title: B-cell tolerance defects in the B6.Aec1/2 mouse model of Sjögren's syndrome.
abstract: OBJECTIVE
  Primary Sjögren's syndrome (SjS) is an autoimmune disorder characterized by lymphocytic infiltration of the salivary and lacrimal glands, B-cell clonal expansions and an increased risk of lymphoma. In order to understand the role of B cells in this disorder, the antibody repertoire and B-cell maturation were studied in a mouse model of SjS called B6.Aec1/2.
  
  
  METHODS
  B6.Aec1/2 serum was analyzed for antibodies by ELISA and immunoprecipitation, B-cell development by flow cytometry, and antibody gene rearrangements by CDR3 spectratyping and quantitative PCR. In order to test the functional consequences of the observed defects, B6.Aec1/2 mice were crossed with anti-dsDNA antibody heavy chain knock-in mice (B6.56R).
  
  
  RESULTS
  B6.Aec1/2 mice exhibit B-cell clonal expansions, have altered serum immunoglobulin levels and spontaneously produce multireactive autoantibodies. B6.Aec1/2 mice also have decreased numbers of bone marrow pre-B cells and decreased frequencies of kappa light chain gene deletion. These findings suggest that B6.Aec1/2 mice have a defective early B-cell tolerance checkpoint. B6.56R.Aec1/2 mice unexpectedly had lower anti-dsDNA antibody levels than B6.56R mice and less salivary gland infiltration than B6.Aec1/2 mice.
  
  
  CONCLUSIONS
  These data suggest that the early tolerance checkpoint defect in B6.Aec1/2 mice is not sufficient to promulgate disease in mice with pre-formed autoantibodies, such as B6.56R. Rather, B6.Aec1/2 mice may require a diverse B-cell repertoire for efficient T-B-cell collaboration and disease propagation. These findings imply that therapies aimed at reducing B-cell diversity or T-B interactions may be helpful in treating SjS.
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Wenzhao
authors.initials: W
authors.lastname: Meng
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Li
authors.forename: Emily
authors.initials: E
authors.lastname: Xue
authors.forename: Minoru
authors.initials: M
authors.lastname: Satoh
authors.forename: Ammon B
authors.initials: AB
authors.lastname: Peck
authors.forename: Philip L
authors.initials: PL
authors.lastname: Cohen
authors.forename: Robert A
authors.initials: RA
authors.lastname: Eisenberg
authors.forename: Eline T
authors.initials: ET
authors.lastname: Luning Prak
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation; D002843:Chromatin / Q000276:immunology; D004247:DNA / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D007108:Immune Tolerance; D007136:Immunoglobulins / Q000097:blood / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D012859:Sjogren's Syndrome / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D002843:Chromatin; D007136:Immunoglobulins; D004247:DNA