Functionally responsive self‐reactive <scp>B</scp> cells of low affinity express reduced levels of surface <scp>I</scp>g<scp>M</scp>

Kirchenbaum, Greg A.; Clair, James St.; Detanico, Thiago; Aviszus, Katja; Wysocki, Lawrence J.

doi:10.1002/eji.201344276

Cited by 23 publications

(23 citation statements)

References 63 publications

(121 reference statements)

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“…An independent study came to similar conclusions by studying the functional properties of IgM LO and IgM HI Fo B cells in mice 81. An independent study came to similar conclusions by studying the functional properties of IgM LO and IgM HI Fo B cells in mice 81.…”

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confidence: 62%

Self‐reactivity on a spectrum: A sliding scale of peripheral B cell tolerance

Tan

Noviski

Huizar

et al. 2019

Immunological Reviews

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Efficient mechanisms of central tolerance, including receptor editing and deletion, prevent highly self-reactive B cell receptors (BCRs) from populating the periphery.Despite this, modest self-reactivity persists in (and may even be actively selected into) the mature B cell repertoire. In this review, we discuss new insights into mechanisms of peripheral B cell tolerance that restrain mature B cells from mounting inappropriate responses to endogenous antigens, and place recent work into historical context. In particular, we discuss new findings that have arisen from application of a novel in vivo reporter of BCR signaling, Nur77-eGFP, expression of which scales with the degree of self-reactivity in both monoclonal and polyclonal B cell repertoires. We discuss new and historical evidence that self-reactivity is not just tolerated, but actively selected into the peripheral repertoire. We review recent progress in understanding how dual expression of the IgM and IgD BCR isotypes on mature naive follicular B cells tunes responsiveness to endogenous antigen recognition, and discuss how this may be integrated with other features of clonal anergy. Finally, we discuss how expression of Nur77 itself couples chronic antigen stimulation with B cell tolerance. K E Y W O R D Sanergy, B cell, IgD, IgM, Nur77/Nr4a1, tolerance Previous work from our laboratory exploiting an in vivo reporter of antigen recognition, Nur77-eGFP BAC Tg, addresses this important point ( Figure 1A). 15 GFP expression in this reporter line is under the control of the regulatory region of Nr4a1/ Nur77. Nr4a1-3 encode a small family of orphan nuclear hormone receptors which were originally cloned as signal-dependent primary response genes (also known as immediate-early genes), and are highly upregulated by a range of mitogens, including antigen receptor stimulation. [16][17][18] Consequently, antigen stimulation rapidly triggers reporter expression in B and T cells in vitro ( Figure 1B), and GFP is also induced by infection or immunization in antigen-specific lymphocytes in

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confidence: 62%

Self‐reactivity on a spectrum: A sliding scale of peripheral B cell tolerance

Tan

Noviski

Huizar

et al. 2019

Immunological Reviews

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“…Kirchenbaum et al (119) used a different approach to substantiate the hypothesis that dynamic downmodulation of surface IgM serves as a mechanism for maintaining weakly self-reactive B cells in a responsive state to foreign antigens by decreasing their avidity for self-antigen. They performed functional tests with IgM low and IgM high B cells from mice and showed that they mobilized Ca 2+ equivalently when the same number of IgM molecules were engaged.…”

Section: Beyond T Cells B Cell Tuningmentioning

confidence: 98%

Dynamic Tuning of Lymphocytes: Physiological Basis, Mechanisms, and Function

Grossman

Paul

2015

Annu. Rev. Immunol.

104

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Dynamic tuning of cellular responsiveness as a result of repeated stimuli improves the ability of cells to distinguish physiologically meaningful signals from each other and from noise. In particular, lymphocyte activation thresholds are subject to tuning, which contributes to maintaining tolerance to self-antigens and persisting foreign antigens, averting autoimmunity and immune pathogenesis, but allowing responses to strong, structured perturbations that are typically associated with acute infection. Such tuning is also implicated in conferring flexibility to positive selection in the thymus, in controlling the magnitude of the immune response, and in generating memory cells. Additional functional properties are dynamically and differentially tuned in parallel via subthreshold contact interactions between developing or mature lymphocytes and self-antigen-presenting cells. These interactions facilitate and regulate lymphocyte viability, maintain their functional integrity, and influence their responses to foreign antigens and accessory signals, qualitatively and quantitatively. Bidirectional tuning of T cells and antigen-presenting cells leads to the definition of homeostatic set points, thus maximizing clonal diversity.

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“…The proportion of CD19+IgD+ B cells was lower in NSG- cmah -/- mice at 3 months and did not decline by 6 months as was found in NSG wt humanized mice. The proportion of CD19+IgM+IgD+ B cells in peripheral blood of both strains declined, and the proportion of CD19+IgM - IgD+ cells [32, 33] increased. We did not observe significant differences in the numbers of CD19+IgM+IgD - mature B cells between strains at 6 months (5.9 ± 0.9% and 7.7 ± 1.3% NSG- cmah -/- and NSG, respectively).…”

Section: Resultsmentioning

confidence: 99%