Development of self-reactive germinal center B cells and plasma cells in autoimmune FcγRIIB-deficient mice

Tiller, Thomas; Köfer, J.; Kreschel, Cornelia; Busse, Christian E.; Riebel, Stefan; Wickert, Susanne; Oden, Felix; Mertes, Maria M.M.; Ehlers, Marc; Wardemann, Hedda

doi:10.1084/jem.20100171

Cited by 83 publications

(92 citation statements)

References 62 publications

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“…Autoreactive B cells from SW HEL X HEL 2X mice may have an intrinsic impairment preventing the differentiation into IgG plasma cells due to chronic exposure to the autoAg, especially at the GC level. The existence of a tolerance checkpoint between the GC and plasma cell compartments has been previously suspected in other transgenic mice and in FcRIIb −/− mice [44][45][46].This study reveals control mechanisms that are effective during chronic infection even when self-reactive B cells are activated and pushed to SHM in GCs. Thereby, we provide an explanation for the low prevalence of pathogenic IgG autoAbs in healthy individuals' sera.…”

supporting

confidence: 52%

Chronic bacterial infection activates autoreactive B cells and induces isotype switching and autoantigen‐driven mutations

et al. 2015

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The links between infections and the development of B-cell-mediated autoimmune diseases are still unclear. In particular, it has been suggested that infection-induced stimulation of innate immune sensors can engage low affinity autoreactive B lymphocytes to mature and produce mutated IgG pathogenic autoantibodies. To test this hypothesis, we established a new knock-in mouse model in which autoreactive B cells could be committed to an affinity maturation process. We show that a chronic bacterial infection allows the activation of such B cells and the production of nonmutated IgM autoantibodies. Moreover, in the constitutive presence of their soluble antigen, some autoreactive clones are able to acquire a germinal center phenotype, to induce Aicda gene expression and to introduce somatic mutations in the IgG heavy chain variable region on amino acids forming direct contacts with the autoantigen. Paradoxically, only lower affinity variants are detected, which strongly suggests that higher affinity autoantibodies secreting B cells are counterselected. For the first time, we demonstrate in vivo that a noncross-reactive infectious agent can activate and induce autoreactive B cells to isotype switching and autoantigen-driven mutations, but on a nonautoimmune background, tolerance mechanisms prevent the formation of consequently dangerous autoimmunity.Keywords: Affinity maturation r Autoreactive B cell r B-cell tolerance r Germinal center r Infection Additional supporting information may be found in the online version of this article at the publisher's web-site 132Sophie Jung et al. Eur. J. Immunol. 2016. 46: 131-146 Introduction B-cell receptors (BCRs) are assembled in developing B-lymphocyte precursors via a stochastic process of joining immunoglobulin (Ig) genes. These random rearrangements inevitably result in the genesis of multiple receptors that recognize self-antigens (Ags) [1]. Despite the fact that known mechanisms of central tolerance take place in the bone marrow, many self-reactive B cells escape toward the periphery [2][3][4][5]. Most of them are the so-called natural autoimmune B cells with a mature naïve phenotype, which produce-in normal individuals-small amounts of polyreactive low affinity IgM autoantibodies (Abs) devoid of somatic mutations. A recent study performed in mice also suggests that quiescent autoreactive B cells persist in the adult repertoire and could serve as a source of pathogenic autoAbs under circumstances that still have to be defined [6]. Both genetic background and environmental factors could influence B-cell maturation in a way that favors the appearance of high affinity IgG switched autoAbs. Among known environmental factors, epidemiological studies have clearly linked infections with the occurrence of autoimmune diseases in humans and in animal models [7]. In some organ-specific autoimmune diseases, this link is attributed to molecular mimicry between pathogens and self-Ags [8][9][10][11]. The role of such mechanism in the breakdown of B-cell tolerance during systemic auto...

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supporting

confidence: 52%

Chronic bacterial infection activates autoreactive B cells and induces isotype switching and autoantigen‐driven mutations

et al. 2015

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“…In human and mouse, switched autoantibodies to nuclear antigens are shown to be derived from both extrafollicular and GC reactions (15,(37)(38)(39)(40)(41)(42)(43)(44)(45). In response to exogenous antigens, miR-155 regulates both GC and non-GC reactions.…”

Section: Discussionmentioning

confidence: 99%

“…FcγRIIB inactivation has been implicated in the development of autoreactive GC B cells and plasma cells (15), as well as in the regulation of the persistence and longevity of bone marrow plasma cells (16). After coligation of the FcγRIIB with the B-cell receptor (BCR), FcγRIIB recruits SHIP-1 to the plasma membrane, where it negatively regulates cell survival, Ca 2+ -dependent effector functions, and ERK activation, thus controlling cell proliferation, anergy, and apoptosis (17)(18)(19)(20)(21)(22)(23).…”

mentioning

confidence: 99%

Deletion of microRNA-155 reduces autoantibody responses and alleviates lupus-like disease in theFas^lprmouse

Thai

Patterson

Pham

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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regulates antibody responses and subsequent B-cell effector functions to exogenous antigens. However, the role of miR-155 in systemic autoimmunity is not known. Using the death receptor deficient (Fas lpr ) lupus-prone mouse, we show here that ablation of miR-155 reduced autoantibody responses accompanied by a decrease in serum IgG but not IgM anti-dsDNA antibodies and a reduction of kidney inflammation. MiR-155 deletion in Fas lpr B cells restored the reduced SH2 domain-containing inositol 5′-phosphatase 1 to normal levels. In addition, coaggregation of the Fc γ receptor IIB with the B-cell receptor in miR-155 −/− -Fas lpr B cells resulted in decreased ERK activation, proliferation, and production of switched antibodies compared with miR-155 sufficient Fas lpr B cells. Thus, by controlling the levels of SH2 domaincontaining inositol 5′-phosphatase 1, miR-155 in part maintains an activation threshold that allows B cells to respond to antigens.ERK pathways | SHIP-1 M icroRNA-155 (miR-155) plays a critical role in the generation of effective antibody responses to exogenous antigenic challenges in mice (1-3). MiR-155 levels have been reported to be elevated in B but low in T cells from patients with systemic lupus erythamosus (4), yet it is not known whether miR-155 controls autoimmune responses and the expression of related pathology.Mice harboring ubiquitous or B-cell-specific ablation of the death receptor Fas develop a severe lupus-like disease. B-cellspecific deletion of the death receptor (fas −/− ) fas −/− mice develop an excessive germinal center (GC)-derived IgG autoantibody deposition in their kidneys and succumb to renal failure (5). It has been suggested that loss of tolerance in lpr mice results from the down-regulation of the low-affinity IgG inhibitory receptor FcγRIIB (Fc γ receptor IIB), thereby rendering their B cells incapable of terminating stimulatory signals delivered by autoantigen-containing immune complexes (6-8). However, the mechanisms whereby lack of FcγRIIB engagement would lead to autoimmunity, and whether additional factors contribute to autoimmunity, are still unclear.The SH2 domain-containing inositol 5′-phosphatase 1 (SHIP-1) phosphatase acts downstream of inhibitory cell-surface receptors (9-12), including the FcγRIIB, which is essential in opposing B-cell activation signals in mice and humans (13,14). FcγRIIB inactivation has been implicated in the development of autoreactive GC B cells and plasma cells (15), as well as in the regulation of the persistence and longevity of bone marrow plasma cells (16). After coligation of the FcγRIIB with the B-cell receptor (BCR), FcγRIIB recruits SHIP-1 to the plasma membrane, where it negatively regulates cell survival, Ca 2+ -dependent effector functions, and ERK activation, thus controlling cell proliferation, anergy, and apoptosis (17-23). As a consequence of these wideranging activities, germ-line or B-cell-specific deletion of FcγRIIB or SHIP-1 in mice results in a severe lupus-like disease characterized by high-titer serum IgG antinucl...

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“…Besides enhanced Ig production, FcγRIIB-deficient mice break humoral tolerance and produce anti-double-stranded DNA (anti-dsDNA) antibodies on the C57BL/6 background (8,(20)(21)(22). Consistent with this data from classic mouse models, human B cells in humanized mice that received stem cells from five different FcγRIIB-232T/T donors started to produce autoantibodies directed against dsDNA, glucose phosphate 6-isomerase (GPI), rheumatoid factor (RF), and antibodies directed against cyclic citrullinated peptides (anti-CCP) ( Fig.…”

Section: Loss Of Humoral Tolerance In the Absence Of Functional Humanmentioning

confidence: 99%

Fcγ receptor IIB (FcγRIIB) maintains humoral tolerance in the human immune system in vivo

Baerenwaldt

Lux

Danzer

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Maintenance of immunological tolerance is crucial to prevent development of autoimmune disease. The production of autoantibodies is a hallmark of many autoimmune diseases and studies in mouse model systems suggest that inhibitory signaling molecules may be important checkpoints of humoral tolerance. By generating humanized mice with normal and functionally impaired Fcγ receptor IIB (FcγRIIB) variants, we show that the inhibitory Fcγ-receptor is a checkpoint of humoral tolerance in the human immune system in vivo. Impaired human FcγRIIB function resulted in the generation of higher levels of serum immunoglobulins, the production of different autoantibody specificities, and a higher proportion of human plasmablasts and plasma cells in vivo. Our results suggest that the inhibitory FcγRIIB may be an important checkpoint of humoral tolerance in the human immune system.

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Development of self-reactive germinal center B cells and plasma cells in autoimmune FcγRIIB-deficient mice

Abstract: The leukemogenic effects of Myc drive recurrent trisomy in a mouse model of acute myeloid leukemia.

Cited by 83 publications

References 62 publications

Chronic bacterial infection activates autoreactive B cells and induces isotype switching and autoantigen‐driven mutations

Chronic bacterial infection activates autoreactive B cells and induces isotype switching and autoantigen‐driven mutations

Deletion of microRNA-155 reduces autoantibody responses and alleviates lupus-like disease in theFas^lprmouse

Fcγ receptor IIB (FcγRIIB) maintains humoral tolerance in the human immune system in vivo

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Development of self-reactive germinal center B cells and plasma cells in autoimmune FcγRIIB-deficient mice

Abstract: The leukemogenic effects of Myc drive recurrent trisomy in a mouse model of acute myeloid leukemia.

Cited by 83 publications

References 62 publications

Chronic bacterial infection activates autoreactive B cells and induces isotype switching and autoantigen‐driven mutations

Chronic bacterial infection activates autoreactive B cells and induces isotype switching and autoantigen‐driven mutations

Deletion of microRNA-155 reduces autoantibody responses and alleviates lupus-like disease in theFaslprmouse

Fcγ receptor IIB (FcγRIIB) maintains humoral tolerance in the human immune system in vivo

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Deletion of microRNA-155 reduces autoantibody responses and alleviates lupus-like disease in theFas^lprmouse