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Modulation of peripheral B cell tolerance by CD72 in a murine model.

ABSTRACT: B cells play a dominant role in the pathogenesis of several autoimmune diseases, including systemic lupus erythematosus. It is not well understood how B cell signaling contributes to autoantibody production. The goal of this study was to elucidate the role of CD72 in modulating B cell receptor (BCR)-mediated tolerogenic signaling and peripheral B cell tolerance.A mouse model utilizing hen egg lysozyme (HEL) "anergic" B cells was studied. CD72-deficient mice carrying the BCR-specific IgHEL and/or soluble HEL (sHEL) transgenes were generated by breeding IgHEL-transgenic MD4 mice and/or sHEL-transgenic ML5 mice with congenic, CD72-deficient C57BL/6J mice. Normal and anergic B cells were isolated for analyses of B cell signaling. Aged wild-type and CD72-deficient mice were also examined for autoimmune phenomena.In the absence of CD72, anergic B cells inappropriately proliferated and survived in response to stimulation with self antigen. Biochemical analyses indicated that in anergic B cells, CD72 dominantly down-regulated BCR signaling to limit the antigen-induced elevation in [Ca2+]i and the activation of NFATc1, NF-kappaB, MAPK, and Akt. Mechanistically, CD72 was associated with, and regulated, the molecular adaptor Cbl-b in anergic B cells, suggesting that Cbl-b may play a role in mediating the negative effects of CD72 on BCR signaling. Moreover, in aged CD72-deficient mice, spontaneous production of antinuclear and anti-double-stranded DNA autoantibodies and features of lupus-like autoimmune disease were observed.CD72 is required to maintain B cell anergy and functions as a regulator of peripheral B cell tolerance. Thus, altered CD72 expression may play a role during the development of systemic lupus erythematosus.

SUBMITTER: Li DH

PROVIDER: S-EPMC2790383 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Modulation of peripheral B cell tolerance by CD72 in a murine model.

Li Daniel Hsieh-Hsin DH Winslow Monte M MM Cao Thai M TM Chen Albert H AH Davis Corrine R CR Mellins Elizabeth D ED Utz Paul J PJ Crabtree Gerald R GR Parnes Jane R JR

Arthritis and rheumatism 20081001 10

<h4>Objective</h4>B cells play a dominant role in the pathogenesis of several autoimmune diseases, including systemic lupus erythematosus. It is not well understood how B cell signaling contributes to autoantibody production. The goal of this study was to elucidate the role of CD72 in modulating B cell receptor (BCR)-mediated tolerogenic signaling and peripheral B cell tolerance.<h4>Methods</h4>A mouse model utilizing hen egg lysozyme (HEL) "anergic" B cells was studied. CD72-deficient mice carr ...[more]

PMID: 18821699

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Project description:Interventions: Individuals with stage IV colorectal cancer who are planned to undergo surgery to remove their primary tumour +/- metastatic disease as part of their routine cancer care will be recruited to this study. At the time of surgery, once the specimen has been surgically resected, a number of fresh tissue samples will be obtained from the specimen for the research study. These samples will include lymph nodes, a small sample of the primary tumour, a sample of normal tissue, and a sample of a metastasis. These samples will be obtained by a senior colorectal surgeon under the supervision of pathology staff. In addition, a blood sample (up to 40ml) will be taken from the participant via their routinely inserted peripheral vein cannula once the participant is under general anaesthesia or at the appropriate time prior to surgery co-ordinated with diagnostic sampling by the anaesthetist. Samples obtained will be processed for single cell RNA sequencing analysis. Remaining tissue, cells and plasma that have been isolated from tissue and blood will be cryopreserved and stored in a secure manner. Participants will not be required to attend any follow up study visits for this study. The Peter MacCallum Cancer Centre hospital electronic medical record will be reviewed from time of initial diagnosis up to 3 years post-surgery for all participants who choose to enrol. Only relevant clinical data regarding the participant will be obtained and stored in a secure and de-identified manner. This will include basic demographics, diagnosis, stage and site of primary tumour, site(s) of metastatic disease, prior anti-cancer treatment, relapse date, death date and follow up dates, past and concurrent medical history, and concurrent medications at time of surgery. Primary outcome(s): Identification of a lymph node restricted CD8+ T cell population with a gene expression profile consistent with peripheral tolerance using single cell RNA sequence (scRNAseq) analysis of all obtained samples.[At completion of scRNAseq analysis of all obtained samples] Study Design: Timing: Prospective

Dataset Information

Modulation of peripheral B cell tolerance by CD72 in a murine model.

Publications

Modulation of peripheral B cell tolerance by CD72 in a murine model.

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