Biomedical subjects

Rudolf A Manz

Publications and source records attributed to Rudolf A Manz.

15 recordsLinked to original sources

PubMed2006

VCAM-1-positive stromal cells from human bone marrow producing cytokines for B lineage progenitors and for plasma cells: SDF-1, flt3L, and BAFF.

The differentiation of B lymphocytes in the bone marrow is guided by the surrounding microenvironment determined by cytokines, adhesion molecules, and the extracellular matrix. These microenvironmental factors are mainly provided by stromal cells. In this paper, we report the identification of a VCAM-1-positive stromal cell population by flow cytometry. This population showed the expression of cell surface markers known to be present on stromal cells (CD10, CD13, CD90, CD105) and had a fibroblastoid phenotype in vitro. Single cell RT-PCR analysis of its cytokine expression pattern revealed transcripts for haematopoietic cytokines important for either the early B lymphopoiesis like flt3L or the survival of long-lived plasma cells like BAFF or both processes like SDF-1. Whereas SDF-1 transcripts were detectable in all VCAM-1-positive cells, flt3L and BAFF were only expressed by some cells suggesting the putative existence of different subpopulations with distinct functional properties. In summary, the VCAM-1-positive cell population seems to be a candidate stromal cell population supporting either developing B cells and/or long-lived plasma cells in human bone marrow.

B-Cell Activating Factor↗

PubMed2006

Stromal niches, plasma cell differentiation and survival.

Contacts made with other cells and stroma have a major impact on proliferation, differentiation, survival, migration and immunoglobulin class switching of plasma cell precursors as well as on the lifespan of the antibody-secreting cells. Induction of tissue-specific chemokine receptors and adhesion molecules directs migratory plasma cell precursors to tissues close to those in which the original immune stimulation occurred. This mechanism focuses the production of specific antibodies within a particular type of tissue, thus providing a means for the most efficient protection against tissue-specific pathogens. Relocation does not apply to long-lived plasma cells responsible for sustained titers of high-affinity systemic antibody. These are formed in germinal centers and migrate to specific niches in the bone marrow that support their further differentiation and long-term survival.

Animals↗

PubMed2006

Tolls for B cells.

Priming of naive lymphocytes is important for yielding efficient immune responses. Mechanisms controlling this process are also important for preventing immune cells from attacking self-antigens. It is well known that signals provided by innate immune receptors, such as Toll-like receptors (TLR), are essential to induce dendritic cell maturation that subsequently allows the priming of naive T cells. In this issue of the European Journal of Immunology, it is shown that TLR stimulation effectively potentiates naive human B cell activation and production of antibodies in T-dependent immune responses. TLR signals can be delivered to B cells directly, or indirectly via cytokines provided by TLR-activated dendritic cells.

Animals↗

PubMed2006

Plasma cell differentiation in T-independent type 2 immune responses is independent of CD11c(high) dendritic cells.

Dendritic cells (DC) play an important role as antigen-presenting cells in T cell stimulation. Interestingly, a number of recent studies also imply DC as critical accessory cells in B cell activation, isotype switching and plasma blast maintenance. Here we use the conditional in vivo ablation of CD11c(high) DC to investigate the role of these cells in T-independent type 2 immune responses. We show that CD11c(high) DC are dispensable for the initiation and maintenance of a primary immune response against the T-independent type 2 antigen (4-hydroxy-3-nirophenyl)acetyl-Ficoll. Our results suggest that support for plasma cell formation in T cell-independent immune responses can be provided by non-DC such as stromal cells, or is independent of external signals. Interestingly, we found plasma blasts to express CD11c and to be diphtheria toxin-sensitive in CD11c-diphtheria toxin receptor-transgenic mice, providing a unique tool for future analysis of in vivo aspects of plasma cell biology.

Animals↗

PubMed2006

Adaptation of humoral memory.

Immunological memory, as provided by antibodies, depends on the continued presence of antibody-secreting cells, such as long-lived plasma cells of the bone marrow. Survival niches for these memory plasma cells are limited in number. In an established immune system, acquisition of new plasma cells, generated in response to recent pathogenic challenges, requires elimination of old memory plasma cells. Here, we review the adaptation of plasma cell memory to new pathogens. This adaptation is dependent upon the influx of plasmablasts, generated in a secondary systemic immune reaction, into the pool of memory plasma cells, the efficiency of competition of new plasmablasts with old plasma cells, and the frequency of infection with novel pathogens. To maintain old plasma cells at frequencies high enough to provide protection and to accommodate as many specificities as possible, an optimal influx rate per infection exists. This optimal rate is approximately three times higher than the minimal number of plasma cells providing protection. Influx rates of plasmablasts generated by vaccination approximately match this optimum level. Furthermore, the observed stability of serum concentrations of vaccine-specific antibodies implies that the influxing plasmablasts mobilize a similar number of plasma cells and that competitive infectious challenges are not more frequent than once per month.

Adaptation, Biological↗

PubMed2005

Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma.

Mutation of p53 is a rare event in multiple myeloma, but it is unknown if p53 signaling is functional in myeloma cells, and if targeted nongenotoxic activation of the p53 pathway is sufficient to kill tumor cells. Here, we demonstrate that treatment of primary tumor samples with a small-molecule inhibitor of the p53-murine double minute 2 (MDM2) interaction increases the level of p53 and induces p53 targets and apoptotic cell death. Significantly, given the importance of the bone marrow microenvironment for the support and drug resistance of myeloma cells, tumor cells undergo effective apoptosis also in the presence of stromal cells, which themselves appear to tolerate exposure to nutlin-3. The in vitro toxicity of nutlin-3 was similar to that of the genotoxic drug melphalan. Because nutlin-mediated p53 activation is not dependent on DNA damage, MDM2 antagonists may help to avoid or reduce the severe genotoxic side effects of chemotherapeutic agents currently used to treat multiple myeloma. Therefore, MDM2 antagonists may offer a new treatment option for this disease.

Animals↗

PubMed2005

Regulation of CXCR3 and CXCR4 expression during terminal differentiation of memory B cells into plasma cells.

C-X-C motif chemokine receptor 3 (CXCR3) and CXCR4 expressed on immunoglobulin G (IgG)-plasma-cell precursors formed in memory immune responses are crucial modulators of the homing of these cells. Here, we studied the regulation of the expression of these chemokine receptors during the differentiation of human memory B cells into plasma cells. We show that CXCR3 is absent on CD27- naive B cells but is expressed on a fraction of memory B cells, preferentially on those coexpressing IgG1. On differentiation into plasma-cell precursors, CXCR3+ memory B cells maintain the expression of this chemokine receptor. CXCR3- memory B cells up-regulate CXCR3 and migrate toward concentration gradients of its ligands only when costimulated with interferon gamma (IFN-gamma), but not interleukin 4 (IL-4), IL-1beta, IL-6, IFN-alpha, IFN-beta, or tumor necrosis factor alpha (TNF-alpha). In contrast, the differentiation of CXCR4- B cells into plasma cells is generally accompanied by the induction of CXCR4 expression. These results show that lack of CXCR4 expression on plasma-cell precursors is not a limiting factor for plasma-cell homing and that the expression of CXCR3 on memory B cells and plasma-cell precursors is induced by IFN-gamma, provided in human T helper type 1 (Th1)-biased immune responses. Once induced in memory B cells, CXCR3 expression remains part of the individual cellular memory.

B-Lymphocytes↗

PubMed2005

Maintenance of serum antibody levels.

In vertebrates, serum antibodies are an essential component of innate and adaptive immunity and immunological memory. They also can contribute significantly to immunopathology. Their composition is the result of tightly regulated differentiation of B lymphocytes into antibody-secreting plasma blasts and plasma cells. The survival of antibody-secreting cells determines their contribution to the immune response in which they were generated and to long-lasting immunity, as provided by stable serum antibody levels. Short-lived plasma blasts and/or plasma cells secrete antibodies for a reactive immune response. Short-lived plasma blasts can become long-lived plasma cells, probably by competition with preexisting plasma cells for occupation of a limited number of survival niches in the body, in a process not yet fully understood. Limitation of the number of long-lived plasma cells allows the immune system to maintain a stable humoral immunological memory over long periods, to react to new pathogenic challenges, and to adapt the humoral memory in response to these antigens.

Animals↗

PubMed2005

Long-lived plasma cells and their contribution to autoimmunity.

The current view holds that chronic autoimmune diseases are driven by the continuous activation of autoreactive B and T lymphocytes. However, despite the use of potent immunosuppressants, the production of autoantibodies may persist and contribute to the autoimmune pathology. We recently demonstrated in autoimmune mice that both short-lived plasmablasts and long-lived plasma cells are involved in autoantibody production. While anti-proliferative immunosuppressive therapy and monoclonal anti-CD20 antibody deplete short-lived plasmablasts, long-lived plasma cells survive and continue to produce (auto)antibodies. Thus, strategies for targeting long-lived plasma cells may provide potent new treatment modalities.

Animals↗

PubMed2004

Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice.

The current view holds that chronic autoimmune diseases are driven by the continuous activation of autoreactive B and T lymphocytes. However, despite the use of potent immunosuppressive drugs designed to interfere with this activation the production of autoantibodies often persists and contributes to progression of the immunopathology. In the present study, we analyzed the life span of (auto)antibody-secreting cells in the spleens of NZB x NZW F1 (NZB/W) mice, a murine model of systemic lupus erythematosus. The number of splenic ASCs increased in mice aged 1-5 mo and became stable thereafter. Less than 60% of the splenic (auto)antibody-secreting cells were short-lived plasmablasts, whereas 40% were nondividing, long-lived plasma cells with a half-life of >6 mo. In NZB/W mice and D42 Ig heavy chain knock-in mice, a fraction of DNA-specific plasma cells were also long-lived. Although antiproliferative immunosuppressive therapy depleted short-lived plasmablasts, long-lived plasma cells survived and continued to produce (auto)antibodies. Thus, long-lived, autoreactive plasma cells are a relevant target for researchers aiming to develop curative therapies for autoimmune diseases.

Animals↗

PubMed2004

CD38 low IgG-secreting cells are precursors of various CD38 high-expressing plasma cell populations.

Despite the important role immunoglobulin G (IgG)-secreting plasma cells play in memory immune responses, the differentiation and homeostasis of these cells are not completely understood. Here, we studied the differentiation of human IgG-secreting cells ex vivo and in vitro, identifying these cells by the cellular affinity matrix technology. Several subpopulations of IgG-secreting cells were identified among the cells isolated from tonsils and bone marrow, particularly differing in the expression levels of CD9, CD19, and CD38. CD38 low IgG-secreting cells were present exclusively in the tonsils. A major fraction of these cells appeared to be early plasma cell precursors, as upon activation of B cells in vitro, IgG secretion preceded up-regulation of CD38, and on tonsillar sections, IgG-containing, CD38 low cells with a plasmacytoid phenotype were found in follicles, where plasma cell differentiation starts. A unitary phenotype of migratory peripheral blood IgG-secreting cells suggests that all bone marrow plasma cell populations share a common precursor cell. These data are compatible with a multistep model for plasma cell differentiation and imply that a common CD38 low IgG-secreting precursor gives rise to a diverse plasma cell compartment.

ADP-ribosyl Cyclase↗

PubMed2003

Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals.

Recent results suggest that plasma cell longevity is not an intrinsic capacity, but depends on yet unknown factors produced in their environment. In this study, we show that the cytokines IL-5, IL-6, TNF-alpha, and stromal cell-derived factor-1alpha as well as signaling via CD44 support the survival of isolated bone marrow plasma cells. The cytokines IL-7 and stem cell factor, crucially important for early B cell development, do not mediate plasma cell survival, indicating that plasma cells and early B cells have different survival requirements. As shown in IL-6-deficient mice, IL-6 is required for a normal induction, but not for the maintenance of plasma cell responses in vivo, indicating that the effects of individual survival factors are redundant. Optimal survival of isolated plasma cells requires stimulation by a combination of factors acting synergistically. These results strongly support the concept that plasma cell survival depends on niches in which a combination of specific signals, including IL-5, IL-6, stromal cell-derived factor-1alpha, TNF-alpha, and ligands for CD44, provides an environment required to mediate plasma cell longevity.

Animals↗

PubMed2002

Chemotactic responsiveness toward ligands for CXCR3 and CXCR4 is regulated on plasma blasts during the time course of a memory immune response.

Plasma blasts formed during memory immune responses emigrate from the spleen to migrate into the bone marrow and into chronically inflamed tissues where they differentiate into long-lived plasma cells. In this study, we analyze the chemokine responsiveness of plasma blasts formed after secondary immunization with OVA. Starting from day 4 and within approximately 48 h, OVA-specific plasma blasts emigrate from spleen and appear in the bone marrow. Although these migratory cells have lost their responsiveness to many B cell attracting chemokines, e.g., CXC chemokine ligand (CXCL)13 (B lymphocyte chemoattractant), they migrate toward CXCL12 (stromal cell-derived factor 1 alpha), and toward the inflammatory chemokines CXCL9 (monokine induced by IFN-gamma), CXCL10 (IFN-gamma-inducible protein 10), and CXCL11 (IFN-inducible T cell alpha chemoattractant). However, the responsiveness of plasma blasts to these chemokines is restricted to a few days after their emigration from the spleen, indicating a role for these molecules and their cognate receptors, i.e., CXCR3 and CXCR4, in the regulation of plasma blast migration into the bone marrow and/or inflamed tissues.

Animals↗

PubMed2002

Plasma cells for a lifetime?

Antigen-specific serum antibodies are protective for long periods of time 1, 2. These serum antibodies, the "humoral memory", are secreted by plasma cells derived from activated, antigen-specific B lymphocytes. Given their crucial role in immunity, surprisingly little is known about the biology of plasma cells. One of the fundamental questions is whether persisting protective serum antibody responses are maintained by long-lived plasma cells, or by short-lived plasma cells generated continuously from activated memory B cells. Here, we review some recent experiments suggesting that plasma cells have the capacity to live for unlimited time if rescued by specific factors provided in a limited number of survival niches in the body.

Animals↗

PubMed2002

Humoral immunity and long-lived plasma cells.

A selected fraction of plasmablasts enters the compartment of nondividing, long-lived plasma cells to maintain humoral antibody memory. In accord with a current model for lymphocyte homeostasis, the lifetime of long-lived plasma cells is probably regulated by competition for a limited number of survival niches present in splenic red pulp, bone marrow and inflamed tissue. Plasma cells secreting autoantibodies specific for some, but not all, self-antigens are probably 'allowed' to enter the compartment of long-lived plasma cells and provide antibody-mediated 'autoimmune memory' that is resistant to conventional therapies.

Animals↗