The Journal of Immunology, Vol 159, Issue 3 1530-1536, Copyright © 1997 by American Association of Immunologists

ARTICLES

Characterization of thyroglobulin-directed and polyreactive catalytic antibodies in autoimmune disease

S Paul, L Li, R Kalaga, J O'Dell, RE Dannenbring Jr, S Swindells, S Hinrichs, P Caturegli and NR Rose
Department of Anesthesiology, Eppley Cancer Research Institute, University of Nebraska Medical Center, Omaha 68198, USA. spaul@mail.unmc.edu

Polyreactive and thyroglobulin (Tg)-directed proteolytic activities present in the serum IgG of healthy controls and patients with autoimmune disease were studied by electrophoretic separation of 125I- labeled Tg reaction products and spectrofluorometric measurement of Pro- Phe-Arg-methylcoumarinamide cleavage at the Arg-methylcoumarinamide bond. A decrease of the polyreactive proteolytic activity accompanying an increase of the Tg-cleaving activity in IgG from autoimmune thyroiditis (ATh) and systemic lupus erythematosus (SLE) patients was evident. The Tg, a known target of autoimmune reactions in ATh, was cleaved at lower levels by Abs from patients with this disease than from SLE patients. The Tg-cleaving and Tg-binding activities of the autoantibody preparations were not correlated. Enhanced rates of cleavage at saturating substrate concentrations (Vmax), not increased Tg-binding affinities, were evident in IgG preparations with the greatest Tg-cleaving activity. Similarly, diminution of the polyreactive proteolytic activity in IgG from the autoimmune disease patients was due to decreased Vmax values, not decreased substrate- binding affinities. No cleavage of Tg by IgG from subjects with HIV-1 infection, or from mice hyperimmunized with an albumin-hapten conjugate was evident, suggesting that generation of Tg-cleaving Abs does not accompany V region affinity maturation in response to unrelated Ags. These observations establish Tg as a target of catalytic autoantibodies in SLE and ATh, suggest a transition from polyreactive proteolytic activity to autoantigen-directed activity in autoimmune disease, and open the possibility that combining site chemical reactivity is a factor driving the expression of catalytic activity by autoantibodies.

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