Quantitatively Reduced Participation of Anti-Nuclear Antigen B Cells That Down-Regulate B Cell Receptor during Primary Development in the Germinal Center/Memory B Cell Response to Foreign Antigen
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Abstract The peripheral B cell compartment contains high levels of “polyreactivity” including autospecificities. We have described a pathway that certain autoreactive B cells may take in gaining stable access to the foreign Ag-responsive peripheral compartment. This pathway was revealed in mice expressing a targeted Ig H chain transgene encoding BCRs with “multireactivity” for the hapten arsonate and DNA-based autoantigens. B cells expressing such BCRs develop to mature follicular phenotype and locale, and are not short-lived. These B cells express very low levels of BCR, indicating that they are not “ignorant” of self Ag, but do not display features of anergy in in vitro assays. Nonetheless, a variety of states of lymphocyte anergy has been described, and some may only be manifested in vivo. As such, we analyzed the ability of these B cells to participate in a T cell-dependent immune response to arsonate in vivo. These B cells mount an early primary response similar to control B cells, including homing to follicles, migration to the T-B interface, and induction of costimulatory molecules, proliferation, differentiation to AFCs, class switching, and entry into GCs and somatic hypermutation. Nonetheless, these B cells display reduced participation in the latter stages of the GC response and in the anamnestic AFC response. In total, these data suggest that while the autoreactivity of this type of B cell does not result in anergy, the ability of such B cells to participate in a cross-reactive immune response to foreign Ag is compromised.Keywords:
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We investigated the ability of monoclonal B cells to restore primary and secondary T-cell dependent antibody responses in adoptive immune-deficient hosts. Priming induced B cell activation and expansion, AID expression, antibody production and the generation of IgM+IgG- and IgM-IgG+ antigen-experienced B-cell subsets that persisted in the lymphopenic environment by cell division. Upon secondary transfer and recall the IgM-IgG+ cells responded by the production of antigen-specific IgG while the IgM+ memory cells secreted mainly IgM and little IgG, but generated new B cells expressing germinal center markers. The recall responses were more efficient if the antigenic boost was delayed suggesting that a period of adaptation is necessary before the transferred cells are able to respond. Overall these findings indicate that reconstitution of a functional and complete memory pool requires transfer of all different antigen-experienced B cell subsets. We also found that the size of the memory B cell pool did not rely on the number of the responding naïve B cells, suggesting autonomous homeostatic controls for naïve and memory B cells. By reconstituting a stable memory B cell pool in immune-deficient hosts using a monoclonal high-affinity B cell population we demonstrate the potential value of B cell adoptive immunotherapy.
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Abstract It is generally accepted that memory B cells can be defined by their ability to produce, upon antigenic challenge, somatically mutated antibody molecules characterized by an increased affinity and by the expression of a downstream heavy chain isotype. However, the inability to isolate this particular B cell compartment has precluded the study of memory B lymphocyte physiology in man. We previously reported on the identification of an IgD − B cell subset in human tonsils that we defined as CD38 − B cells, whose phenotype is highly reminiscent of that of memory B lymphocytes from the splenic marginal zone of rodents. In the present study, we developed a model of the measles virus (MV)‐specific secondary antibody response in vitro to assess the presence of memory B lymphocytes in different B cell subsets isolated from human tonsils and explore the activation requirements of human memory B cells. Our findings show that the memory B cell pool resides in the CD38 − B cell subpopulation and that the differentiation of MV‐activated memory B cells into antibody‐secreting cells can be achieved upon co‐stimulation with interleukin (IL)‐2 and IL‐10, but does not require engagement of CD40. Interestingly, the CD40‐mediated signal was found to synergize with Ig‐cross‐linking agents for the proliferation of memory B cells, but strongly suppressed their capacity to differentiate along the plasmacytoid pathway. Collectively, our results suggest that the CD40 signaling pathway is instrumental for the clonal expansion of the memory B cell pool, but does not operate in the later phase of the response, which allows their maturation into antibody‐secreting cells.
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There are no known specific markers for memory B cells in mice, although studies suggest that the CD38low and CD38high phenotypes are indicative of isotype-switched germinal center (GC) and memory B cells in the mouse, respectively [1]. Further analysis suggested that IgG1+CD38high B cells, but not IgG1+CD38low B cells, are capable of inducing a significant IgG1 secondary response in the adoptive hosts [2], demonstrating that the CD38low and CD38high phenotype distinction can be used to monitor the development of the antigen-specific memory B cells in the T cell-dependent (TD) response. In humans, approximately 30–50% of the peripheral blood B cells are CD27+, and CD27 has been identified as a good surface marker for human memory B cells [3–5]. IgD−CD27+ cells in the peripheral blood have already undergone class switch recombination (CSR) and have accumulated somatic hypermutations (SHMs) in their VH genes in comparison to CD27− B cells, which have not. Polyclonal stimulation of B cells from anthrax vaccine adsorbed (AVA) vaccinated individuals generated AVA-specific IgG+ antibody-secreting cells (ASCs) in vitro, but the deletion of CD27+ B cells abrogated the response [6], indicating that human memory B cells are present in the CD27+ B cell compartment.The immune system memorizes the characteristics of pathogens to provide effective immune protection. Memory B cells and long-lived plasma cells (PCs) account for the long-term humoral immunity elicited by infections and many vaccines. Once generated, memory B cells enter a resting state and persist over long periods of time in the lymphoid organs in the apparent absence of immunizing antigen. T cell-dependent (TD) B cell memory is generated along two fundamentally distinct differentiation pathways. One of these is the classical generation pathway through antibody affinity maturation in the germinal center (GC) reaction with the help of T follicular helper (Tfh) cells. In the other pathway, memory B cells develop in response to a TD antigen before the onset and independently of the GC reaction with the help of T cells other than Tfh. The maintenance of these cells over time may depend on interactions with cells in their environment, perhaps in specialized “niches” akin to those postulated for the maintenance of PCs. Memory B cells provide the quick anamnestic antibody response that follows after antigen reexposure. This activity is critical for eliminating pathogens and toxins that are not efficiently eliminated by preexisting circulating antibodies.Plasma cells are terminally differentiated cells of the B lymphocyte lineage, the cells uniquely able to secrete antibody and thus the cell responsible for antibody-mediated immunity. In addition, because plasma cells can be maintained for extended periods, providing potentially life-long immunity to pathogens and their toxic products, they constitute a crucial component of immune memory. As such, plasma cell biology is fundamental in health in terms of immunity resulting from infection and vaccines. Furthermore, information regarding plasma cell development, differentiation, and survival and the molecular mediators of these processes provides potentially unprecedented insights into plasma cells participating in disease processes such as antibody-mediated autoimmune diseases such as systemic lupus erythematosus and the development of plasma cell cancers such as multiple myeloma.Memory plasma cells residing as mature long-lived plasma cells in bone marrow and inflamed tissues secrete antibodies independently of antigen contact, T cell help and memory B cells and are therefore crucial for maintaining antibody levels. They are refractory to irradiation, immunosuppression and therapies targeting B cells. Consequently, memory plasma cells secreting pathogenic antibodies substantially contribute to the chronicity and therapy resistance of antibody-mediated diseases. Their therapeutic targeting is a promising challenge.
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