AID−/−μs−/− Mice Are Agammaglobulinemic and Fail to Maintain B220−CD138+ Plasma Cells

Kumazaki, Kaori; Tirosh, Boaz; Maehr, René; Boes, Marianne; Honjo, Tasuku; Ploegh, Hidde L.

doi:10.4049/jimmunol.178.4.2192

Cited by 42 publications

(39 citation statements)

References 46 publications

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“…There may be multiple explanations for the large increase in splenocytes compared with the modest increase of the lymphocytes assessed, mainly B220 + cells. As shown by the increase in cIg + cells (present study), and the large increase of serum Igs described in GSTM-treated A.SW mice [45], there must be an increased number of plasma cells, which are B220 - [56]. Other B cell subpopulations may also be B220 -, for example preplasma memory cells [57].…”

Section: Discussionsupporting

confidence: 55%

Gold causes genetically determined autoimmune and immunostimulatory responses in mice

Havarinasab

Johansson

Pollard

et al. 2007

Clinical and Experimental Immunology

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SummaryNatrium aurothiomaleate (GSTM) is a useful disease-modifying antirheumatic drug, but causes a variety of immune-mediated adverse effects in many patients. A murine model was used to study further the interaction of GSTM with the immune system, including induction of systemic autoimmunity. Mice were given weekly intramuscular injections of GSTM and controls equimolar amounts of sodium thiomaleate. The effects of gold on lymphocyte subpopulations were determined by flow cytometry. Humoral autoimmunity was measured by indirect immunofluorescence and immunoblotting, and deposition of immunoglobulin and C3 used to assess immunopathology. Gold, in the form of GSTM, stimulated the murine immune system causing strain-dependent lymphoproliferation and autoimmunity, including a major histocompatibility complex (MHC)-restricted autoantibody response against the nucleolar protein fibrillarin. GSTM did not cause glomerular or vessel wall IgG deposits. However, it did elicit a strong B cell-stimulating effect, including both T helper 1 (Th1)-and Th2-dependent isotypes. All these effects on the immune system were dependent on the MHC genotype, emphasizing the clinical observations of a strong genetic linkage for the major adverse immune reactions seen with GSTM treatment.

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Section: Discussionsupporting

confidence: 55%

Gold causes genetically determined autoimmune and immunostimulatory responses in mice

Havarinasab

Johansson

Pollard

et al. 2007

Clinical and Experimental Immunology

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“…Mice that were either deficient in both B cells and antibodies (μMT) or antibodies alone (AID/μS KO) were utilized as recipients. AID/μS KO mice lack the genes encoding both secretory IgM (μs; secretory Ighm) and activation-induced deaminase (AID; Aicda), and their B cells cannot undergo affinity maturation or secrete antibodies of any isotype (21). μMT mice have a targeted disruption of the immunoglobulin μ chain gene, resulting in lack of both mature B cells and secreted antibodies (22).…”

Section: Resultsmentioning

confidence: 99%

B cells mediate chronic allograft rejection independently of antibody production

Zeng¹,

Ng²,

Singh³

et al. 2014

J. Clin. Invest.

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Chronic rejection is the primary cause of long-term failure of transplanted organs and is often viewed as an antibody-dependent process. Chronic rejection, however, is also observed in mice and humans with no detectable circulating alloantibodies, suggesting that antibody-independent pathways may also contribute to pathogenesis of transplant rejection. Here, we have provided direct evidence that chronic rejection of vascularized heart allografts occurs in the complete absence of antibodies, but requires the presence of B cells. Mice that were deficient for antibodies but not B cells experienced the same chronic allograft vasculopathy (CAV), which is a pathognomonic feature of chronic rejection, as WT mice; however, mice that were deficient for both B cells and antibodies were protected from CAV. B cells contributed to CAV by supporting splenic lymphoid architecture, T cell cytokine production, and infiltration of T cells into graft vessels. In chimeric mice, in which B cells were present but could not present antigen, both T cell responses and CAV were markedly reduced. These findings establish that chronic rejection can occur in the complete absence of antibodies and that B cells contribute to this process by supporting T cell responses through antigen presentation and maintenance of lymphoid architecture.

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“…The results from these studies suggest that B cells and antibody are required for immunity, but the requirement for secreted antibody has not been well defined. While all of the studies thus far have relied on mice lacking mature B cells, in this study we were able to examine immunity to P. berghei in a mouse with intact B cells, which express surface immunoglobulin M (IgM) but are unable to secrete antibody (25).…”

mentioning

confidence: 97%

“…Immunized mice lacking secreted antibody are unable to control secondary P. berghei infection. In order to specifically determine whether secreted anybody is required for adaptive immunity to P. berghei, we tested whether mice lacking secreted antibodies (25) (Fig. 4).…”

Section: Vol 77 2009 Secreted Antibody Required For P Berghei Immumentioning

confidence: 99%

Secreted Antibody Is Required for Immunity toPlasmodium berghei

2009

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Infection with Plasmodium berghei is lethal to mice, causing high levels of parasitemia, severe anemia, and death. However, when mice are treated with antimalarial drugs during acute infection, they have enhanced immunity to subsequent infections. With this infection and cure model of immunity, we systematically examined the basis of adaptive immunity to infection using immunodeficient mice. In order to induce adaptive immunity, mice were infected with blood-stage parasites. When the mice developed 2 to 3% parasitemia, they were treated with chloroquine to cure the infection. These convalescent mice were then challenged with homologous blood-stage parasites. Immunized wild-type mice were able to control the level of infection. In contrast, mice lacking mature B cells and T cells were unable to control a challenge infection, indicating the critical role of lymphocytes in immunity to P. berghei. Furthermore, mice lacking secreted antibody were unable to control the level of parasitemia following a challenge infection. Our results indicate that secreted antibody is a requirement for immunity to P. berghei.Each year there are approximately 500 million cases of malaria worldwide, resulting in 2 to 3 million deaths, primarily in children in sub-Saharan Africa (42). Malaria is caused by infection with one of four protozoan Plasmodium species: P. falciparum, P. vivax, P. malariae, and P. ovale. P. falciparum is responsible for the majority of severe disease, which can manifest itself in anemia, cerebral malaria, organ failure, and death. Repeated infection and treatment of individuals in areas of malaria endemicity eventually induce a level of immunity that limits morbidity and results in chronic infection with low levels of parasitemia (41). A fully effective vaccine that reduces parasite burden and severe disease has not been developed.Murine models of malaria have long been used to examine the immune response to Plasmodium parasites and to understand the host factors required for the development of immunity. P. berghei infection in mice is lethal, causing high levels of parasitemia, severe anemia, and body weight loss. However, mice can become resistant to subsequent infections by treatment with antimalarial drugs during acute infection (27). This is known as the infection and cure model, and mice that develop this immunity mimic the human experience of disease in that they are reinfected but experience low-level patent parasitemia and survive. However, it takes years to establish this level of immunity in humans (36), while in mice it is accomplished by only one infection and drug cure, which provides long-lasting protection (12,13,48). An understanding of the basis of rodent immunity to blood-stage infection will help to direct future vaccine approaches.The fact that immunity induced by infection and cure is long-lasting suggests that the adaptive immune system is required for immunity. Evidence from previous work indicates a role for B and T cells in immunity. Mice lacking both mature B and T cells (SCID mice) (6)...

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AID−/−μs−/− Mice Are Agammaglobulinemic and Fail to Maintain B220−CD138+ Plasma Cells

Cited by 42 publications

References 46 publications

Gold causes genetically determined autoimmune and immunostimulatory responses in mice

Gold causes genetically determined autoimmune and immunostimulatory responses in mice

B cells mediate chronic allograft rejection independently of antibody production

Secreted Antibody Is Required for Immunity toPlasmodium berghei

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