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-Fodrin in Sjögren’s Syndrome Reveals Novel Apoptosis-Induced Specificity
From the Department of Immunology,* The Scripps Research Institute, La Jolla, California; the Allergy and Rheumatology Clinic, The Scripps Memorial Hospital, La Jolla, California; the Department of Pathology, Tsurumi University School of Dental Medicine, Yokohama, Japan; the Department of Pathology, Tokushima University School of Dentistry, Tokushima, Japan; Center of Medical Biotechnology,¶ Institute of Medical Biology, University of Southern Denmark, Odense, Denmark; and Department of Internal Medicine C,|| Odense University Hospital, Odense, Denmark
Lymphocyte infiltration of salivary and lacrimal glands leading to diminished secretion and gland destruction as a result of apoptosis is thought to be pivotal in the pathogenesis of Sjögren’s syndrome (SS). The cytoskeletal protein 
-fodrin is cleaved during this apoptotic process, and a strong antibody (Ab) response is elicited to a 120-kd fragment of cleaved -fodrin in the majority of SS patients, but generally not in other diseases in which apoptosis also occurs. Little is known about the anti--fodrin autoantibody response on a molecular level. To address this issue, IgG phage display libraries were generated from the bone marrow of two SS donors and a panel of anti--fodrin IgGs was isolated by selection on -fodrin immunoblots. All of the human monoclonal Abs (hmAbs) reacted with a 150-kd fragment and not with the 120-kd fragment or intact -fodrin, indicating that the epitope recognized became exposed after -fodrin cleavage. Analysis of a large panel of SS patients (defined by the strict San Diego diagnostic criteria) showed that 25% of SS sera exhibited this 150-kd -fodrin specificity. The hmAbs stained human cultured salivary acinar cells and the staining was redistributed to surface blebs during apoptosis. They also stained inflamed acinar/ductal epithelial cells in SS salivary tissue biopsies, and only partially co-localized with monoclonal Abs recognizing the full-length -fodrin. Our study shows that in SS patients, neoepitopes on the 150-kd cleaved product of -fodrin become exposed to the immune system, frequently eliciting anti-150-kd -fodrin Abs in addition to the previously reported anti-120-kd Abs. The anti-150-kd -fodrin hmAbs may serve as valuable reagents for the study of SS pathogenesis and diagnostic analyses of SS salivary gland tissue.
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