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Anti-Tumor Necrosis Factor-a Therapy Augments Dipeptidyl Peptidase IV Activity and Decreases Autoantibodies to GRP78/BIP and Phosphoglucose Isomerase in Patients with Rheumatoid Arthritis
JOHN C. MAVROPOULOS, MIGUEL CUCHACOVICH, CAROLINA LLANOS, JUAN C. AGUILLÓN, HECTOR GATICA, SALVATORE V. PIZZO, and MARIO GONZALEZ-GRONOW
ABSTRACT.
Objective. To assess the enzymatic activity and biochemical status of dipeptidyl peptidase IV (DPP IV), an enzyme that participates in the degradation of proinflammatory molecules, in sera from a group of patients with rheumatoid arthritis (RA; n = 15) treated with a human anti-tumor necrosis factor-a (anti-TNF-a) antibody (adalimumab) for 32 weeks. IgG antibody titers against chaperone Bip (GRP78), phosphoglucose isomerase (PGI), lactate dehydrogenase (LDH), fibronectin (FN), and actin were also studied. Methods. DPP IV activity was measured in sera using Gly-Pro-p-nitroanilide as substrate. The biochemical profile of circulating DPP IV glycoforms was assessed by isoelectric focusing gel electrophoresis. All IgG autoantibody titers and their sialylation levels were determined by ELISA. Results. Patients showed significant increases in serum DPP IV enzymatic activity from basal values (3.554 ± 1.096) with respect to those obtained at 32 weeks (4.787 ± 0.953; p < 0.05). Changes in the biochemical profile of circulating DPP IV from acidic to more neutral isoelectric point glycoforms were also seen during treatment. The elevated titers of anti-GRP78 and anti-PGI IgG observed at the beginning of treatment decreased significantly during therapy, whereas those of anti-LDH, anti-FN, and anti-actin IgG remained unchanged. At the end of treatment, sialylation levels of anti-GRP78 and anti-PGI IgG antibodies increased to nearly normal levels. The DPP IV biochemical changes were accompanied by a significant improvement of the Disease Activity Score (DAS28). Conclusion. The reduced activity of DPP IV along with increased titers of circulating antibodies to GRP78 and PGI may play a role in the pathogenesis of RA and can be successfully modified by administration of adalimumab. (J Rheumatol 2005;32:2116-24) Key Indexing Terms:
TUMOR NECROSIS FACTOR-a From the Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA; Department of Medicine, Division of Rheumatology, Clinical Hospital of the University of Chile; and Disciplinary Program of Immunology, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile. Supported by grants from the National Heart, Lung, and Blood Institutes (HL0-24066), the National Cancer Institute (CA-86344), FONDECYT-Chile (1040439), and FONDEF-Chile (D03I1055). J.C. Mavropoulos, MPH, MD/PhD Candidate; S.V. Pizzo, MD, PhD; M. Gonzalez-Gronow, PhD, Assistant Research Professor, Department of Pathology, Duke University Medical Center; M. Cuchacovich, MD, Professor of Medicine; C. Llanos, MD, Fellow in Rheumatology; H. Gatica, MD, Assistant Professor, Department of Medicine, Division of Rheumatology, Clinical Hospital of the University of Chile; J.C. Aguillón, PhD, Associate Professor, Disciplinary Program of Immunology, ICBM, Faculty of Medicine, University of Chile. Address reprint requests to Dr. M. Gonzalez-Gronow, Department of Pathology, Box 3712, Duke University Medical Center, Durham, NC 27710. E-mail: gonza002@mc.duke.edu Accepted for publication June 27, 2005. |