title: Increased Autoreactivity of the Complement-Activating Molecule Mannan-Binding Lectin in a Type 1 Diabetes Model.
abstract: BACKGROUND
  Diabetic kidney disease is the leading cause of end-stage renal failure despite intensive treatment of modifiable risk factors. Identification of new drug targets is therefore of paramount importance. The complement system is emerging as a potential new target. The lectin pathway of the complement system, initiated by the carbohydrate-recognition molecule mannan-binding lectin (MBL), is linked to poor kidney prognosis in diabetes. We hypothesized that MBL activates complement upon binding within the diabetic glomerulus.
  
  
  METHODS
  We investigated this by comparing complement deposition and activation in kidneys from streptozotocin-induced diabetic mice and healthy control mice.
  
  
  RESULTS
  After 20 weeks of diabetes, glomerular deposition of MBL was significantly increased. Diabetic animals had 2.0-fold higher (95% CI 1.6-2.5) immunofluorescence intensity from anti-MBL antibodies compared with controls (P < 0.001). Diabetes and control groups did not differ in glomerular immunofluorescence intensity obtained by antibodies against complement factors C4, C3, and C9. However, the circulating complement activation product C3a was increased in diabetes as compared to control mice (P = 0.04).
  
  
  CONCLUSIONS
  20 weeks of diabetes increased MBL autoreactivity in the kidney and circulating C3a concentration. Together with previous findings, these results indicate direct effects of MBL within the kidney in diabetes.
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital and Department of Clinical Medicine, Faculty of Health, Aarhus University, 8000 Aarhus, Denmark; The Danish Diabetes Academy, 5000 Odense, Denmark.
authors.forename: Jakob Appel
authors.initials: JA
authors.lastname: Østergaard
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College London, London W12 0NN, UK.
authors.forename: Marieta Milkova
authors.initials: MM
authors.lastname: Ruseva
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College London, London W12 0NN, UK.
authors.forename: Talat Habib
authors.initials: TH
authors.lastname: Malik
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital and Department of Clinical Medicine, Faculty of Health, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Ingeborg Torp
authors.initials: IT
authors.lastname: Hoffmann-Petersen
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College London, London W12 0NN, UK.
authors.forename: Matthew Caleb
authors.initials: MC
authors.lastname: Pickering
authors.affiliation: Department of Biomedicine, Faculty of Health, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Steffen
authors.initials: S
authors.lastname: Thiel
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital and Department of Clinical Medicine, Faculty of Health, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Troels Krarup
authors.initials: TK
authors.lastname: Hansen
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003167:Complement Activation; D015926:Complement C3a / Q000276:immunology; D037582:Complement Pathway, Mannose-Binding Lectin; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications / Q000276:immunology*; D003928:Diabetic Nephropathies / Q000097:blood / Q000209:etiology / Q000276:immunology*; D007678:Kidney Glomerulus / Q000276:immunology* / Q000378:metabolism; D008297:Male; D037601:Mannose-Binding Lectin / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL
chemical_list: D001786:Blood Glucose; D037601:Mannose-Binding Lectin; D015926:Complement C3a