Tracking germinal center B cells expressing germ-line immunoglobulin γ1 transcripts by conditional gene targeting

Casola, Stefano; Cattoretti, Giorgio; Uyttersprot, Nathalie; Koralov, Sergei B.; Seagal, Jane; Zhou, Hao; Waisman, Ari; Egert, Angela; Ghitza, Dvora; Rajewsky, Klaus

doi:10.1073/pnas.0602353103

Cited by 209 publications

(289 citation statements)

References 41 publications

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“…Although CSR is associated with B-cell proliferation and differentiation in germinal centers [22,23], CSR is also induced during extrafollicular plasmablast differentiation. During the initial response to T-dependent antigens [6], and in responses to thymus-independent type 2 antigens, it is the only pathway of productive B-cell differentiation and CSR [17].…”

Section: Discussionmentioning

confidence: 99%

Early B blasts acquire a capacity for Ig class switch recombination that is lost as they become plasmablasts

et al. 2011

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Rapid production of neutralizing antibody can be critical for limiting the spread of infection. Such early antibody results when B-cell blasts mature directly to plasmablasts without forming germinal centers. These extrafollicular responses can involve Ig class switch recombination (CSR), producing antibody that can readily disseminate through infected tissues. The present study identifies the differentiation stage where CSR occurs in an extrafollicular response induced by 4-hydroxy-3-nitrophenyl acetyl (NP) conjugated to Ficoll (NP-Ficoll). To do this, we took advantage of the antigen dose dependency of CSR in this response. Thus, while both 30 and 1 lg NP-Ficoll induce plasmablasts, only the higher antigen dose induces CSR. Activation-induce cytidine deaminase (AID) is critical for CSR and in keeping with this a proportion of NP-specific B-cell blasts induced by 30 lg NP-Ficoll express AID. None of the B blasts responding to the non-CSR-inducing 1 lg dose of NP-Ficoll express AID. We confirmed that CSR occurs in B blasts by demonstrating the presence of rearranged heavy-chain transcripts in B blasts in the 30 lg response. CSR in this extrafollicular response is confined to B blasts, because NP-specific plasmablasts, identified by expressing CD138 and Blimp-1, no longer express AID and cannot undergo CSR.

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Section: Discussionmentioning

confidence: 99%

Early B blasts acquire a capacity for Ig class switch recombination that is lost as they become plasmablasts

et al. 2011

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“…To distinguish these possibilities, we used C-gamma-1 Cre transgenic mice (Cγ1 Cre), in which Cre recombinase is induced by transcription of the Ig gamma-1 constant region gene segment ( Figure 3E and ref. 25). Lrf inactivation in GCB cells (Lrf Flox/Flox Cγ1 Cre + ) led to reduction of GCB cell numbers ( Figure 3F).…”

Section: Lrfmentioning

confidence: 99%

The LRF transcription factor regulates mature B cell development and the germinal center response in mice

Sakurai¹,

Maeda²,

Lee³

et al. 2011

J. Clin. Invest.

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IntroductionHSCs give rise to immature B cells in the BM, which subsequently migrate to the secondary lymphoid organs, such as the LNs and spleen. The vast majority of newly formed BM B cells die at the transitional B cell stage during the following few days and fail to enter the long-lived mature B cell pool, which mainly consists of B1, follicular B (FOB), and marginal zone B (MZB) cells in the secondary lymphoid organs. During B cell maturation, signals driven by cell-surface receptors and downstream transcription factors must be regulated in a coordinated fashion to maintain mature B cell homeostasis. In particular, both B cell antigen receptor (BCR) and BAFF, the B cell-activating factor belonging to the TNF family, relay crucial signals for mature B cell development and survival, while the Notch pathway regulates MZB cell development (1-5).B cells are indispensable for humoral immunity, as they ultimately give rise to antibody-secreting plasma cells. During T celldependent (TD) antibody responses, naive B cells form germinal centers (GCs), a distinct histologic structure found in secondary lymphoid organs. Naive B cells become activated upon interaction with T cells and antigen-presenting cells and begin to rapidly proliferate and form the characteristic GC structure, in which 2 major genetic changes occur: somatic hypermutation (SHM) and class switch recombination (CSR). SHM modifies the affinity of the BCR for the cognate antigen by introducing predominantly point mutations into the variable region of Ig genes, while CSR replaces the constant regions of the Ig heavy (IgH) chain with those of other isotypes and allows the expression of antibodies that have the same antigen specificity but are different secondary IgH isotypes.

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“…We used Cγ1-Cre, which is active in GC B cells (26), to drive expression of LMP1 and LMP2A, either alone or in combination. we analyzed the frequencies of GC B cells (CD19…”

Section: Expression Of Lmp1 and Lmp2a In Gc B Cells Leads To Fatal B-mentioning

confidence: 99%

Mouse model for acute Epstein–Barr virus infection

Wirtz

Weber

Kracker

et al. 2016

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

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Epstein-Barr Virus (EBV) infects human B cells and drives them into continuous proliferation. Two key viral factors in this process are the latent membrane proteins LMP1 and LMP2A, which mimic constitutively activated CD40 receptor and B-cell receptor signaling, respectively. EBVinfected B cells elicit a powerful T-cell response that clears the infected B cells and leads to life-long immunity. Insufficient immune surveillance of EBV-infected B cells causes life-threatening lymphoproliferative disorders, including mostly germinal center (GC)-derived B-cell lymphomas. We have modeled acute EBV infection of naive and GC B cells in mice through timed expression of LMP1 and LMP2A. Although lethal when induced in all B cells, induction of LMP1 and LMP2A in just a small fraction of naive B cells initiated a phase of rapid B-cell expansion followed by a proliferative T-cell response, clearing the LMP-expressing B cells. Interfering with T-cell activity prevented clearance of LMPexpressing B cells. This was also true for perforin deficiency, which in the human causes a life-threatening EBV-related immunoproliferative syndrome. LMP expression in GC B cells impeded the GC reaction but, upon loss of T-cell surveillance, led to fatal B-cell expansion. Thus, timed expression of LMP1 together with LMP2A in subsets of mouse B cells allows one to study major clinically relevant features of human EBV infection in vivo, opening the way to new therapeutic approaches.pstein-Barr Virus (EBV) is a γ-herpes virus that infects human B cells and growth-transforms them in vitro. Infection is usually asymptomatic, but can lead to infectious mononucleosis (IM) in teenagers and adults (1). EBV drives infected B cells into proliferation, but the symptoms of IM, mainly fever, lymphadenopathy, and splenomegaly, are believed to result from the subsequent activation and massive proliferation of EBV-reactive T cells (2). After the acute phase of infection, EBV persists in a small subset of memory B cells throughout life and is kept in check by memory T cells (2-4). Although an EBV infection is harmless to most people, immunocompromised individuals can develop severe complications. Genetic defects that lead to impaired T-cell function predispose to EBV-driven lymphoproliferative diseases, such as familial hemophagocytic lymphohistiocytosis (FHL) (5, 6). FHL presents in infants and is characterized by persistent fever, hemophagocytosis, and cytokine storms. These symptoms are attributed to proliferation and cytokine production by macrophages and T cells (5-7). About onethird of FHL cases are caused by mutations in the PRF1 gene encoding perforin (8). EBV is also highly associated with HIV-related and posttransplantation lymphomas, which are usually derived from germinal center (GC) B cells. Most likely EBV is the causative agent for these lymphomas, transforming GC B cells when T-cell immunosurveillance is impeded owing to HIV infection or immunosuppressive therapy after organ transplantation (1, 9, 10).The activation and proliferation of EBV-infect...

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Tracking germinal center B cells expressing germ-line immunoglobulin γ1 transcripts by conditional gene targeting

Cited by 209 publications

References 41 publications

Early B blasts acquire a capacity for Ig class switch recombination that is lost as they become plasmablasts

Early B blasts acquire a capacity for Ig class switch recombination that is lost as they become plasmablasts

The LRF transcription factor regulates mature B cell development and the germinal center response in mice

Mouse model for acute Epstein–Barr virus infection

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