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© The Rockefeller University Press, 0022-1007/1997/1/71/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 1, January 6, 1997 71-80

Articles

Scleroderma Autoantigens Are Uniquely Fragmented by Metal-catalyzed Oxidation Reactions: Implications for Pathogenesis

Livia Casciola-Rosen*,{ddagger}, Fredrick Wigley§, and Antony Rosen§,{ddagger}

From the * Department of Dermatology, § Department of Medicine, and {ddagger} Department of Cell Biology & Anatomy, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

The observation that revelation of immunocryptic epitopes in self antigens may initiate the autoimmune response has prompted the search for processes which induce novel fragmentation of autoantigens as potential initiators of autoimmunity. The reversible ischemia reperfusion which characterizes scleroderma has focused attention on reactive oxygen species as molecules which might induce autoantigen fragmentation. We demonstrate that several of the autoantigens targeted in diffuse scleroderma are uniquely susceptible to cleavage by reactive oxygen species, in a metal-dependent manner. Multiple features of the fragmentation reaction and its inhibition indicate that these autoantigens possess metal-binding sites, which focus metal-catalyzed oxidation reactions (and consequent fragmentation) to specific regions of the antigens. These data suggest that the autoantibody response in scleroderma is the immune marker of unique protein fragmentation, induced by ischemia reperfusion in the presence of appropriate metals, and focus attention on abnormal metal status as a potential pathogenic principle in this disease.

Address correspondence to Dr. A. Rosen, Johns Hopkins University School of Medicine, 720 Rutland Ave. Rm 1055, Baltimore, MD 21205.

This work was supported by the Scleroderma Research Foundation. The authors acknowledge the personal committment of Sharon Monsky in initiating and supporting these studies. A. Rosen is a Pew Scholar in the Biomedical Sciences. L. Casciola-Rosen is supported by a Career Development award from the Dermatology Foundation/Lever Brothers Company.

1Abbreviations used in this paper: EDAC, 1-ethyl 1-3-(3-dimethylaminopropyl) carbodiimide; Fe, ferrous sulfate; ICE, interleukin 1β converting enzyme; NuMA, nuclear mitotic apparatus protein; OH•, hydroxyl radical; ROS, reactive oxygen species; SLE, systemic lupus erythematosus.


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