Ikaros Is a Negative Regulator of B1 Cell Development and Function

Macias-Garcia, Alejandra; Heizmann, Beate; Sellars, MacLean; Marchal, Patricia; Dali, Hayet; Pasquali, Jean‐Louis; Muller, Sylviane; Kastner, Philippe; Chan, Susan

doi:10.1074/jbc.m115.704239

Cited by 24 publications

(13 citation statements)

References 67 publications

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“…Consistent with the B cell activation phenotype in Aiolos -null mice, we observed increased GC B cell production in response to SRBC stimulation in Vav-Cre Mta2 fl/fl mice. It is worth noting that B cell-specific Ikaros KO mice also show dramatic losses of pre-B, immature B, and recirculating B in bone marrow, and both MZB and FOB cells in spleen, but increased splenic B1-B cells (Macias-Garcia et al, 2016; Schwickert et al, 2014)—demonstrating non-redundant functions of different IKAROS family members during B cell development.…”

Section: Discussionmentioning

confidence: 99%

MTA2/NuRD Regulates B Cell Development and Cooperates with OCA-B in Controlling the Pre-B to Immature B Cell Transition

Chu

Fang

et al. 2019

Cell Reports

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SUMMARY The NuRD complex contains both chromatin remodeling and histone deacetylase activities. Mice lacking the MTA2 subunit of NuRD show developmental defects in pro-B, pre-B, immature B, and marginal zone B cells, and abnormal germinal center B cell differentiation during immune responses. Mta2 inactivation also causes a derepression of Igll1 and VpreB1 genes in pre-B cells. Furthermore, MTA2/NuRD interacts directly with AIOLOS/IKAROS and shows a striking overlap with AIOLOS/IKAROS target genes in human pre-B cells, suggesting a functional interdependence between MTA2/NuRD and AIOLOS. Mechanistically, MTA2 deficiency in mice leads to increased H3K27 acetylation at both Igll1 and VpreB1 promoters. Gene profiling analyses also identify distinct MTA2-dependent transcription programs in pro-B and pre-B cells. In addition, we find a strong synergy between MTA2 and OCA-B in repressing Igll1 and VpreB1 at the pre-B cell stage, and in regulating both the pre-B to immature B transition and splenic B cell development.

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Section: Discussionmentioning

confidence: 99%

MTA2/NuRD Regulates B Cell Development and Cooperates with OCA-B in Controlling the Pre-B to Immature B Cell Transition

Chu

Fang

et al. 2019

Cell Reports

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“…First, IgE production by B cells is controlled in general by an inhibitory feedback mechanism mediated by binding of IgE to CD23 22. Second, as autoreactive antibodies are often produced as natural antibodies by B1 B cells, the homeostatic control of those cells might set a maximum amount of autoreactive IgE that can be produced 23, 24.…”

Section: Discussionmentioning

confidence: 99%

On the Lipophilic Nature of Autoreactive IgE in Chronic Spontaneous Urticaria

Lakin¹,

Church²,

Maurer³

et al. 2019

Theranostics

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Chronic spontaneous urticaria (CSU) is a skin disease related to autoreactive IgE in at least a subgroup of patients. However, the nature of this autoreactive IgE remains poorly characterized. This investigation had three objectives: first, to quantity CSU autoreactive IgE; second, to recognize the patterns of CSU autoreactive IgE compared with healthy control IgE; and third, to investigate the physiochemical nature of CSU autoreactive IgE. Methods: IgE autoreactivity was assessed in sera from 7 CSU and 7 healthy individuals. Autoantigen recognition patterns were assessed using principal component analysis (PCA) and heatmap visualization. Lipophilicity was assessed using NanoOrange reagent. Results: First, although total IgE levels did not differ significantly, the autoreactive proportion of IgE of CSU patients was 62% ± 37%, 1000-fold higher than that of healthy controls 0.03% ± 0.008% ( P = 0.0006). Second, CSU autoreactive IgE differed from healthy control IgE by recognizing more and different autoantigens (226 vs. 34; P = 0.01). Third, the median (with 10-90% percentiles) serum level of lipophilic IgE was 39% (38-40%) in 232 CSU patients, 1.4-fold higher than the 28% (26-29%) of 173 healthy controls ( P < 0.0001). Furthermore, lipophilicity correlated with autoreactivity (r = 0.8; P < 0.0001), connecting these two observed features. Conclusion: We believe that these novel observations about CSU autoreactive IgE, particularly the finding that it is more lipophilic than that of IgE from healthy individuals, will lead to the development of new diagnostic tests and therapies for autoreactive IgE-mediated diseases.

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“…Other elements that play an essential role during B‐1 lymphocytes ontogenesis have been described: regarding transcription factors associated to this process, the proteins PU.1, Ikaros, and NF‐κB2 have been implicated in B‐1 cell divergence from the B‐2 lineage. Accordingly, B‐2 but not B‐1 cell differentiation is restricted in the absence of PU.1 expression, Ikzf1 −/− mice (Ikaros‐deficient) shows a significant increment in B‐1 progenitors and mature B‐1 cell numbers, and finally, the maturation of B‐1 transitional cells independent of the noncanonical NF of κ light polypeptide gene enhancer in B cells (NF‐κB2) signaling (necessary for the development of their B‐2 counterparts) has been documented . Soluble factors also exert a critical role during B‐1 lymphopoiesis; in this way, it has been observed that murine B‐1 progenitors proliferate in response to thymic stromal lymphopoietin (TSLP) and seems to differentiate independently from BAFF and IL‐7 receptors‐induced signaling; all opposed features to what is detected in B‐2 cell progenitors …”

Section: B‐1 Lymphocytesmentioning

confidence: 99%

Innate-like B cell subsets during immune responses: Beyond antibody production

Romero‐Ramírez

Navarro-Hernandez

Cervantes‐Díaz

et al. 2018

Journal of Leukocyte Biology

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B lymphocytes are recognized for their crucial role in the adaptive immunity since they represent the only leukocyte lineage capable of differentiating into Ab‐secreting cells. However, it has been demonstrated that these lymphocytes can exert several Ab‐independent functions, including engulfing and processing Ags for presentation to T cells, secreting soluble mediators, providing co‐stimulatory signals, and even participating in lymphoid tissues development. Beyond that, several reports claiming the existence of multiple B cell subsets contributing directly to innate immune responses have appeared. These “innate‐like” B lymphocytes, whose phenotype, development pathways, tissue distribution, and functions are in most cases notoriously different from those of conventional B cells, are crucial to early protective responses against pathogens by exerting “crossover” defensive strategies that blur the established boundaries of innate and adaptive branches of immunity. Examples of these mechanisms include the rapid secretion of the polyspecific natural Abs, increased susceptibility to innate receptors‐mediated activation, cytokine secretion, downstream priming of other innate cells, usage of specific variable immunoglobulin gene‐segments, and other features. As these new insights emerge, it is becoming preponderant to redefine the functionality of B cells beyond their classical adaptive‐immune tasks.

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Ikaros Is a Negative Regulator of B1 Cell Development and Function

Cited by 24 publications

References 67 publications

MTA2/NuRD Regulates B Cell Development and Cooperates with OCA-B in Controlling the Pre-B to Immature B Cell Transition

MTA2/NuRD Regulates B Cell Development and Cooperates with OCA-B in Controlling the Pre-B to Immature B Cell Transition

On the Lipophilic Nature of Autoreactive IgE in Chronic Spontaneous Urticaria

Innate-like B cell subsets during immune responses: Beyond antibody production

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