title: Anti-tumor necrosis factor-alpha therapy augments dipeptidyl peptidase IV activity and decreases autoantibodies to GRP78/BIP and phosphoglucose isomerase in patients with rheumatoid arthritis.
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-alpha) 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Mavropoulos
authors.forename: Miguel
authors.initials: M
authors.lastname: Cuchacovich
authors.forename: Carolina
authors.initials: C
authors.lastname: Llanos
authors.forename: Juan C
authors.initials: JC
authors.lastname: Aguillón
authors.forename: Hector
authors.initials: H
authors.lastname: Gatica
authors.forename: Salvatore V
authors.initials: SV
authors.lastname: Pizzo
authors.forename: Mario
authors.initials: M
authors.lastname: Gonzalez-Gronow
mesh_terms: D000199:Actins / Q000276:immunology; D000068879:Adalimumab; D000243:Adenosine Deaminase / Q000378:metabolism*; D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005260:Female; D005353:Fibronectins / Q000276:immunology; D005956:Glucose-6-Phosphate Isomerase / Q000276:immunology*; D006023:Glycoproteins / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000276:immunology; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000276:immunology*; D019158:N-Acetylneuraminic Acid / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000199:Actins; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001323:Autoantibodies; D000091342:Endoplasmic Reticulum Chaperone BiP; D005353:Fibronectins; D006023:Glycoproteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D007074:Immunoglobulin G; D018832:Molecular Chaperones; D014409:Tumor Necrosis Factor-alpha; D007770:L-Lactate Dehydrogenase; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000243:Adenosine Deaminase; D005956:Glucose-6-Phosphate Isomerase; D000068879:Adalimumab; D019158:N-Acetylneuraminic Acid