title: Anti-type II collagen immune complex-induced granulocyte reactivity is associated with joint erosions in RA patients with anti-collagen antibodies.
abstract: BACKGROUND
  Rheumatoid arthritis (RA) patients with autoantibodies against collagen type II (CII) are characterized by acute RA onset with elevated inflammatory measures and early joint erosions as well as increased production of tumor necrosis factor-α (ΤΝF-α) by peripheral blood mononuclear cells (PBMC) stimulated by anti-CII immune complexes (IC) in vitro. Polymorphonuclear granulocytes (PMN) are abundant in RA synovial fluids, where they might interact directly with anti-CII IC in the articular cartilage, but no studies have investigated PMN responses towards anti-CII IC. The aim was to investigate whether PMN react towards anti-CII IC, and to what extent such reactivity might relate to the clinical acute onset RA phenotype associated with elevated levels of anti-CII.
  
  
  METHODS
  PMN and PBMC isolated from healthy donors were stimulated with IC made with a set of 72 baseline patient sera (24 anti-CII positive, 48 anti-CII negative) chosen from a clinically well-characterized RA cohort with two-year radiological follow-up with Larsen scoring. PMN expression of cluster of differentiation (CD)11b, CD66b, CD16 and CD32 was measured by flow cytometry, whereas PMN production of myeloperoxidase (MPO) and interleukin (IL)-17, and PBMC production of ΤΝF-α was measured with enzyme linked immunosorbent assay.
  
  
  RESULTS
  PMN expression of CD11b, CD66b and MPO, and PBMC production of ΤΝF-α were upregulated whereas PMN expression of CD16 and CD32 were downregulated by anti-CII IC. CD16, CD66b, and MPO production correlated to serum anti-CII levels (Spearman's ρ = 0.315, 0.675 and 0.253, respectively). CD16 was associated with early joint erosions (P = 0.024, 0.034, 0.046 at baseline, one and two years) and CD66b was associated with changes in joint erosions (P = 0.017 and 0.016, at one and two years compared to baseline, respectively). CD66b was associated with baseline C-reactive protein and PBMC production of ΤΝF-α was associated with baseline erythrocyte sedimentation rate, in accordance with our earlier findings. No clinical associations were observed for MPO or IL-17.
  
  
  CONCLUSIONS
  PMN responses against anti-CII IC are more closely associated with early joint erosions than are PBMC cytokine responses. PMN reactivity against anti-CII IC may contribute to joint destruction in newly diagnosed RA patients with high levels of anti-CII.
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. vivek.anand@igp.uu.se.
authors.forename: Vivek Anand
authors.initials: VA
authors.lastname: Manivel
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. azita.sohrabian@igp.uu.se.
authors.forename: Azita
authors.initials: A
authors.lastname: Sohrabian
authors.affiliation: Department of Radiology, Karolinska University Hospital, Stockholm, Sweden. marius.wick@karolinska.se.
authors.forename: Marius C
authors.initials: MC
authors.lastname: Wick
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. mmullazehi@yahoo.se.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Mullazehi
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden. lena.douhan-hakansson@medsci.uu.se.
authors.forename: Lena Douhan
authors.initials: LD
authors.lastname: Håkansson
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. johan.ronnelid@igp.uu.se.|Unit of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. johan.ronnelid@igp.uu.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Rönnelid
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000936:Antigen-Antibody Complex / Q000097:blood*; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000175:diagnosis; D001323:Autoantibodies / Q000097:blood*; D002478:Cells, Cultured; D015331:Cohort Studies; D024043:Collagen Type II / Q000097:blood*; D005260:Female; D006098:Granulocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007596:Joints / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D024043:Collagen Type II