Optimal Development of Mature B Cells Requires Recognition of Endogenous Antigens

Noviski, Mark; Tan, Chung-I; Huizar, John; Vykunta, Vivasvan; Mueller, James L.; Zikherman, Julie

doi:10.4049/jimmunol.1900175

Cited by 20 publications

(33 citation statements)

References 49 publications

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“…The consistency of the nAb self-reactivity among individuals was considered evidence for the existence of preferred self-antigens. Such “public reactivities” are most probably related to the germline repertoire of antibodies generated by evolutionarily encoded paratope features and negative/positive selection (34, 69, 70). They were hypothesized to represent the repertoire compartment characterized also by idiotypic interactions (71).…”

Section: Discussionmentioning

confidence: 99%

Diagnostic Profiling of the Human Public IgM Repertoire With Scalable Mimotope Libraries

et al. 2019

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Specific antibody reactivities are routinely used as biomarkers, but the antibody repertoire reactivity (igome) profiles are still neglected. Here, we propose rationally designed peptide arrays as efficient probes for these system level biomarkers. Most IgM antibodies are characterized by few somatic mutations, polyspecificity, and physiological autoreactivity with housekeeping function. Previously, probing this repertoire with a set of immunodominant self-proteins provided a coarse analysis of the respective repertoire profiles. In contrast, here, we describe the generation of a peptide mimotope library that reflects the common IgM repertoire of 10,000 healthy donors. In addition, an appropriately sized subset of this quasi-complete mimotope library was further designed as a potential diagnostic tool. A 7-mer random peptide phage display library was panned on pooled human IgM. Next-generation sequencing of the selected phage yielded 224,087 sequences, which clustered in 790 sequence clusters. A set of 594 mimotopes, representative of the most significant sequence clusters, was shown to probe symmetrically the space of IgM reactivities in patients' sera. This set of mimotopes can be easily scaled including a greater proportion of the mimotope library. The trade-off between the array size and the resolution can be explored while preserving the symmetric sampling of the mimotope sequence and reactivity spaces. BLAST search of the non-redundant protein database with the mimotopes sequences yielded significantly more immunoglobulin J region hits than random peptides, indicating a considerable idiotypic connectivity of the targeted igome. The proof of principle predictors for random diagnoses was represented by profiles of mimotopes. The number of potential reactivity profiles that can be extracted from this library is estimated at more than 1070. Thus, a quasi-complete IgM mimotope library and a scalable representative subset thereof are found to address very efficiently the dynamic diversity of the human public IgM repertoire, providing informationally dense and structurally interpretable IgM reactivity profiles.

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Section: Discussionmentioning

confidence: 99%

Diagnostic Profiling of the Human Public IgM Repertoire With Scalable Mimotope Libraries

et al. 2019

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“…Tonic signaling is characterized by a low-level phosphorylation of signaling intermediates in resting B cells in the absence of robust and activating antigen triggers and this tonic signaling is driven by the surface expression of the BCR in B cells [ 33 ]. Both tonic and antigen-specific signaling are required for B cell survival [ 24 , 34 , 35 ]. To date, it is not known whether tonic BCR signaling is altered in atherosclerosis, and how tonic BCR signaling regulates B cell phenotypes in this disease; however, these are important questions that need to be answered.…”

Section: Bcr Signaling B Cell Development and Atherosclerosismentioning

confidence: 99%

Functional Role of B Cells in Atherosclerosis

Shelby

Mußbacher

Galkina

2021

Cells

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Atherosclerosis is a lipid-driven inflammatory disease of blood vessels, and both innate and adaptive immune responses are involved in its development. The impact of B cells on atherosclerosis has been demonstrated in numerous studies and B cells have been found in close proximity to atherosclerotic plaques in humans and mice. B cells exert both atheroprotective and pro-atherogenic functions, which have been associated with their B cell subset attribution. While B1 cells and marginal zone B cells are considered to protect against atherosclerosis, follicular B cells and innate response activator B cells have been shown to promote atherosclerosis. In this review, we shed light on the role of B cells from a different, functional perspective and focus on the three major B cell functions: antibody production, antigen presentation/T cell interaction, and the release of cytokines. All of these functions have the potential to affect atherosclerosis by multiple ways and are dependent on the cellular milieu and the activation status of the B cell. Moreover, we discuss B cell receptor signaling and the mechanism of B cell activation under atherosclerosis-prone conditions. By summarizing current knowledge of B cells in and beyond atherosclerosis, we are pointing out open questions and enabling new perspectives.

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“…Recently, we took a novel approach to address this question by capitalizing on the Nur77-eGFP reporter of endogenous antigen recognition. 42 B1-8i Tg mice express a fixed H chain, but a polyclonal set of endogenous L chains, approximately 5% of which are capable of binding the NP hapten. 43 We identified two minor B cell populations in B1-8i H chain Tg mice that each recognize the NP hapten, but differ in their L chain use and their degree of self-reactivity (as marked both by Nur77-eGFP expression and other indicators).…”

Section: T H Y 1 -/ -H O S T / a T Amentioning

confidence: 99%

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

Tan

Noviski

Huizar

et al. 2019

Immunological Reviews

Self Cite

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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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Optimal Development of Mature B Cells Requires Recognition of Endogenous Antigens

Cited by 20 publications

References 49 publications

Diagnostic Profiling of the Human Public IgM Repertoire With Scalable Mimotope Libraries

Diagnostic Profiling of the Human Public IgM Repertoire With Scalable Mimotope Libraries

Functional Role of B Cells in Atherosclerosis

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

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