 15, 2007)

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