Publications (18)248.63 Total impact
-
Article: Recent advances in dynamic intravital multi-photon microscopy.
[show abstract] [hide abstract]
ABSTRACT: Standard multiphoton laser scanning microscopy (MPLSM) has revolutionized our view of physiologic and pathologic processes in living organisms by enlightening different aspects of cellular choreography in immune responses, that is, cellular motility and co-localization. To understand cellular communication on a molecular level, novel transgenic reporter mice have been generated. In parallel, MPLSM systems have been developed, which make it possible for this technique to be more widely used to address crucial immunological questions. Here, we review the latest progress concerning transgenic mouse technology and multiphoton imaging capacities and discuss further developments which will enable us to visualize all around monitoring and quantification of cellular function at a molecular level directly in vivo.Cytometry Part A 09/2011; 79(10):789-98. · 3.73 Impact Factor -
Article: Control of TH17 cells occurs in the small intestine.
[show abstract] [hide abstract]
ABSTRACT: Interleukin (IL)-17-producing T helper cells (T(H)17) are a recently identified CD4(+) T cell subset distinct from T helper type 1 (T(H)1) and T helper type 2 (T(H)2) cells. T(H)17 cells can drive antigen-specific autoimmune diseases and are considered the main population of pathogenic T cells driving experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. The factors that are needed for the generation of T(H)17 cells have been well characterized. However, where and how the immune system controls T(H)17 cells in vivo remains unclear. Here, by using a model of tolerance induced by CD3-specific antibody, a model of sepsis and influenza A viral infection (H1N1), we show that pro-inflammatory T(H)17 cells can be redirected to and controlled in the small intestine. T(H)17-specific IL-17A secretion induced expression of the chemokine CCL20 in the small intestine, facilitating the migration of these cells specifically to the small intestine via the CCR6/CCL20 axis. Moreover, we found that T(H)17 cells are controlled by two different mechanisms in the small intestine: first, they are eliminated via the intestinal lumen; second, pro-inflammatory T(H)17 cells simultaneously acquire a regulatory phenotype with in vitro and in vivo immune-suppressive properties (rT(H)17). These results identify mechanisms limiting T(H)17 cell pathogenicity and implicate the gastrointestinal tract as a site for control of T(H)17 cells.Nature 07/2011; 475(7357):514-8. · 36.28 Impact Factor -
Article: Long-lived autoreactive plasma cells drive persistent autoimmune inflammation.
[show abstract] [hide abstract]
ABSTRACT: Aberrant production of autoantibodies by inappropriately self-reactive plasma cells is an inherent characteristic of autoimmune diseases. Several therapeutic strategies aim to deplete the plasma cell pool, or to prevent maturation of B cells into plasma cells. However, accepted views of B-cell biology are changing; recent findings show that long-lived plasma cells refractory to immunosuppressants and B-cell depletion therapies contribute to the maintenance of humoral memory and, in autoimmunity, to autoreactive memory. As a consequence of their longevity and persistence, long-lived plasma cells can support chronic inflammatory processes in autoimmune diseases by continuously secreting pathogenic antibodies, and they can contribute to flares of symptoms. As long-lived plasma cells are not sufficiently eliminated by current therapies, these findings are extremely relevant to the development of novel concepts for the treatment of autoimmune diseases. Thus, long-lived plasma cells appear to be a promising new therapeutic target.Nature Reviews Rheumatology 02/2011; 7(3):170-8. · 8.39 Impact Factor -
Article: Activated germinal centre B cells undergo directed migration.
IJDMB. 01/2011; 5:321-331. -
Article: Activated germinal centre B cells undergo directed migration.
[show abstract] [hide abstract]
ABSTRACT: Affinity maturation, the fundamental basis for adaptive immunity, is accomplished through somatic hypermutation of B-cell receptors followed by expansion of rare mutants with higher affinity for the immunising antigen. This process occurs over a period of weeks in unique micro-anatomic sites known as germinal centres. Two-photon microscopy has recently made it possible to track individual cells moving within germinal centres in living animals. Here we apply statistical approaches to test the hypothesis that B-cell motion is random. Our results show that activated B cells move in a directed manner that sharply contrasts with the behaviour of naïve B cells.International Journal of Data Mining and Bioinformatics 01/2011; 5(3):321-31. · 0.43 Impact Factor -
Article: Cellular choreography in the germinal center: new visions from in vivo imaging.
[show abstract] [hide abstract]
ABSTRACT: Germinal centers (GC) are large aggregates of proliferating B lymphocytes within follicles of lymphoid tissue that form during adaptive immune responses. GCs are the source of long-lived B cells that form the basis for pathogen-specific lifelong B cell immunity. The complex architecture of these structures includes subdomains that differ significantly in their stromal cell and T lymphocyte subset composition. In part due to their structural complexity and potential to generate some lymphomas, much interest and many theories about GC dynamics have emerged. Here, we review recent research employing in vivo imaging that has begun to untangle some of the mysteries.Seminars in Immunopathology 09/2010; 32(3):239-55. · 6.27 Impact Factor -
Article: Organization of immunological memory by bone marrow stroma.
[show abstract] [hide abstract]
ABSTRACT: Immunological memory is a hallmark of the adaptive immune system. Plasma cells and memory B and T cells collectively provide protective immunity and effective secondary immune responses to invading pathogens. Here, we discuss how mesenchymal stromal cells regulate immunological memory by organizing defined numbers of dedicated survival niches for plasma cells and memory T cells in the bone marrow and also, to a lesser extent, in secondary lymphoid organs. An understanding of the biology of mesenchymal stromal cells and their interaction with cells of the immune system is key to fully understanding immunological memory.Nature Reviews Immunology 02/2010; 10(3):193-200. · 32.25 Impact Factor -
Article: Expanding two-photon intravital microscopy to the infrared by means of optical parametric oscillator.
[show abstract] [hide abstract]
ABSTRACT: Chronic inflammation in various organs, such as the brain, implies that different subpopulations of immune cells interact with the cells of the target organ. To monitor this cellular communication both morphologically and functionally, the ability to visualize more than two colors in deep tissue is indispensable. Here, we demonstrate the pronounced power of optical parametric oscillator (OPO)-based two-photon laser scanning microscopy for dynamic intravital imaging in hardly accessible organs of the central nervous and of the immune system, with particular relevance for long-term investigations of pathological mechanisms (e.g., chronic neuroinflammation) necessitating the use of fluorescent proteins. Expanding the wavelength excitation farther to the infrared overcomes the current limitations of standard Titanium:Sapphire laser excitation, leading to 1), simultaneous imaging of fluorophores with largely different excitation and emission spectra (e.g., GFP-derivatives and RFP-derivatives); and 2), higher penetration depths in tissue (up to 80%) at higher resolution and with reduced photobleaching and phototoxicity. This tool opens up new opportunities for deep-tissue imaging and will have a tremendous impact on the choice of protein fluorophores for intravital applications in bioscience and biomedicine, as we demonstrate in this work.Biophysical Journal 02/2010; 98(4):715-23. · 3.65 Impact Factor -
Conference Proceeding: Activated Germinal-Center B Cells Undergo Directed Migration.
2009 IEEE International Conference on Bioinformatics and Biomedicine, BIBM 2009, Washington, DC, USA, 1-4 November 2009, Proceedings; 01/2009 -
Article: In vivo imaging studies shed light on germinal-centre development.
[show abstract] [hide abstract]
ABSTRACT: Affinity maturation of antibodies during the course of an adaptive immune response requires germinal centre (GC) formation within B-cell follicles. Much of the current understanding of GC function has been derived from histology, but these static views have left unresolved many questions about cell movement in GCs. In this Progress article, we describe how several recent studies using time-resolved multiphoton microscopy to track GC B-cell movement within lymph nodes have shed light on the processes that influence GC B-cell dynamics.Nature reviews. Immunology 08/2007; 7(7):499-504. · 33.29 Impact Factor -
Article: Definition of germinal-center B cell migration in vivo reveals predominant intrazonal circulation patterns.
[show abstract] [hide abstract]
ABSTRACT: Proliferation, mutation, and selection in the germinal center (GC) are thought to occur in distinct microanatomical compartments-the dark zone (DZ) and the light zone (LZ). Thus, affinity maturation has been posited to require frequent trafficking between zones. Here we report the use of multiphoton in vivo microscopy to determine migration patterns of GC B cells. Analysis of time-resolved images revealed unexpected patterns of movement as well as GC B cell morphology. Though frequent movement between the DZ and LZ was anticipated, few cells were observed to cross the interface between the two compartments. Moreover, cell-track trajectories indicated that cell movement in this region is predominantly parallel to the interface, suggesting that B cells circulate within individual LZ and DZ compartments. The results suggest a revision to our views of B cell circulation within GCs and the functional relationship of its two major compartments.Immunity 06/2007; 26(5):655-67. · 21.64 Impact Factor -
Article: Regulation of CXCR3 and CXCR4 expression during terminal differentiation of memory B cells into plasma cells.
[show abstract] [hide abstract]
ABSTRACT: 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.Blood 06/2005; 105(10):3965-71. · 9.90 Impact Factor -
Article: Maintenance of serum antibody levels.
[show abstract] [hide abstract]
ABSTRACT: 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.Annual Review of Immunology 02/2005; 23:367-86. · 52.76 Impact Factor -
Article: Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice.
[show abstract] [hide abstract]
ABSTRACT: 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.Journal of Experimental Medicine 06/2004; 199(11):1577-84. · 13.85 Impact Factor -
Article: Early granuloma formation after aerosol Mycobacterium tuberculosis infection is regulated by neutrophils via CXCR3-signaling chemokines.
[show abstract] [hide abstract]
ABSTRACT: Among the first cells to invade a site of infection, polymorphonuclear neutrophils (PMN) play an important role in the control of numerous infections. While PMN are considered critical for control of acute infections, their role in chronic infections remains less well understood. Here we report that PMN are essential for accurate early granuloma formation during chronic M. tuberculosis infection without influencing mycobacterial growth restriction. The PMN-mediated regulation of granuloma formation depended on chemokines signaling through CXCR3, in particular MIG, as indicated by immune histochemical analysis of lung sections from C57BL/6 wild-type and CXCR3(-/-) mutant mice and supported by microarray transcriptome analysis. Hence, PMN play a central role in regulating the focal granulomatous response in the lung, and this early granuloma formation can be segregated from long-term protection against pulmonary M. tuberculosis infection.European Journal of Immunology 11/2003; 33(10):2676-86. · 5.10 Impact Factor -
Article: Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals.
[show abstract] [hide abstract]
ABSTRACT: 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.The Journal of Immunology 09/2003; 171(4):1684-90. · 5.79 Impact Factor -
Article: Chemotactic responsiveness toward ligands for CXCR3 and CXCR4 is regulated on plasma blasts during the time course of a memory immune response.
[show abstract] [hide abstract]
ABSTRACT: 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.The Journal of Immunology 09/2002; 169(3):1277-82. · 5.79 Impact Factor -
Article: Humoral immunity and long-lived plasma cells.
[show abstract] [hide abstract]
ABSTRACT: 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.Current Opinion in Immunology 09/2002; 14(4):517-21. · 9.52 Impact Factor
Top co-authors
Top Journals
Institutions
-
2011
-
University of Massachusetts Medical School
Worcester, MA, USA
-
-
2004–2011
-
Charité Universitätsmedizin Berlin
- Medical Department, Division of Rheumatology and Clinical Immunology
Berlin, Land Berlin, Germany
-
-
2002–2010
-
German Rheumatism Research Centre
Berlin, Land Berlin, Germany
-
-
2007
-
Yale University
- Department of Laboratory Medicine
New Haven, CT, USA
-
-
2003–2005
-
Deutsches Herzzentrum Berlin
Berlin, Land Berlin, Germany
-
