A Novel Mouse Model for the Hyper-IgM Syndrome: A Spontaneous Activation-Induced Cytidine Deaminase Mutation Leading to Complete Loss of Ig Class Switching and Reduced Somatic Hypermutation

Dahlberg, Carin; He, Minghui; Visnes, Torkild; Torres, Magda Liz; Cortizas, Elena M.; Verdún, Ramiro E.; Westerberg, Lisa S.; Severinson, Eva; Ström, Lena

doi:10.4049/jimmunol.1401242

Cited by 5 publications

(4 citation statements)

References 24 publications

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“…2B). Consistent with reports of AID ablation in other strains (41), Fas + GL7 + GC B-lymphocytes were expanded in both the spleens and PLNs of NOD. Aicda -/- mice (Fig.…”

Section: Resultssupporting

confidence: 90%

Genetic and Small Molecule Disruption of the AID/RAD51 Axis Similarly Protects Nonobese Diabetic Mice from Type 1 Diabetes through Expansion of Regulatory B Lymphocytes

Ratiu

Racine

Hasham

et al. 2017

The Journal of Immunology

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B-lymphocytes play a key role in type 1 diabetes (T1D) development by serving as a subset of APC preferentially supporting expansion of autoreactive pathogenic T-cells. As a result of their pathogenic importance, B-lymphocyte-targeted therapies have received considerable interest as potential T1D interventions. Unfortunately, B-lymphocyte-directed T1D interventions tested to date failed to halt β-cell demise. IgG autoantibodies marking humans at future T1D risk indicate B-lymphocytes producing them have undergone the affinity maturation processes of class switch recombination (CSR) and possibly somatic hypermutation (SHM). This study found that CRISPR/Cas9-mediated ablation of the Aicda gene required for CSR/SHM induction, inhibits T1D development in the NOD mouse model. The Aicda encoded AID molecule induces genome-wide DNA breaks that, if not repaired through RAD51-mediated homologous recombination (HR), result in B-lymphocyte death. Treatment with the RAD51 inhibitor 4,4′-diisothiocyanatostilbene-2, 2′-disulfonic acid (DIDS) also strongly inhibited T1D development in NOD mice. Both the genetic and small molecule-targeting approaches expanded CD73+ B-lymphocytes exerting regulatory activity suppressing diabetogenic T-cell responses. Hence, an initial CRISPR/Cas9 mediated genetic modification approach has identified the AID/RAD51 axis as a target for a potentially clinically translatable pharmacological approach that can block T1D development by converting B-lymphocytes to a disease inhibitory CD73+ regulatory state.

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“…2B). Consistent with reports of AID ablation in other strains (41), Fas + GL7 + GC B-lymphocytes were expanded in both the spleens and PLNs of NOD. Aicda -/- mice (Fig.…”

Section: Resultssupporting

confidence: 90%

Genetic and Small Molecule Disruption of the AID/RAD51 Axis Similarly Protects Nonobese Diabetic Mice from Type 1 Diabetes through Expansion of Regulatory B Lymphocytes

Ratiu

Racine

Hasham

et al. 2017

The Journal of Immunology

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“…To investigate the intrinsic capacity of Rac1 B Rac2 −/− B cells to undergo Ig class switching, we stimulated spleen B cells with cytokines in vitro and examined Ig class switching on day 4 ( 16 ). WT, Rac1 B , Rac2 −/− , and Rac1 B Rac2 −/− B cells had similar switching to IgG1, IgE, and IgA (Figure 7 A).…”

Section: Resultsmentioning

confidence: 99%

The Small Rho GTPases Rac1 and Rac2 Are Important for T-Cell Independent Antigen Responses and for Suppressing Switching to IgG2b in Mice

Gerasimčik

Dahlberg

et al. 2017

Front. Immunol.

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The Rho GTPases Cdc42, Rac1, and Rac2 coordinate receptor signaling to cell adhesion, migration, and proliferation. Deletion of Rac1 and Rac2 early during B cell development leads to failure in B cell entry into the splenic white pulp. Here, we sought to understand the role of Rac1 and Rac2 in B cell functionality and during the humoral antibody response. To circumvent the migratory deficiency of B cells lacking both Rac1 and Rac2, we took the approach to inducibly delete Rac1 in Rac2−/− B cells in the spleen (Rac1BRac2−/− B cells). Rac1BRac2−/− mice had normal differentiation of splenic B cell populations, except for a reduction in marginal zone B cells. Rac1BRac2−/− B cells showed normal spreading response on antibody-coated layers, while both Rac2−/− and Rac1BRac2−/− B cells had reduced homotypic adhesion and decreased proliferative response when compared to wild-type B cells. Upon challenge with the T-cell-independent antigen TNP-conjugated lipopolysaccharide, Rac1BRac2−/− mice showed reduced antibody response. In contrast, in response to the T-cell-dependent antigen sheep red blood cells, Rac1BRac2−/− mice had increased serum titers of IgG1 and IgG2b. During in vitro Ig class switching, Rac1BRac2−/− B cells had elevated germline γ2b transcripts leading to increased Ig class switching to IgG2b. Our data suggest that Rac1 and Rac2 serve an important role in regulation of the B cell humoral immune response and in suppressing Ig class switching to IgG2b.

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“…The double chain constant region of IgM is replaced with the other same type through DSB initiated by AID, finally realizing CSR 22 . The low affinity IgM antibodies with CSR and/or SHM impairment are produced in patients with AID mutations, which is known as a syndrome called high IgM immunodeficiency 23 . However, AID can also induce “off-target” DNA damage, leading to c-Myc/IgH DSB oncogenic chromosomal translocation 24 .…”

Section: Discussionmentioning

confidence: 99%

Activation-induced cytidine deaminase overexpression in double-hit lymphoma: potential target for novel anticancer therapy

Zhang

Shi

Zhao

et al. 2020

Sci Rep

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Activation-induced cytidine deaminase (AID) is one kind of the mutant enzymes, which target regulating the immunoglobulin (Ig) gene in Burkitt’s lymphoma to initiate class switch recombination (CSR), resulting in c-Myc chromosomal translocation. However, it is not clear that whether AID induces c-Myc/IgH translocation in double-hit lymphoma (DHL) with c-Myc gene translocation. In this study, the AID in DHL tissues and classical diffuse large b-cell lymphoma (DLBCL) tissues were compared. The results suggested that AID is of important value in predicting DHL, stronger CSR of AID was observed in DHL patients, which exhibited AID overexpression and c-Myc gene translocation of DHL after CSR induction. It is concluded that AID directly induces CSR in DHL and may result in c-Myc gene translocation. Targeting AID may be a good treatment regimen for DHL.

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A Novel Mouse Model for the Hyper-IgM Syndrome: A Spontaneous Activation-Induced Cytidine Deaminase Mutation Leading to Complete Loss of Ig Class Switching and Reduced Somatic Hypermutation

Cited by 5 publications

References 24 publications

Genetic and Small Molecule Disruption of the AID/RAD51 Axis Similarly Protects Nonobese Diabetic Mice from Type 1 Diabetes through Expansion of Regulatory B Lymphocytes

Genetic and Small Molecule Disruption of the AID/RAD51 Axis Similarly Protects Nonobese Diabetic Mice from Type 1 Diabetes through Expansion of Regulatory B Lymphocytes

The Small Rho GTPases Rac1 and Rac2 Are Important for T-Cell Independent Antigen Responses and for Suppressing Switching to IgG2b in Mice

Activation-induced cytidine deaminase overexpression in double-hit lymphoma: potential target for novel anticancer therapy

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