Clonal Evolution of Autoreactive Germinal Centers

Degn, Søren E.; Poel, Cees E. van der; Firl, Daniel J.; Ayoglu, Burcu; Qureshah, Fahd Al; Bajic, Goran; Mesin, Luka; Reynaud, Claude‐Agnès; Weill, Jean‐Claude; Utz, Paul J.; Victora, Gabriel D.; Carroll, Michael

doi:10.1016/j.cell.2017.07.026

Cited by 118 publications

(187 citation statements)

References 42 publications

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“…In full agreement, we found that, in contrast to WT controls, GCs can hardly be detected in IgD‐deficient mice at days 4 and 7 of immunization (Fig D and E). On day 10 after immunization, the GC cells in IgD‐deficient mice were mostly localized in multiple small aggregations as compared to the compact GC structures observed in WT mice (Fig E and F; Sander et al , ; Degn et al , ; Inoue et al , ). Moreover, sera from TNP‐Ova‐immunized IgD‐deficient mice contained less TNP‐specific IgG compared to sera from immunized WT mice (Fig G).…”

Section: Resultsmentioning

confidence: 91%

Pten controls B‐cell responsiveness and germinal center reaction by regulating the expression of IgD BCR

et al. 2019

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In contrast to other B‐cell antigen receptor ( BCR ) classes, the function of IgD BCR on mature B cells remains largely elusive as mature B cells co‐express IgM, which is sufficient for development, survival, and activation of B cells. Here, we show that IgD expression is regulated by the forkhead box transcription factor FoxO1, thereby shifting the responsiveness of mature B cells towards recognition of multivalent antigen. FoxO1 is repressed by phosphoinositide 3‐kinase ( PI 3K) signaling and requires the lipid phosphatase Pten for its activation. Consequently, Pten‐deficient B cells expressing knock‐ins for BCR heavy and light chain genes are unable to upregulate IgD. Furthermore, in the presence of autoantigen, Pten‐deficient B cells cannot eliminate the autoreactive BCR specificity by secondary light chain gene recombination. Instead, Pten‐deficient B cells downregulate BCR expression and become unresponsive to further BCR ‐mediated stimulation. Notably, we observed a delayed germinal center ( GC ) reaction by IgD‐deficient B cells after immunization with trinitrophenyl‐ovalbumin ( TNP ‐Ova), a commonly used antigen for T‐cell‐dependent antibody responses. Together, our data suggest that the activation of IgD expression by Pten/FoxO1 results in mature B cells that are selectively responsive to multivalent antigen and are capable of initiating rapid GC reactions and T‐cell‐dependent antibody responses.

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Section: Resultsmentioning

confidence: 91%

Pten controls B‐cell responsiveness and germinal center reaction by regulating the expression of IgD BCR

et al. 2019

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“…A non-mutually exclusive alternative model would implicate a generalized process of naïve B-cell activation in SLE and stochastic acquisition of pathogenic autoreactivity through SHM and selection by self-antigen within the GC, an environment specialized in prolonged antigen presentation and cyclical clonal expansion which is rich in self-antigens in part due to high levels of apoptosis and defective apoptotic cell clearance. Another possibility, described in the mouse anti-DNA response (19, 20), is that after being first stimulated by a triggering antigen, autoreactive B cells would subsequently acquire a separate autoreactivity against a different self-antigen (target antigen), through SHM either in the GC (21) or in the local environment of target tissues such as the kidney in patients with lupus nephritis (22). Indeed, this process could also help explain the well-documented phenomenon of epitope spreading responsible for the progressive addition of antigenic targets leading to disease development and progression (23).…”

Section: B-cell and Antibody Repertoires In Slementioning

confidence: 99%

Understanding B‐cell activation and autoantibody repertoire selection in systemic lupus erythematosus: A B‐cell immunomics approach

Tipton

Hom

Fucile

et al. 2018

Immunological Reviews

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Understanding antibody repertoires and in particular, the properties and fates of B cells expressing potentially pathogenic antibodies is critical to define the mechanisms underlying multiple immunological diseases including autoimmune and allergic conditions as well as transplant rejection. Moreover, an integrated knowledge of the antibody repertoires expressed by B cells and plasma cells (PC) of different functional properties and longevity is essential to develop new therapeutic strategies, better biomarkers for disease segmentation, and new assays to measure restoration of B-cell tolerance or, at least, of normal B-cell homeostasis. Reaching these goals, however, will require a more precise phenotypic, functional and molecular definition of B-cell and PC populations, and a comprehensive analysis of the antigenic reactivity of the antibodies they express. While traditionally hampered by technical and ethical limitations in human experimentation, new technological advances currently enable investigators to address these questions in a comprehensive fashion. In this review, we shall discuss these concepts as they apply to the study of Systemic Lupus Erythematosus.

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“…47 Perhaps a more ubiquitous feature of the disease is the presence of robust extrafollicular (EF) pathways, a pathogenic mechanism well documented in murine lupus and more recently in human SLE. 47 Perhaps a more ubiquitous feature of the disease is the presence of robust extrafollicular (EF) pathways, a pathogenic mechanism well documented in murine lupus and more recently in human SLE.…”

Section: G Erminal Center Checkp Oints and Toler An Ce Enforcement mentioning

confidence: 99%

Understanding and measuring human B‐cell tolerance and its breakdown in autoimmune disease

Cashman

Jenks

Woodruff

et al. 2019

Immunological Reviews

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It is well established that normal immune systems are endowed with a significant degree of autoreactivity. Accordingly, effective tolerogenic mechanisms are required to censor autoreactive cells and to ultimately prevent their differentiation into pathogenic effector cells. In this review, we will discuss how immunological tolerance is enforced in the human B-cell compartment. We shall also discuss the breakdown of B-cell tolerance in human autoimmune diseases.Finally, we will review different experimental approaches to measure B-cell tolerance in human disease. | B-CELL TOLER AN CE . CHECK P OINTS AND MECHANIS MS . LE SSONS LE ARNED THROUG H MOUS E S TUD IE SMouse models have been instrumental in defining multiple checkpoints and distinct mechanisms underpinning the enforcement of B-cell tolerance. Tolerance checkpoints are classified into central and peripheral mechanisms based on anatomical location and stage AbstractThe maintenance of immunological tolerance of B lymphocytes is a complex and critical process that must be implemented as to avoid the detrimental development of autoreactivity and possible autoimmunity. Murine models have been invaluable to elucidate many of the key components in B-cell tolerance; however, translation to human homeostatic and pathogenic immune states can be difficult to assess.Functional autoreactive, flow cytometric, and single-cell cloning assays have proven to be critical in deciphering breaks in B-cell tolerance within autoimmunity; however, newer approaches to assess human B-cell tolerance may prove to be vital in the further exploration of underlying tolerance defects. In this review, we supply a comprehensive overview of human immune tolerance checkpoints with associated mechanisms of enforcement, and highlight current and future methodologies which are likely to benefit future studies into the mechanisms that become defective in human autoimmune conditions.

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Clonal Evolution of Autoreactive Germinal Centers

Cited by 118 publications

References 42 publications

Pten controls B‐cell responsiveness and germinal center reaction by regulating the expression of IgD BCR

Pten controls B‐cell responsiveness and germinal center reaction by regulating the expression of IgD BCR

Understanding B‐cell activation and autoantibody repertoire selection in systemic lupus erythematosus: A B‐cell immunomics approach

Understanding and measuring human B‐cell tolerance and its breakdown in autoimmune disease

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