title: Autoantibodies contribute to the immunopathogenesis of experimental dry eye disease.
abstract: OBJECTIVE
  The purpose of this study was to determine if autoantibodies play a role in the immunopathogenesis of experimental dry eye disease.
  
  
  METHODS
  Dry eye was induced by exposing female C57BL/6 wild-type mice or hen egg lysozyme B-cell receptor transgenic mice to desiccating stress (subcutaneous scopolamine [0.5 mg/0.2 mL] 3 times a day, humidity < 40%, and sustained airflow) for 3 weeks, allowing sufficient time for a humoral immune response. Serum or purified IgG isolated from dry-eye mice or untreated controls was passively transferred to nude recipient mice, which were evaluated for ocular surface inflammation 3 days after transfer. To determine if complement activation contributed to serum-induced dry eye disease, cobra venom factor was used to deplete complement activity.
  
  
  RESULTS
  Autoantibodies against kallikrein 13 were identified in serum from dry-eye mice, but were undetectable in untreated controls. Autoantibody-containing serum or purified IgG from dry-eye mice was sufficient to mediate complement-dependent ocular surface inflammation. Serum or purified IgG caused marked inflammatory burden and tissue damage within the ocular surface tissues, including elevated Gr1+ neutrophil infiltration and proinflammatory cytokines/chemokines associated with goblet cell loss. Moreover, complement C3b deposition was found within the ocular surface tissues of mice receiving dry-eye serum, but not in recipients of control serum. Functionally, complement depletion attenuated the ability to transfer dry-eye-specific serum or IgG-mediated disease.
  
  
  CONCLUSIONS
  These data demonstrate for the first time a complement-dependent pathogenic role of dry-eye-specific autoantibodies, and suggest autoantibody deposition within the ocular surface tissues contributes to the predominantly T-cell-mediated immunopathogenesis of dry eye disease.
authors.affiliation: Allergan, Inc, Biological Sciences, Inflammation Research Program, Irvine, California 92612, USA. stern_michael@allergan.com
authors.forename: Michael E
authors.initials: ME
authors.lastname: Stern
authors.forename: Chris S
authors.initials: CS
authors.lastname: Schaumburg
authors.forename: Karyn F
authors.initials: KF
authors.lastname: Siemasko
authors.forename: Jianping
authors.initials: J
authors.lastname: Gao
authors.forename: Larry A
authors.initials: LA
authors.lastname: Wheeler
authors.forename: Devin A
authors.initials: DA
authors.lastname: Grupe
authors.forename: Cintia S
authors.initials: CS
authors.lastname: De Paiva
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Calder
authors.forename: Margarita
authors.initials: M
authors.lastname: Calonge
authors.forename: Jerry Y
authors.initials: JY
authors.lastname: Niederkorn
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Pflugfelder
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens / Q000276:immunology*; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003167:Complement Activation / Q000276:immunology; D003179:Complement C3b / Q000378:metabolism; D004195:Disease Models, Animal; D015352:Dry Eye Syndromes / Q000276:immunology* / Q000473:pathology; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D056724:Immunity, Humoral / Q000502:physiology; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000276:immunology; D007610:Kallikreins; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D020840:Tissue Kallikreins / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D007074:Immunoglobulin G; D003179:Complement C3b; D007610:Kallikreins; C489120:Klk13 protein, mouse; D020840:Tissue Kallikreins