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Andreas Radbruch

Publications and source records attributed to Andreas Radbruch.

At least 19 recordsLinked to original sources
PubMed2006

Competence and competition: the challenge of becoming a long-lived plasma cell.

Plasma cells provide humoral immunity. They have traditionally been viewed mainly as short-lived end-stage products of B-cell differentiation that deserve little interest. This view is changing, however, because we now know that plasma cells can survive for long periods in the appropriate survival niches and that they are an independent cellular component of immunological memory. Studies of the biology of plasma cells reveal a mechanism of intriguing simplicity and elegance that focuses memory provided by plasma cells on recently encountered pathogens while minimizing the 'fading' of memory for pathogens encountered in the distant past. This mechanism is based on competition for survival niches between newly generated plasmablasts and older plasma cells.

Animals↗
PubMed2006

Membrane glucocorticoid receptor expression on peripheral blood mononuclear cells in patients with ankylosing spondylitis.

OBJECTIVE: To investigate the expression of membrane glucocorticoid receptors (mGCR) on peripheral blood mononuclear cells (PBMC) in patients with ankylosing spondylitis (AS). METHODS: We used high sensitivity immunofluorescence with magnetofluorescent liposomes for the detection of mGCR on PBMC from patients with AS (n = 26) and healthy controls (n = 11). RESULTS: The frequency of mGCR+ monocytes and B lymphocytes was significantly higher in patients with AS than in controls (monocytes 12.5 +/- 9.9% vs 4.8 +/- 1.4%, B lymphocytes 8.7 +/- 6.3% vs 4.4 +/- 3.6%). We did not find mGCR on T lymphocytes. The frequency of mGCR+ cells did not correlate with variables of AS disease activity [C-reactive protein, erythrocyte sedimentation rate, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASDAI 6, or numerical rating scales]. CONCLUSION: mGCR are upregulated in monocytes and B lymphocytes of patients with AS. This upregulation does not correlate with the humoral or overall disease activity. mGCR are not present on T lymphocytes. Our findings may be related to the limited benefit of low-dose and the efficacy of high-dose (intravenous pulse or intraarticular) glucocorticoid treatment in AS. Drugs binding selectively to mGCR may be a new therapeutic option for AS.

Adult↗
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

Cis- and trans-acting gene regulation is associated with osteoarthritis.

Osteoarthritis (OA) is a complex disease of the skeleton and is associated with aging. Both environmental and genetic factors contribute to its pathogenesis. We set out to identify novel genes associated with OA, concentrating on regulatory polymorphisms allowing for differential expression. Our strategy to identify differentially expressed genes included an initial transcriptome analysis of the peripheral blood mononuclear cells of six patients with OA and six age-matched healthy controls. These were screened for allelic expression imbalances and potentially regulatory single-nucleotide polymorphisms (SNPs) in the 5' regions of the genes. To establish disease association, disparate promoter SNP distributions correlating with the differential expression were tested on larger cohorts. Our approach yielded 26 candidate genes differentially expressed between patients and controls. Whereas BLP2 and CIAS1 seem to be trans-regulated, as the absence of allelic expression imbalances suggests, the presence of allelic imbalances confirms cis-regulatory mechanisms for RHOB and TXNDC3. Interestingly, on/off-switching suggests additional trans-regulation for TXNDC3. Moreover, we demonstrate for RHOB and TXNDC3 statistically significant associations between 5' SNPs and the disease that hint at regulatory functions. Investigating the respective genes functionally will not only shed light on the disease association but will also add to the understanding of the pathogenic processes involved in OA and may point out novel therapeutic approaches.

Adult↗
PubMed2006

Identification of immunodominant CD4+ T cell epitopes in patients with Yersinia-induced reactive arthritis by cytometric cytokine secretion assay.

OBJECTIVE: In reactive arthritis (ReA), a bacteria-specific T cell response to the triggering microbe is detected in synovial fluid. So far, direct characterization of bacteria-specific T cells and identification of the immunodominant fine specificities remain difficult due to the lack of appropriate techniques. The aim of the present study was to directly determine the fine specificity of CD4+ T cells specific to ReA-associated bacteria-derived protein. METHODS: In 2 patients with Yersinia-induced ReA, live Yersinia Hsp60-specific CD4+ T cells were directly isolated from synovial fluid after stimulation with Yersinia-derived protein Hsp60 using a cytometric cytokine secretion assay. Generated short-term T cell lines were then tested in vitro for their peptide epitope specificity. Also, direct cross-reactivity of one line with Chlamydia- and human-derived Hsp60 was assessed. RESULTS: Generated short-term CD4+ T cell lines were highly antigen-specific and revealed single immunodominant peptide epitopes that were confirmed by direct testing with single peptides in both peripheral blood and synovial fluid cells. Yersinia Hsp60-specific T cells of one patient cross-reacted directly with human Hsp60. CONCLUSION: Our results demonstrate the feasibility of direct assessment of live, potentially pathogenic, antigen-specific interferon-gamma+ CD4+ T cells taken from inflammatory lesions of patients with rheumatic diseases such as ReA. This might have implications not only regarding pathogenesis, but also in the design of new immunotherapies.

Adult↗
PubMed2006

Is long-term humoral immunity in the mucosa provided by long-lived plasma cells? A question still open.

The biology of antibody-secreting cells is still a matter of controversial discussion. One of the key questions is how the migration and lifespan of antibody-secreting cells is linked to their generation. A paper in this issue of the European Journal of Immunology provides further information on the generation of long-term mucosal immune responses; however, the study leaves many questions unanswered as discussed in this brief Commentary.

Adjuvants, Immunologic↗
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

Long-lived plasma cells in immunity and immunopathology.

Following tetanus vaccination, a wave of antibody-secreting cells appear in the peripheral blood composed of vaccine-specific, migratory plasmablasts and plasma cells secreting antibodies specific for other antigens. The latter probably were tissue resident plasma cells formed in earlier immune responses that are mobilized due to competition with the newly formed tetanus-specific plasmablasts. Newly formed plasma cells secreting antibodies specific for a particular antigen/vaccine are accommodated in the bone marrow likely at the global expense of the pre-existing long-lived plasma cell population providing humoral memory for other antigens. Plasmablasts but not mature plasma cells are attracted by the ligands for the chemokine receptors CXCR4 and CXCR3. While CXCR4 and its cognate ligand is important for plasma cell homing to the bone marrow, CXCR3 and its ligand IP10 are likely to be involved in attracting them to inflamed tissue. In NZB/W mice, a model for systemic lupus, long-lived autoreactive plasma cells are present not only in bone marrow, but also in inflamed tissues and spleen. Autoreactive plasma cells in the spleen are present long before the onset of the disease, suggesting that these cells contribute to induction of immunopathology.

Animals↗
PubMed2005

A critical control element for interleukin-4 memory expression in T helper lymphocytes.

Naive T helper (Th) lymphocytes are induced to express the il4 (interleukin-4) gene by simultaneous signaling through the T cell receptor and the interleukin (IL)-4 receptor. Upon restimulation with antigen, such preactivated Th lymphocytes can reexpress the il4 gene independent of IL-4 receptor signaling. This memory for expression of the il4 gene depends on epigenetic modification of the il4 gene locus and an increased expression of GATA-3, the key transcription factor for Th2 differentiation. Here, we have identified a phylogenetically conserved sequence, the conserved intronic regulatory element, in the first intron of the il4 gene containing a tandem GATA-3 binding site. We show that GATA-3 binds to this sequence in a position- and orientation-dependent manner, in vitro and in vivo. DNA demethylation and histone acetylation of this region occurs early and selectively in differentiating, IL-4-secreting Th2 lymphocytes. Deletion of the conserved element by replacement of the first exon and part of the first intron of the il4 gene with gfp leads to a defect in the establishment of memory for expression of IL-4, in that reexpression of IL-4 still requires costimulation by exogenous IL-4. The conserved intronic regulatory element thus links the initial epigenetic modification of the il4 gene to GATA-3 and serves as a genetic control element for memory expression of IL-4.

Animals↗
PubMed2005

Selecting B cells and plasma cells to memory.

Humoral immunity appears to be based on immunological memory provided by memory plasma cells, which secrete protective antibodies, and memory B cells, which react to antigen challenge by differentiating into plasma cells. How these differentiation pathways relate to each other, how cells are selected into these memory populations, and how these populations are maintained remains enigmatic.

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

Nibrin functions in Ig class-switch recombination.

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder characterized by predisposition to hematopoietic malignancy, cell-cycle checkpoint defects, and ionizing radiation sensitivity. NBS is caused by a hypomorphic mutation of the NBS1 gene, encoding nibrin, which forms a protein complex with Mre11 and Rad50, both involved in DNA repair. Nibrin localizes to chromosomal sites of class switching, and B cells from NBS patients show an enhanced presence of microhomologies at the sites of switch recombination. Because nibrin is crucial for embryonic survival, direct demonstration by targeted deletion that nibrin functions in class switch recombination has been lacking. Here, we show by cell-type-specific conditional inactivation of Nbn, the murine homologue of NBS1, that nibrin plays a role in the repair of gamma-irradiation damage, maintenance of chromosomal stability, and the recombination of Ig constant region genes in B lymphocytes.

Animals↗
PubMed2005

The role of regulatory T cells in antigen-induced arthritis: aggravation of arthritis after depletion and amelioration after transfer of CD4+CD25+ T cells.

It is now generally accepted that CD4+CD25+ Treg cells play a major role in the prevention of autoimmunity and pathological immune responses. Their involvement in the pathogenesis of chronic arthritis is controversial, however, and so we examined their role in experimental antigen-induced arthritis in mice. Depletion of CD25-expressing cells in immunized animals before arthritis induction led to increased cellular and humoral immune responses to the inducing antigen (methylated bovine serum albumin; mBSA) and autoantigens, and to an exacerbation of arthritis, as indicated by clinical (knee joint swelling) and histological scores. Transfer of CD4+CD25+ cells into immunized mice at the time of induction of antigen-induced arthritis decreased the severity of disease but was not able to cure established arthritis. No significant changes in mBSA-specific immune responses were detected. In vivo migration studies showed a preferential accumulation of CD4+CD25+ cells in the inflamed joint as compared with CD4+CD25- cells. These data imply a significant role for CD4+CD25+ Treg cells in the control of chronic arthritis. However, transferred Treg cells appear to be unable to counteract established acute or chronic inflammation. This is of considerable importance for the timing of Treg cell transfer in potential therapeutic applications.

Animals↗
PubMed2005

The intracellular 52-kd Ro/SSA autoantigen in keratinocytes is up-regulated by tumor necrosis factor alpha via tumor necrosis factor receptor I.

OBJECTIVE: Previous studies have shown that the nuclear Ro/SSA autoantigens involved in photosensitive cutaneous lupus manifestations are regulated by ultraviolet B (UVB) irradiation. UVB exposure triggers the release of tumor necrosis factor alpha (TNFalpha) from keratinocytes in the epidermis and from mast cells in the dermis. The present study aimed to characterize the effect of TNFalpha on messenger RNA (mRNA) and protein expression of the intracellular 52-kd Ro/SSA autoantigen in primary human keratinocytes and to elucidate the TNFalpha receptor (TNFR) signaling pathways mediating this effect. METHODS: Expression of 52-kd Ro/SSA mRNA in primary human keratinocytes was investigated by quantitative real-time polymerase chain reaction (LightCycler system) using GAPDH as the housekeeping gene. Expression of 52-kd Ro/SSA protein was studied by flow cytometry after staining intracellular protein with IgG purified from an anti-52-kd Ro/SSA-positive serum. TNFR function was assessed by culturing cells in the presence and absence of neutralizing antibodies directed against the TNFR subunits TNFRI and TNFRII. RESULTS: TNFalpha-induced up-regulation of 52-kd Ro/SSA mRNA expression peaked at 4 hours, followed by up-regulation of intracellular 52-kd Ro/SSA protein expression at 24 hours, independently of apoptosis. Between different donors, a high variability of both constitutive expression levels and TNFalpha-induced changes in 52-kd Ro/SSA mRNA and protein expression was observed. The up-regulatory effect of TNFalpha on 52-kd Ro/SSA mRNA and protein expression was inhibited by anti-TNFRI antibodies but enhanced by anti-TNFRII antibodies. CONCLUSION: The finding that TNFalpha up-regulates 52-kd Ro/SSA expression in keratinocytes via TNFRI suggests that it may play a role in the pathogenesis of anti-Ro/SSA-associated cutaneous lupus erythematosus.

Apoptosis↗
PubMed2005

Activation of human NK cells by plasmacytoid dendritic cells and its modulation by CD4+ T helper cells and CD4+ CD25hi T regulatory cells.

Plasmacytoid dendritic cells (pDC) represent a specialized cell population that produce type I interferon (IFN) in response to virus. Although type I IFN is a natural killer (NK) cell modulator, a direct role for pDC in coordinating NK cell functions has not yet been elucidated in detail, especially in humans. Here we report that human pDC, following engagement of Toll-like receptor (TLR) 9, not only activate autologous NK cells, as indicated by the induction of CD69 expression, but also enhance their effector functions, especially cytotoxicity. Moreover, they can induce selective proliferation of CD56bright CD16- NK cells. This activity can be strongly augmented by the addition of autologous CD4+ CD25- T helper cells in an IL-2-dependent fashion. Strikingly, CD4+ CD25hi T regulatory (Treg) cells completely abrogate this IL-2-dependent proliferation of NK cells, while they are not able to influence NK cell activation or proliferation solely induced by pDC. Our data show that TLR9-engaged pDC represent a critical stimulus for human NK cells and that CD4+ Th cells and CD4+ CD25hi Treg cells play an important role in modulating human NK cell responses.

Adult↗
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↗