Protein tyrosine phosphatase 1C negatively regulates antigen receptor signaling in B lymphocytes and determines thresholds for negative selection

AbstractMotheaten viable (mev) mice are deficient in the cytosolic protein tyrosine phosphatase, PTP1C, and exhibit severe B cell immunodeficiency and autoantibody production. The role of PTP1 C in B cell selection and function was analyzed by breeding immunoglobulin transgenes specific for a defined antigen, hen egg lysozyme, into mav mice. Antigen triggered a greater and more rapid elevation of intracellular calcium in PTP1 C-deficient B cells, indicating that this phosphatase negatively regulates immunoglobulin signaling. Elimination of self-reactive B cells carrying this signal-enhancing mutation was triggered during their development by binding a lower valency form of self-antigen than is normally required. These findings establish that activation of distinct repertoire-censoring mechanisms depends on quantitative differences in antigen receptor signaling, whose thresholds are determined by negative regulation through PTP1C

The use of genomewide ENU mutagenesis screens to unravel complex mammalian traits: Identifying genes that regulate organ-specific and systemic autoimmunity

T-cell development is perhaps one of the best understood processes of mammalian cell differentiation, as many of the genes and pathways have been identified. By contrast, relatively little is known about the genes and pathways involved in immunological tolerance to self-antigens. Here, we describe the challenges associated with a genomewide screen designed at identifying new immune regulatory genes that uses a model of organ-specific autoimmunity leading to type 1 diabetes. The successful propagation and identification of the new gene variants will shed light on the various developmental checkpoints in lymphocyte development that are crucial for establishing tolerance to self-antigens

Genome-Wide ENU Mutagenesis to Reveal Immune Regulators

AbstractA complete list of molecular components for immune system function is now available with the completion of the human and mouse genome sequences. However, identification and functional annotation of genes involved in immunological processes require a discovery methodology that can efficiently and broadly analyze the complex interplay of these components in vivo. Our recent experience indicates that genome-wide chemical mutagenesis in the mouse is an extremely powerful methodology for the identification of genes required for complex immunological processes

Immunological tolerance: Danger – pathogen on the premises!

AbstractRecent results show that immune responses can be induced in neonatal mice. Do they really refute the traditional view that the ability to discriminate between ‘self’ and ‘non-self’ is a fundamental property of the immune system

An analysis of the methodology and effectiveness of the marketing efforts to redevelop former military bases

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Urban Studies and Planning, 1997.Includes bibliographical references (leaves 98-100).by Christopher Burke Goodnow.S.M

Consequences of the recurrent MYD88 L265P somatic mutation for B cell tolerance

MYD88L265P has recently been discovered as an extraordinarily frequent somatic mutation in benign monoclonal IgM gammopathy, Waldenström's macroglobulinemia, and diffuse large B cell lymphoma. In this study, we analyze the consequences for antigen-activ

Human lymphoma mutations reveal CARD11 as the switch between self-antigen-induced B cell death or proliferation and autoantibody production

Self-tolerance and immunity are actively acquired in parallel through a poorly understood ability of antigen receptors to switch between signaling death or proliferation of antigenbinding lymphocytes in different contexts. It is not known whether this tolerance-immunity switch requires global rewiring of the signaling apparatus or if it can arise from a single molecular change. By introducing individual CARD11 mutations found in human lymphomas into antigen-activated mature B lymphocytes in mice, we find here that lymphoma-derived CARD11 mutations switch the effect of self-antigen from inducing B cell death into T cell- independent proliferation, Blimp1-mediated plasmablast differentiation, and autoantibody secretion. Our findings demonstrate that regulation of CARD11 signaling is a critical switch governing the decision between death and proliferation in antigen-stimulated mature B cells and that mutations in this switch represent a powerful initiator for aberrant B cell responses in vivo