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

Abstract

Purpose 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 (auto)antibodies by ELISA and immunoprecipitation, B-cell development by flow cytometry, 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.

Differentially Expressed Gene Pathways in the Conjunctiva of Sjögren Syndrome Keratoconjunctivitis Sicca

“…The involvement of B cells in SS is well established, as SS patients have B cell infiltration in salivary and lacrimal glands in humans and rodents. SS patients have an increased risk for non-Hodgkin lymphomas (93)(94)(95)(96). The role of B cell receptor signaling in the conjunctiva of SS KCS patients has not been thoroughly investigated.…”

Mechanisms of central tolerance for B cells

“…Many mouse studies have identified defects in B cell central tolerance, in terms of either receptor editing or clonal deletion, in spontaneous models of SLE 107,108 , Sjogren syndrome 109 and type 1 diabetes 110 , although there is as yet no real consensus as to the mechanisms involved. As editing can both destroy and create certain autoantibody specificities, insufficient as well as excessive editing may be deleterious 111,112 .…”

The T cell in Sjogren's syndrome: Force majeure, not spectateur

“…Transfer of wild type T cells into young NOD IL-4 knockoutmice reconstituted the production of anti-M3R autoantibodies and subsequent decline in salivary secretory activity. In the related, NOD-derived Aec1/Aec2 model, glandular disease is preceded by the appearance in spleens and lymph nodes of activated CD4+ T cells bearing markers of effector-memory cells [49]. These cells are present before the appearance of activated B cells and autoantibodies and before salivary flow is reduced.…”