Role of inhibitory signaling in peripheral B cell tolerance*

Getahun, Andrew

doi:10.1111/imr.13070

Cited by 16 publications

(17 citation statements)

References 207 publications

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“…Silenced by anergy in healthy humans and diabetes-resistant mice, high-affinity IBCs loose anergy in individuals with new-onset diabetes and in some of their first-degree relatives, and diabetes-susceptible VH125.NOD mice ( 13 , 23 ). Intrinsic factors that compromise anergy include perturbations in the B cell receptor signaling pathway and other autoimmunity risk alleles ( 14 , 34 ). It is unclear to what extent affinity of BCR for autoantigens, notably insulin, plays a role in B cell participation in autoimmune diabetes.…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of the repertoire of insulin-reactive B cells in type 1 diabetes-prone and resistant mice

et al. 2022

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Seropositivity for autoantibodies against multiple islet antigens is associated with development of autoimmune type 1 diabetes (T1D), suggesting a role for B cells in disease. The importance of B cells in T1D is indicated by the effectiveness of B cell-therapies in mouse models and patients. B cells contribute to T1D by presenting islet antigens, including insulin, to diabetogenic T cells that kill pancreatic beta cells. The role of B cell receptor (BCR) affinity in T1D development is unclear. Here, we employed single cell RNA sequencing to define the relationship between BCR affinity for insulin and B cell phenotype during disease development. We utilized immunoglobulin (Ig) heavy chain (VH125) mouse models in which high-affinity insulin-reactive B cells (IBCs) were previously shown to be anergic in diabetes-resistant VH125.C57BL/6-H2g7 and activated in VH125. NOD mice developing disease. Here, high-affinity IBCs were found in the spleen of prediabetic VH125. NOD mice and exhibited marginal zone or follicular phenotypes. Ig light chains expressed by these B cells are unmutated and biased toward Vκ4-74 and Vκ4-57 usage. Receptors expressed by anergic high-affinity IBCs of diabetes-resistant VH125.C57BL/6-H2g7 are also unmutated; however, in this genetic background light chains are polymorphic relative to those of NOD. Light chains derived from NOD and C57BL/6-H2g7 genetic backgrounds conferred divergent kinetics of binding to insulin when paired with the VH125 heavy chain. These findings suggest that relaxation of tolerance mechanisms in the NOD mouse leads to accumulation and partial activation of B cells expressing germline encoded high-affinity BCRs that support development of autoimmunity.

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Section: Discussionmentioning

confidence: 99%

Comparative analysis of the repertoire of insulin-reactive B cells in type 1 diabetes-prone and resistant mice

et al. 2022

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“…Linked to this, increased availability of self‐antigen, such as in defective clearance of apoptotic cell in SLE [53], can contribute to break of tolerance. The expression of inhibitory receptors, such as CD22 and FCγ receptor IIb, regulates the activation of B cells, and mice deficient in those develop autoimmunity [54]. Furthermore, an imbalance between extrafollicular and GC maturation may result in autoimmunity.…”

Section: Impaired B‐cell Selection Upon Antigen Encountermentioning

confidence: 99%

Inborn errors of immunity and immunodeficiencies: Antibody‐mediated pathology and autoimmunity as a consequence of impaired immune reactions

et al. 2022

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B-cell tolerance to self-antigen is an active process that requires the temporal and spatial integration of signals of defined intensity. In common variable immune deficiency disorders, CTLA-4 deficiency, autoimmune lymphoproliferative syndrome, or in collagen VII deficiency, genetic defects in molecules regulating development, activation, maturation, and ECM composition alter the generation of B cells, resulting in immunodeficiency. Paradoxically, at the same time, the defective immune processes favor autoantibody production and immunopathology through impaired establishment of tolerance. The development of systemic autoimmunity in the framework of defective BCR signaling is relatively unusual in genetic mouse models. In sharp contrast, such reduced signaling in humans is clearly linked to pathological autoimmunity. The molecular mechanisms by which tolerance is broken in these settings are only starting to be explored resulting in novel therapeutic interventions. For instance, in CTLA-4 deficiency, homeostasis can be restored by CTLA-4 Ig treatment. Following this example, the identification of the molecular targets causing the reduced signals and their restoration is a visionary way to reestablish tolerance and develop novel therapeutic avenues for immunopathologies. Keywords: B-cell receptor r autoantibodies r autoimmunity r extracellular matrix r inborn errors of immunity See accompanying Commentary by Ehl and Thimme.

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“…These ITIM co‐receptors in turn recruit the tyrosine phosphatase SHP‐1 or the lipid phosphatase SHIP1. In this issue, Getahun reviews how this inhibitory pathway operates and discusses work from his group and others elucidating which arms of the pathway are required to maintain anergy in mature B cells 10 . The PTPase SHP‐1 dephosphorylates key signaling molecules that operate proximally in the BCR signal transduction cascade.…”

Section: Mechanisms Of B Cell Tolerancementioning

confidence: 99%

“…In this issue, Getahun reviews how this inhibitory pathway operates and discusses work from his group and others elucidating which arms of the pathway are required to maintain anergy in mature B cells. 10 The PTPase SHP-1 dephosphorylates key signaling molecules that operate proximally in the BCR signal transduction cascade. By contrast, SHIP1 targets membrane-associated PIP3 which is a key second messenger that facilitates assembly of a B cell signalosome at the membrane and is essential for signal amplification.…”

Section: Inhibitory Signaling Circuits In B Cellsmentioning

confidence: 99%