A form of immunologic tolerance through impairment of germinal center development.

Pulendran, Bali; Karvelas, Maria; Nossal, G. J. V.

doi:10.1073/pnas.91.7.2639

Cited by 28 publications

(12 citation statements)

References 15 publications

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“…This postulate was later reinforced by several in vivo studies, some of which demonstrated apoptosis-mediated deletion of germinal center (GC) B cells that had acquired heightened capacity to bind the immunizing Ags (11-14). These studies suggested two plausible mechanisms for censoring newly created autoreactive GC B-cells during ongoing immune responses (15).…”

Section: Introductionmentioning

confidence: 99%

Deletion of IgG-Switched Autoreactive B Cells and Defects in Faslpr Lupus Mice

Aït-Azzouzene

Kono

Gonzalez-Quintial

et al. 2010

The Journal of Immunology

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During a T cell-dependent antibody (Ab) response, B cells undergo Ab class-switching and variable region hypermutation, with the latter process potentially rendering previously innocuous B cells autoreactive. Class switching and hypermutation are temporally and anatomically linked with both processes dependent on the enzyme, activation-induced deaminase, and occurring principally, but not exclusively, in germinal centers. To understand tolerance regulation at this stage, we generated a new transgenic (Tg) mouse model expressing a membrane-tethered γ2a-reactive superantigen (γ2a-macroself Ag) and assessed the fate of emerging IgG2a-expressing B cells that have, following class switch, acquired self-reactivity of its Ag receptor to the macroself-Ag. In normal mice, self-reactive IgG2a-switched B cells were deleted, leading to the selective absence of IgG2a memory responses. These findings identify a novel negative selection mechanism for deleting mature B cells that acquire reactivity to self-Ag. This process was only partly dependent on the Bcl-2 pathway, but markedly inefficient in MRL-Faslpr lupus mice, suggesting that defective apoptosis of isotype-switched autoreactive B cells is central to Fas mutation-associated systemic autoimmunity.

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Section: Introductionmentioning

confidence: 99%

Deletion of IgG-Switched Autoreactive B Cells and Defects in Faslpr Lupus Mice

Aït-Azzouzene

Kono

Gonzalez-Quintial

et al. 2010

The Journal of Immunology

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“…Tissues were embedded, stored, sectioned, and stained as described (28). Abs used were unlabeled anti-Emb and biotinylated anti-CD19.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Identification of Pax5 Target Genes in Early B Cell Differentiation

Pridans

Holmes

Polli

et al. 2008

The Journal of Immunology

130

123

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The transcription factor Pax5 is essential for B cell commitment in the mouse, where it represses lineage-inappropriate gene expression while simultaneously activating the B cell gene expression program. In this study we have performed a global gene expression screen of wild-type and Pax5-deficient pro-B cells in an attempt to identify the crucial Pax5 targets in early B lymphopoiesis. These studies have identified 109 Pax5 targets comprising 61% activated and 39% repressed genes. Interestingly, Pax5 directly regulates the genes encoding a number of transcription factors that are required at the pre-B cell stage of differentiation, including Irf8, Spib, and Ikzf3 (Aiolos), suggesting that a key function of Pax5 is to activate secondary transcription factors that further reinforce the B cell program. Pax5 is also required for the expression of many genes known to be involved in adhesion and signaling, indicating that Pax5 modulates the homing and or migration properties of B cell progenitors. Finally, Pax5 also represses a cohort of genes that are involved in multiple biological processes, many of which are not typically associated with B cells. These include the repression of the adhesion molecule Embigin, which is expressed in bone marrow progenitors, T cells, and myeloid cells but is specifically repressed by Pax5 in B cells.

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“…Additional considerations will clearly be the presence of T-cell cytokine products, 'danger signals' from microorganisms and Toll-like receptor-bearing cells, and other aspects of the microenvironment local to antigen-binding B cells (which, at the population level, will also display a spectrum of avidity for antigen). This line of work extended to Klinman's 'second window' of susceptibility to tolerance induction [3], this time in germinal centres (the sites of hypermutation in B-cell V genes) (Box 2), perhaps through apoptotic mechanisms [4]. Virtually all of the work outlined above was performed in non-transgenic systems, with use of labour-intensive flow cytometry and fluorescence-activated cell sorting and single-cell cloning analyses.…”

Section: More Recent Researchmentioning

confidence: 99%