A new model of experimental autoimmune keratoconjunctivitis sicca (KCS) induced in Lewis rat by the autoantigen Klk1b22.

PURPOSE This study was designed to generate an inducible autoimmune model of keratoconjunctivitis sicca (KCS) for study of pathogenesis of the disease. METHODS Lewis rats were immunized with a mixture of lacrimal and salivary gland extract or recombinant mouse protein kallikrein 1b22 (Klk1b22) emulsified in complete Freund's adjuvant (CFA). For disease induction by adoptive transfer of primed cells, donor rats were received with T-cell blasts. KCS were observed by either clinical signs or histology. RESULTS The autoantigen Klk1b22, isolated from the lacrimal and salivary glands, readily induced Sjögren's syndrome (SS)-like KCS in the recipients. The diseased animals presented the clinical and pathologic symptoms that resemble related human disease. Most immunized rats showed an increase, then a decrease in tear volume, together with corneal opacity and ocular lesions. Histologic examination revealed that the rats displayed the cardinal signs of primary SS-like KCS, including marked lymphocytic infiltration of the lacrimal and salivary glands and destruction of the acinar cells. Immunofluorescence studies showed that both CD8(+) and CD4(+) T cells were heavily infiltrated, with the former cells predominant in the damaged ducts. Finally, adoptive transfer of Klk1b22-reactive T cells induced more severe disease with earlier onset. CONCLUSIONS Klk1b22 is an autoantigen for inducing an experimental SS-like KCS in Lewis rats. The availability of this new and reproducible rat model should provide a new and needed tool for studying the pathogenesis of SS.

[1]  C. Delporte,et al.  Usefulness of mouse models to study the pathogenesis of Sjögren's syndrome. , 2007, Oral diseases.

[2]  J. Cowell,et al.  Development of Autoimmunity in IL-14α-Transgenic Mice1 , 2006, The Journal of Immunology.

[3]  R. Fox,et al.  Sjögren's syndrome in dermatology. , 2006, Clinics in dermatology.

[4]  J. Anaya,et al.  Genetic Basis of Sjögren's Syndrome. How Strong is the Evidence? , 2006, Clinical & developmental immunology.

[5]  J. Clements,et al.  A comprehensive nomenclature for serine proteases with homology to tissue kallikreins , 2006, Biological chemistry.

[6]  P. Lipsky,et al.  Immunopathogenesis of primary Sjögren's syndrome: implications for disease management and therapy , 2005, Current opinion in rheumatology.

[7]  M. Takiguchi,et al.  Autoimmunity against a Tissue Kallikrein in IQI/Jic Mice , 2005, Journal of Biological Chemistry.

[8]  M. Dana,et al.  Tear film and ocular surface tests in animal models of dry eye: uses and limitations. , 2004, Experimental eye research.

[9]  Y. Zhuang,et al.  A T cell intrinsic role of Id3 in a mouse model for primary Sjogren's syndrome. , 2004, Immunity.

[10]  M. Takiguchi,et al.  Spontaneous development of multiple glandular and extraglandular lesions in aged IQI/Jic mice: a model for primary Sjogren's syndrome. , 2004, Rheumatology.

[11]  T. Nishida,et al.  A novel grading method for superficial punctate keratopathy magnitude and its correlation with corneal epithelial permeability. , 2003, Archives of ophthalmology.

[12]  W. Pierce,et al.  Identification of the p16-Arc Subunit of the Arp 2/3 Complex as a Substrate of MAPK-activated Protein Kinase 2 by Proteomic Analysis* , 2003, Journal of Biological Chemistry.

[13]  O. Beg,et al.  Kallikrein-like prorenin-converting enzymes in inbred hypertensive mice. , 2003, Biochemical and biophysical research communications.

[14]  Kenji Inoue,et al.  Ocular factors relevant to keratoepitheliopathy in glaucoma patients with and without diabetes mellitus. , 2003, Japanese journal of ophthalmology.

[15]  Z. Dlamini,et al.  Kallikrein and Kinin Receptor Expression in Inflammation and Cancer , 2001, Biological chemistry.

[16]  N. Ishimaru,et al.  Severe destructive autoimmune lesions with aging in murine Sjögren's syndrome through Fas-mediated apoptosis. , 2000, The American journal of pathology.

[17]  J. Tschopp,et al.  Mice Transgenic for Baff Develop Lymphocytic Disorders along with Autoimmune Manifestations , 1999, The Journal of experimental medicine.

[18]  K. Tsubota,et al.  Preferential Localization of CD8+ αEβ7+ T Cells Around Acinar Epithelial Cells with Apoptosis in Patients with Sjögren’s Syndrome , 1999, The Journal of Immunology.

[19]  T. Noda,et al.  Fas ligand-mediated exocrinopathy resembling Sjögren's syndrome in mice transgenic for IL-10. , 1999, Journal of immunology.

[20]  E. Donadi,et al.  Kininogen-kallikrein-kinin system in plasma and saliva of patients with Sjögren's syndrome. , 1998, The Journal of rheumatology.

[21]  N. Ishimaru,et al.  Anti‐120‐kDa α‐fodrin immune response with Th1‐cytokine profile in the NOD mouse model of Sjögren's syndrome , 1998, European journal of immunology.

[22]  J. Saegusa,et al.  Sialadenitis in IQI/Jic mice: a new animal model of Sjögren's syndrome. , 1997, The Journal of veterinary medical science.

[23]  T. Honjo,et al.  Autoimmune disease of exocrine organs in immunodeficient alymphoplasia mice: a spontaneous model for Sjören's syndrome , 1996, European journal of immunology.

[24]  M. Hollingsworth,et al.  Induction of experimental autoimmune sialoadenitis by immunization of PL/J mice with carbonic anhydrase II. , 1995, Journal of immunology.

[25]  G. Proetzel,et al.  Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease , 1992, Nature.

[26]  D. Zhou,et al.  Experimental autoimmune dacryoadenitis: purification and characterization of a lacrimal gland antigen. , 1992, Investigative ophthalmology & visual science.

[27]  J. Clements,et al.  The glandular kallikrein family of enzymes: tissue-specific expression and hormonal regulation. , 1989, Endocrine reviews.

[28]  S. Hinrichs,et al.  Exocrinopathy resembling Sjögren's syndrome in HTLV-1 tax transgenic mice , 1989, Nature.

[29]  K. Hirokawa,et al.  Immunopathology of experimental autoallergic sialadenitis in C3H/He mice. , 1989, Clinical and experimental immunology.

[30]  D. Jabs,et al.  Murine models of Sjögren's syndrome. Immunohistologic analysis of different strains. , 1988, Investigative ophthalmology & visual science.

[31]  R. Jonsson,et al.  Sialadenitis in the MRL-l mouse: morphological and immunohistochemical characterization of resident and infiltrating cells. , 1987, Immunology.

[32]  E. Tan,et al.  Antibodies to cellular antigens in Sjögren's syndrome. , 1975, The Journal of clinical investigation.

[33]  T. Tomasi,et al.  Characterization of a soluble cytoplasmic antigen reactive with sera from patients with systemic lupus erythmatosus. , 1969, Journal of immunology.

[34]  A. Shevchenko,et al.  Sample preparation methods for mass spectrometric peptide mapping directly from 2-DE gels. , 1999, Methods in molecular biology.

[35]  R. Jonsson,et al.  Immunohistochemical characterization of sialadenitis in NZB X NZW F1 mice. , 1987, Clinical immunology and immunopathology.