B-Cell Tolerance Defects in the B6.Aec1/2 Mouse Model of Sjögren’s Syndrome

• DOI: 10.1007/s10875-012-9663-6
• Publication Date: 2012-02-16T14:32:33Z
• Authors: Wenzhao Meng; Yongmei Li; Emily Xue; Minoru Satoh; Ammon B. Peck; Philip L. Cohen; Robert A. Eisenberg; Eline T. Luning Prak
• Keywords: 0301 basic medicine; B-Lymphocytes; Immunoglobulins; Cell Differentiation; Mice, Transgenic; DNA; Chromatin; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; Sjogren's Syndrome; Immune Tolerance; Animals; Female; Autoantibodies

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.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).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.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.