Deletion of IgG-Switched Autoreactive B Cells and Defects in <i>Faslpr</i> Lupus Mice

Aït-Azzouzene, Djemel; Kono, Dwight H.; Gonzalez-Quintial, Rosana; McHeyzer‐Williams, Louise J.; Lim, Min; Wickramarachchi, Dilki; Gerdes, Tobias; Gavin, Amanda L.; Skog, Patrick; McHeyzer‐Williams, Michael G.; Nemazee, David; Theofilopoulos, Argyrios N.

doi:10.4049/jimmunol.1000698

Cited by 26 publications

(24 citation statements)

References 70 publications

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“…First, we examined viral control in mice with a specific deletion in IgG2a(8). Consistent with the data above, IgG2a KO mice were unable to contain cl13 infection, supporting a key role for IgG2a (Fig 1G).…”

Section: Resultsmentioning

confidence: 99%

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Cutting Edge: B Cell–Intrinsic T-bet Expression Is Required To Control Chronic Viral Infection

Barnett

Staupe

Odorizzi

et al. 2016

The Journal of Immunology

152

177

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The role of antibody and B cells in preventing infection is established. In contrast, the role of B cell responses in containing chronic infections remains poorly understood. IgG2a (IgG1 in humans) can prevent acute infections and T-bet promotes IgG2a isotype switching. However, whether IgG2a and B cell-expressed T-bet influence the host-pathogen balance during persisting infections is unclear. Here we demonstrate that B cell specific loss of T-bet prevents control of persisting viral infection. T-bet in B cells not only controlled IgG2a production, but also mucosal localization, proliferation, glycosylation, and a broad transcriptional program. T-bet controlled a broad antiviral program in addition to IgG2a since T-bet in B cells was important even in the presence of virus-specific IgG2a. Our data supports a model in which T-bet is a universal controller of antiviral immunity across multiple immune lineages.

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Section: Resultsmentioning

confidence: 99%

“…Tbx21 −flox , T-bet-GFP, CD19 −cre , and pURF-Tg (i.e. IgG2a −/− ) mice have been described (6-8). Tbx21 flox/flox and Tbx21 flox/wt mice were crossed to CD19 −cre mice.…”

Section: Methodsmentioning

confidence: 99%

Cutting Edge: B Cell–Intrinsic T-bet Expression Is Required To Control Chronic Viral Infection

Barnett

Staupe

Odorizzi

et al. 2016

The Journal of Immunology

152

177

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“…The main rescue signal from Fas-induced cell death is mediated by BCR upon recognition of the antigen (rev. in [7,8,[18][19][20][21]). However, other receptors, such as BAFFR and TLR9 may also deliver rescue signals for B-cells, although the molecular mechanism of these are less well understood [22,23].…”

Section: Introductionmentioning

confidence: 98%

TLR9-mediated signals rescue B-cells from Fas-induced apoptosis via inactivation of caspases

et al. 2012

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“…The selective removal of Fas from activated B cells results in lupus-like disease and autoantibody production (15)(16)(17). It has been a widely accepted view that the Fas/FasL mutations result in, at least in part, a failure to eliminate self-reactive GC B cells in autoimmune patients and animal models (12,18). However, more recent studies show that FAS is in fact not required for the elimination of self-reactive GC B cells.…”

mentioning

confidence: 99%

Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas

Kong¹,

Yang²,

Xu³

et al. 2016

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

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Humoral immunity involves multiple checkpoints during B-cell development, maturation, and activation. The cell death receptor CD95/Fas-mediated apoptosis plays a critical role in eliminating the unwanted activation of B cells by self-reactive antigens and in maintaining B-cell homeostasis through activation-induced B-cell death (AICD). The molecular mechanisms controlling AICD remain largely undefined. Herein, we show that the E3 ubiquitin ligase Hrd1 protected B cells from activation-induced cell death by degrading the death receptor Fas. Hrd1-null B cells exhibited high Fas expression during activation and rapidly underwent Fas-mediated apoptosis, which could be largely inhibited by FasL neutralization. Fas mutation in Hrd1 KO mice abrogated the increase in B-cell AICD. We identified Hrd1 as the first E3 ubiquitin ligase of the death receptor Fas and Hrd1-mediated Fas destruction as a molecular mechanism in regulating B-cell immunity.Hrd1 | Fas | B cells | ubiquitination B -cell immunity involves several checkpoints, which are important to orchestrate and balance survival and apoptotic signals and control the quality and size of the B-cell compartment (1, 2). The earliest steps in B-cell development occur in the bone marrow, where assembly of the pre-B-cell receptor (pre-BCR) followed by the mature BCR occurs in distinct stages. Once the mature BCR is expressed, B lymphocytes then progress into the immature B-cell stage, where further selection checkpoints occur before the immature B cells transition to the periphery and mature into circulating B cells (2, 3). Mature B cells are maintained through tonic BCR, CD40, and B-cell-activating factor receptor (BAFFR) signaling (4). Activation by cross-linking the BCR leads to rapid proliferation, somatic hypermutation, and further differentiation of B cells (5, 6). The expansion of activated B-cell compartment is subsequently downmodulated through activation-induced cell death (AICD) (7,8).The death receptor Fas has been identified as a key regulator of AICD of B cells (9-11). Fas is highly expressed on activated B cells, particularly in the germinal center, where it mediates the deletion of autoreactive or unproductive somatic hypermutated B cells (12)(13)(14). Fas, as well as its ligand FasL, play critical roles in B-cell apoptosis. The selective removal of Fas from activated B cells results in lupus-like disease and autoantibody production (15-17). It has been a widely accepted view that the Fas/FasL mutations result in, at least in part, a failure to eliminate self-reactive GC B cells in autoimmune patients and animal models (12, 18). However, more recent studies show that FAS is in fact not required for the elimination of self-reactive GC B cells. Instead, Fas inactivation led to accumulation of a population of unconventional GC B cells that underwent somatic hypermutation and survived despite losing antigen reactivity (8). Nevertheless, it is clear that Fasmediated B-cell death is critically involved in B-cell-mediated autoimmune diseases. However, the molecular...

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Deletion of IgG-Switched Autoreactive B Cells and Defects in Faslpr Lupus Mice

Cited by 26 publications

References 70 publications

Cutting Edge: B Cell–Intrinsic T-bet Expression Is Required To Control Chronic Viral Infection

Cutting Edge: B Cell–Intrinsic T-bet Expression Is Required To Control Chronic Viral Infection

TLR9-mediated signals rescue B-cells from Fas-induced apoptosis via inactivation of caspases

Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas

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