R A Eisenberg

University of Pennsylvania, Philadelphia, Pennsylvania, United States

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Publications (184)1006.28 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Bone damage around the joints is one of the major pathophysiological mechanisms that leads to rheumatoid arthritis (RA) chronic disability. Serum tartrate-resistant acid phosphatase 5b (TRACP-5b) is secreted by osteoclasts, its activity can be used as a clinically relevant bone resorption marker. The aim of this study was to test whether the measurement of serum levels of TRACP-5b in patients with RA would correlate with measures of disease activity and with responses to therapy.
    Chinese medical journal. 08/2014; 127(16):2894-9.
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    ABSTRACT: PURPOSE: Recently, genomewide association analysis has revealed that the Tumor Necrosis Factor Receptor-associated factor 1-Complement 5 (TRAF1-C5) containing locus on chromosome 9 was associated with an increased risk for RA. Studies in model systems suggested that either gain- or loss-of-function TRAF1 mutations have immune effects that could plausibly lead to or exacerbate the arthritis phenotype. KRN/I-A(g7) (KxB/N) is a genetic mouse model of inflammatory arthritis. We aimed to assess the impact of TRAF1 deficiency on KRN/I-A(g7) mice. METHODS: We have bred KRN/I-A(g7) mice onto a TRAF1-deficient background and followed cohorts for the spontaneous appearance of arthritis. We have also transferred KxB/N serum to B6.I-A(g7) TRAF1KO recipients. In addition, systemic autoimmunity was induced through cGVH by injecting bm12 splenocytes into TRAF1KO recipient mice. RESULTS: TRAF1-deficient KRN/I-A(g7) mice spontaneously developed severe, progressive arthritis, comparable to that seen in TRAF1-intact KRN/I-A(g7) mice. However, the anti-GPI antibody titer was significantly lower in the former group. Interestingly, the TRAF1KO mice that had background levels of anti-GPI antibodies still showed severe arthritis, although with a brief delay compared to TRAF1 sufficient mice. In addition, TRAF1KO mice were fully susceptible to passive, serum transfer experiments. In another model of autoimmunity, TRAF1KO had no effect on cGVH autoantibodies production; nor was the response to an exogenous antigen impaired. CONCLUSION: The pathogenesis of spontaneous KRN/I-A(g7) arthritis can largely proceed by TRAF1-independent pathways. The production of anti-GPI autoantibody, but not other autoantibody or antibody responses, was markedly impaired by TRAF1 deficiency. The spontaneous arthritis model in KRN mice appears to be much less antibody dependent than previously believed.
    Journal of Clinical Immunology 01/2013; · 3.38 Impact Factor
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    ABSTRACT: CD59 is a GPI-anchored membrane regulator of complement expressed on blood cells as well as peripheral tissues. It protects host cells from complement injury by inhibiting formation of the membrane attack complex. Recent studies in mice have suggested also a role of CD59 in T cell immune response that was mechanistically independent of complement. In the present study, we investigated the function of CD59 in the MRL/lpr model of murine lupus. We backcrossed the Cd59a knockout (Cd59a(-/-)) mouse onto the MRL/lpr background and compared Cd59a(+/+)-MRL/lpr and Cd59a(-/-)-MRL/lpr littermates for the development of systemic autoimmunity. We found that CD59a deficiency significantly exacerbated the skin disease and lymphoproliferation characteristic of MRL/lpr mice. It also increased autoantibody titers and caused a higher level of proteinuria in male MRL/lpr mice. Bone marrow transfer experiments indicated that CD59a expression on both bone marrow-derived cells and peripheral tissues played a role in lymphoproliferation, whereas the skin disease phenotype is determined mainly by local CD59a expression. Importantly, C3 gene deletion or C5 neutralization with a blocking mAb in Cd59a(-/-)-MRL/lpr mice did not rescue the proautoimmune phenotype associated with CD59a deficiency. These results together suggest that CD59a inhibits systemic autoimmunity in MRL/lpr mice through a complement-independent mechanism.
    The Journal of Immunology 10/2012; · 5.52 Impact Factor
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    ABSTRACT: The efficacy of influenza vaccination in patients treated with rituximab is a clinically important question. Rheumatology clinics are populated with patients receiving rituximab for a broad array of disorders. Although several studies have explored the efficacy of other vaccines in rituximab-treated populations, results have been conflicting. We wished to define influenza vaccine efficacy in a rituximab-treated cohort. We examined 17 evaluable subjects treated with rituximab for rheumatologic conditions. T cell subsets, B cells subsets, T cell function, and B cell function were evaluated at specific time points along with hemagglutinination inhibition titers after receiving the standard inactivated influenza vaccine. T cell subset counts were significantly different than controls but did not change with rituximab. B cells depleted in all patients but were in various stages of recovery at the time of vaccination. Influenza vaccine responsiveness was poor overall, with only 16 % of subjects having a four-fold increase in titer. Pre-existing titers were retained throughout the study, however. The ability to respond to the influenza vaccine appeared to be related to the degree of B cell recovery at the time of vaccination. This study emphasizes that antibody responses to vaccine are impaired in subjects treated with rituximab and supports the concept that B cell recovery influences influenza vaccine responsiveness.
    Journal of Clinical Immunology 10/2012; · 3.38 Impact Factor
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    Robert Eisenberg
    Journal of Clinical Immunology 09/2012; · 3.38 Impact Factor
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    ABSTRACT: Activation and migration of marginal zone B (MZB) cells into follicular (FO) regions of the spleen has been proposed as one of the mechanisms that regulate the development of autoreactive B cells. The mer receptor tyrosine kinase (Mertk) mediates apoptotic cell clearance and regulates activation and cytokine secretion. In the well-studied class II chronic GVH model of bm12 cells into B6 hosts, we observed that Mertk deficient B6 mice did not generate autoantibodies in response to this allogeneic stimulus. We posited that Mertk is important in MHC-II-mediated B cell signaling. In the present study, we show that B cells from Mertk(-/-) mice but not WT B6 mice exhibited decreased calcium mobilization and tyrosine phosphorylation when stimulated by MHC-II cross-linking. The finding that Mertk was important for class II signaling in B cells was further supported by the preponderance of a-allotype autoantibodies in cGVH in RAG-KO mice reconstituted with a mixture of bone marrow from Mertk(-/-) mice (b-allotype) and C20 mice (a-allotype). MZB cells from Mertk(-/-) mice were unable to down regulate surface CD1d expression and subsequent inclusion in the MZ, associated with significantly lower germinal center responses compared to MZB cells from WT. Moreover, Mertk(-/-) mice treated with an anti-CD1d down regulating antibody responded significantly to bm12 cells, while no response was observed in Mertk(-/-) mice treated with control antibodies. Taken together, these findings extend the role of Mertk to include CD1d down regulation on MZB cells, a potential mechanism limiting B cell activation in cGVH.
    Journal of Autoimmunity 07/2012; · 8.15 Impact Factor
  • Robert A Eisenberg, Charles S Via
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    ABSTRACT: The chronic graft-versus-host disease (cGVHD) in mice is characterized by the production of autoantibodies and immunopathology characteristic of systemic lupus erythematosus (lupus). The basic pathogenesis involves the cognate recognition of foreign MHC class II of host B cells by alloreactive CD4 T cells from the donor. CD4 T cells of the host are also necessary for the full maturation of host B cells before the transfer of donor T cells. CD8 T cells play critical roles as well. Donor CD8 T cells that are highly cytotoxic can ablate or prevent the lupus syndrome, in part by killing recipient B cells. Host CD8 T cells can reciprocally downregulate donor CD8 T cells, and thus prevent them from suppressing the autoimmune process. Thus, when the donor inoculum contains both CD4 T cells and CD8 T cells, the resultant syndrome depends on the balance of activities of these various cell populations. For example, in one cGVHD model (DBA/2(C57BL/6xDBA/2)F1, the disease is more severe in females, as it is in several of the spontaneous mouse models of lupus, as well as in human disease. The mechanism of this female skewing of disease appears to depend on the relative inability of CD8 cells of the female host to downregulate the donor CD4 T cells that drive the autoantibody response. In general, then, the abnormal CD4 T cell help and the modulating roles of CD8 T cells seen in cGVHD parallel the participation of T cells in genetic lupus in mice and human lupus, although these spontaneous syndromes are presumably not driven by overt alloreactivity.
    Journal of Autoimmunity 06/2012; 39(3):240-7. · 8.15 Impact Factor
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    ABSTRACT: Primary Sjögren's syndrome (SjS) is an autoimmune disorder characterized by lymphocytic infiltration of the salivary and lacrimal glands, B-cell clonal expansions and an increased risk of lymphoma. In order to understand the role of B cells in this disorder, the antibody repertoire and B-cell maturation were studied in a mouse model of SjS called B6.Aec1/2. B6.Aec1/2 serum was analyzed for antibodies by ELISA and immunoprecipitation, B-cell development by flow cytometry, and antibody gene rearrangements by CDR3 spectratyping and quantitative PCR. In order to test the functional consequences of the observed defects, B6.Aec1/2 mice were crossed with anti-dsDNA antibody heavy chain knock-in mice (B6.56R). B6.Aec1/2 mice exhibit B-cell clonal expansions, have altered serum immunoglobulin levels and spontaneously produce multireactive autoantibodies. B6.Aec1/2 mice also have decreased numbers of bone marrow pre-B cells and decreased frequencies of kappa light chain gene deletion. These findings suggest that B6.Aec1/2 mice have a defective early B-cell tolerance checkpoint. B6.56R.Aec1/2 mice unexpectedly had lower anti-dsDNA antibody levels than B6.56R mice and less salivary gland infiltration than B6.Aec1/2 mice. These data suggest that the early tolerance checkpoint defect in B6.Aec1/2 mice is not sufficient to promulgate disease in mice with pre-formed autoantibodies, such as B6.56R. Rather, B6.Aec1/2 mice may require a diverse B-cell repertoire for efficient T-B-cell collaboration and disease propagation. These findings imply that therapies aimed at reducing B-cell diversity or T-B interactions may be helpful in treating SjS.
    Journal of Clinical Immunology 02/2012; 32(3):551-64. · 3.38 Impact Factor
  • Robert A Eisenberg
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    ABSTRACT: Receptor editing is the process that replaces the heavy chain or light chain variable region genes in a B cell immunoglobulin receptor that is already productively rearranged. It is a major mechanism in the bone marrow for maintaining B cell tolerance to autoantigens. We propose that a pathological autoimmune process can use receptor editing to induce the de novo creation and activation of B cells with autoreactive receptors in the peripheral immune system.
    Autoimmunity reviews 02/2012; 11(11):787-9. · 6.37 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) have been implicated in B cell lineage commitment, regulation of T cell differentiation, TCR signalling, regulation of IFN signalling, and numerous other immunological processes. However, their function in autoimmunity, and specifically in systemic lupus erythematosus (SLE), remains poorly understood. B6.Sle123 is a spontaneous genetic mouse model of SLE characterized by autoantibody production, lymphosplenomegaly, and glomerulonephritis. We identified several differentially regulated miRNAs in B and T lymphocytes of B6.Sle123 mice. We found that miR-21 expression in lupus B and T cells is up-regulated and that in vivo silencing of miR-21 using a tiny seed-targeting LNA reversed splenomegaly, one of the cardinal manifestations of autoimmunity in B6.Sle123 mice, and de-repressed PDCD4 expression in vivo and in vitro. In addition, treatment with anti-miR-21 altered CD4/CD8 T cell ratios and reduced Fas receptor-expressing lymphocyte populations. Our study shows that tiny LNAs can be used to efficiently antagonize endogenous miRNAs in peripheral lymphocytes in vivo and in primary lymphocytes cultured ex vivo and can alter the course of a spontaneous genetic disease in mice.
    EMBO Molecular Medicine 09/2011; 3(10):605-15. · 7.80 Impact Factor
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    ABSTRACT: B cells are subjected to selection at multiple checkpoints during their development. The selection of Ab H chains is difficult to study because of the large diversity of the CDR3. To study the selection of individual Ab H chain V region genes (V(H)), we performed CDR3 spectratyping of ∼ 75-300 rearrangements per individual V(H) in C57BL6/J mice. We measured the fraction of rearrangements that were in-frame in B cell DNA. We demonstrate that individual V(H)s have different fractions of in-frame rearrangements (IF fractions) ranging from 10 to 90% and that these IF fractions are reproducible in different mice. For most V(H)s, the IF fraction in pro-B cells approximated 33% and then shifted to the nearly final (mature) B cell value by the cycling pre-B cell stage. The frequency of high in-frame (IF) V(H) usage increased in cycling pre-B cells compared with that in pro-B cells, whereas this did not occur for low IF V(H)s. The IF fraction did not shift as much in BCR-expressing B cells and was minimally affected by L chain usage for most V(H). High IF clan II/III V(H)s share more positively charged CDR2 sequences, whereas high IF clan I J558 CDR2 sequences are diverse. These data indicate that individual V(H)s are subjected to differential selection, that V(H) IF fraction is mainly established through pre-BCR-mediated selection, that it may operate differently in clan I versus II/III V(H)s, and that it has a lasting influence on the Ab repertoire.
    The Journal of Immunology 08/2011; 187(4):1835-44. · 5.52 Impact Factor
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    ABSTRACT: KRN/I-A(g7) (KxB/N) is a mouse model of inflammatory arthritis, which resembles human rheumatoid arthritis. Arthritis in these animals is caused by autoreactivity to a ubiquitously expressed autoantigen, glucose-6 phosphate isomerase. Tolerance is broken at both the T cell and B cell level. The sera from KRN/I-A(g7) mice can induce mouse arthritis in healthy mice. Complement components of the alternative complement pathway, including C3, have been shown to be required in induction of mouse arthritis by serum transfer. We have bred KRN/I-A(g7) mice onto a C3-deficient background and followed cohorts for the spontaneous appearance of arthritis. We have also transferred KxB/N serum to B6.I-A ( g7 ) recipients. C3-deficient KRN/I-A(g7) mice spontaneously developed severe, destructive arthritis, comparable to that seen in C3-intact KRN/I-A(g7) mice. However, serum transfer experiments confirmed the strong requirement for C3 in the passive model. The pathogenesis of spontaneous KRN/I-A(g7) arthritis can largely proceed by complement-independent pathways and must have pathology effector mechanisms in addition to those seen in the passive serum transfer model.
    Journal of Clinical Immunology 07/2011; 31(5):857-63. · 3.38 Impact Factor
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    ABSTRACT: Dendrimers are highly branched "tree-like" polymers that have demonstrated therapeutic potential in drug delivery, medical imaging, and tissue engineering in recent years. In addition, we have shown that an azabisphosphonate (ABP)-capped dendrimer selectively targets monocytes and directs them toward anti-inflammatory activation. We explored this property to assess the therapeutic potential of dendrimer ABP in the treatment of an inflammatory disease, rheumatoid arthritis. Intravenous injections of dendrimer ABP inhibited the development of inflammatory arthritis in two animal models: IL-1ra(-/-) mice and mice undergoing K/BxN serum transfer. Suppression of disease was characterized by normal synovial membranes, reduced levels of inflammatory cytokines, and the absence of cartilage destruction and bone erosion. Dendrimer ABP also exhibited anti-osteoclastic activity on mouse and human cells, mediated by c-FMS (cellular-feline McDonough strain sarcoma virus oncogene homolog) inhibition. These preclinical demonstrations suggest the potential use of dendrimer ABP as a nanotherapeutic for rheumatoid arthritis.
    Science translational medicine 05/2011; 3(81):81ra35. · 10.76 Impact Factor
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    ABSTRACT: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that is characterized by inflamed synovial tissue, cartilage degeneration, and bone erosion, leading to joint deformation and physical handicap. Biologic therapeutic approaches, such as monoclonal antibodies and soluble receptors, have been developed to relieve the symptoms of RA. Unfortunately, these drugs typically act on a single target: proinflammatory cytokines. There is an unmet clinical need for anti-RA drugs that target not only proinflammatory molecules and pathways, but also the osteoclastic differentiation of monocytes—a process that leads to bone resorption. In response, Hayder et al. synthesized a new dendrimer-based therapeutic that boasts a two-pronged attack on RA, with both anti-inflammatory and anti-osteoclastogenic activity. Dendrimers are highly branched polymers whose multivalency allows for interaction with several cellular and molecular targets. The authors created an azabisphosphonate (ABP)–capped dendrimer that has been shown to target human monocytes and direct them toward an anti-inflammatory response. Two animal models of autoimmune arthritis were used: the IL-1ra−/− mouse and the K/BxN serum transfer mouse. Dendrimer ABP was administered to IL-1ra−/− mice via weekly intravenous injections. At high doses, the dendrimer completely inhibited inflammation, as evidenced by a decrease in paw swelling, and prevented arthritis histopathology, with ankle joints showing near-normal synovial membranes and intact cartilage after 12 weeks. Dendrimer ABP also decreased the amount of proinflammatory cytokines and increased levels of anti-inflammatory cytokines interleukin-4 (IL-4) and IL-10, thereby suggesting a skewing toward a T helper 2 (TH2) response. The K/BxN mouse demonstrated similar results upon treatment with dendrimer ABP. Treatment with dendrimer ABP also prevented osteoclastogenesis, as shown in human synovial tissue ex vivo and human peripheral blood monocytes in vitro. The authors further outlined a potential dendrimer-mediated mechanism that involves inhibition of c-FMS—a signaling molecule that promotes monocyte differentiation into osteoclasts. This study by Hayder and colleagues has shown that dendrimer ABP, by doubling up against inflammation and bone erosion, might be more effective at treating RA than existing antibody- and small-molecule–based biologic drugs.
    Sci. Transl. Med. 01/2011; 3:81ra35.
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    Eline T Luning Prak, Marc Monestier, Robert A Eisenberg
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    ABSTRACT: Receptor editing is the process of ongoing antibody gene rearrangement in a lymphocyte that already has a functional antigen receptor. The expression of a functional antigen receptor will normally terminate further rearrangement (allelic exclusion). However, lymphocytes with autoreactive receptors have a chance at escaping negative regulation by "editing" the specificities of their receptors with additional antibody gene rearrangements. As such, editing complicates the Clonal Selection Hypothesis because edited cells are not simply endowed for life with a single, invariant antigen receptor. Furthermore, if the initial immunoglobulin gene is not inactivated during the editing process, allelic exclusion is violated and the B cell can exhibit two specificities. Here, we describe the discovery of editing, the pathways of receptor editing at the heavy (H) and light (L) chain loci, and current evidence regarding how and where editing happens and what effects it has on the antibody repertoire.
    Annals of the New York Academy of Sciences 01/2011; 1217:96-121. · 4.38 Impact Factor
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    ABSTRACT: Control of lymphocyte homeostasis is essential to ensure efficient immune responses and to prevent autoimmunity. Splenic marginal zone B cells are important producers of autoantibodies, and are subject to stringent tolerance mechanisms to prevent autoimmunity. In this paper, we explore the role of the Mer tyrosine kinase (Mertk) in regulating autoreactive B cells. This receptor tyrosine kinase serves to bind apoptotic cells, to mediate their phagocytosis, and to regulate subsequent cytokine production. Mice lacking Mertk suffer from impaired apoptotic cell clearance and develop a lupus-like autoimmune syndrome. Here we show that such Mertk-KO mice have expanded numbers of splenic marginal zone B cells. Mertk-KO mice bearing a DNA-specific immunoglobulin heavy-chain transgene (3H9) produced anti-DNA antibodies that appeared to be secreted largely by marginal zone B cells. Finally, Mertk-KO mice developed greater antibody responses after NP-Ficoll immunization than their B6 counterparts. Taken together, our data show that Mertk has a major effect on the development of the marginal zone B-cell compartment. Mertk is also important in establishing DNA-specific B-cell tolerance in 3H9 anti-DNA transgenic mice.
    Journal of Autoimmunity 12/2010; 35(4):368-74. · 8.15 Impact Factor
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    ABSTRACT: The Mer receptor tyrosine kinase is strongly expressed in the glomerulus. We wondered if this molecule might modify immune-mediated glomerular disease through its functions as a receptor for apoptotic cells and immunoregulatory molecule. Mer-knockout (KO) mice showed decreased survival rate and greatly increased proteinuria and serum urea levels compared to wild type (WT) mice by day 3 after injection of NTS. Their glomeruli were hyperplastic and later became necrotic. In the glomerulus of WT mice, a significant increase of Mer expression was observed. Apoptotic bodies were evident in NTS-treated Mer-KO kidneys, but not in normal controls. NTS-treated Mer-KO mice had massive neutrophil infiltration and inflammatory cytokine expression. Mer thus has a critical role in attenuating renal inflammation, both as a receptor for apoptotic cells and as a molecule that downregulates inflammation.
    Clinical Immunology 05/2010; 136(2):236-44. · 3.77 Impact Factor
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    Arpita Choudhury, Philip L Cohen, Robert A Eisenberg
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    ABSTRACT: The murine chronic GVH (cGVH) model of SLE is induced by allo-recognition of foreign major histocompatibility complex (MHC) class II determinants. Previous studies have shown that syngeneic CD4(+) T cells are needed during B cell development in order to induce cGVH response in CD4KO mice. Our present studies show that B cells require "nurturing" by CD4 T cells through much of their ontogeny in order to respond to allo-signaling and become autoreactive. The nurturing process does not require antigen-specific cognate interactions between CD4 T cells and B cells. It is mediated by IL-4, but not IL-10, IL-6 and IFN-gamma. The CD4 T cell nurturing may be supplanted by large doses of IL-4 and/or by agonistic anti-CD40 mAb. Understanding the mechanism of this "nurturing" process may yield clues to the role of CD4 T cells in lupus and in host defense in general.
    Clinical Immunology 04/2010; 136(1):105-15. · 3.77 Impact Factor
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    ABSTRACT: B cell depletion immunotherapy has been successfully employed to treat non-Hodgkin's lymphoma. In recent years, increasing attention has been directed towards also using B-cell depletion therapy as a treatment option in autoimmune disorders. However, it appears that the further development of these approaches will depend on a methodology to determine the relation of B-cell depletion to clinical response and how individual patients should be dosed. Thus far, patients have generally been followed by quantification of peripheral blood B cells, but it is not apparent that this measurement accurately reflects systemic B cell dynamics. Cellular imaging of the targeted population in vivo may provide significant insight towards effective therapy and a greater understanding of underlying disease mechanics. Superparamagnetic iron oxide (SPIO) nanoparticles in concert with near infrared (NIR) fluorescent dyes were used to label and track primary C57BL/6 B cells. Following antibody mediated B cell depletion (anti-CD79), NIR-only labeled cells were expeditiously cleared from the circulation and spleen. Interestingly, B cells labeled with both SPIO and NIR were not depleted in the spleen. Whole body fluorescent tracking of B cells enabled noninvasive, longitudinal imaging of both the distribution and subsequent depletion of B lymphocytes in the spleen. Quantification of depletion revealed a greater than 40% decrease in splenic fluorescent signal-to-background ratio in antibody treated versus control mice. These data suggest that in vivo imaging can be used to follow B cell dynamics, but that the labeling method will need to be carefully chosen. SPIO labeling for tracking purposes, generally thought to be benign, appears to interfere with B cell functions and requires further examination.
    PLoS ONE 01/2010; 5(5):e10655. · 3.53 Impact Factor
  • Ann Duskin, Robert A Eisenberg
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    ABSTRACT: Inflammatory arthritis presents in a variety of diseases, from rheumatoid arthritis to hepatitis. Antibodies to autoantigens or to microbial constituents are commonly associated with these conditions. In some cases, the antibodies have diagnostic and prognostic relevance. It cannot as yet be determined definitively that any of them mediate joint damage, although the evidence from animal models indicates that this mechanism is likely. The purpose of this article is to give an overview of the spectrum of antibodies found in a variety of inflammatory arthritides. The relevant animal models are also discussed.
    Immunological Reviews 01/2010; 233(1):112-25. · 12.16 Impact Factor

Publication Stats

6k Citations
1,006.28 Total Impact Points

Institutions

  • 1998–2014
    • University of Pennsylvania
      • • Division of Rheumatology
      • • Department of Medicine
      Philadelphia, Pennsylvania, United States
  • 2009–2012
    • Temple University
      • Department of Medicine
      Philadelphia, PA, United States
  • 1999–2011
    • Hospital of the University of Pennsylvania
      • • Department of Pathology and Laboratory Medicine
      • • Department of Medicine
      • • Division of Rheumatology
      Philadelphia, PA, United States
  • 2008
    • Geisel School of Medicine at Dartmouth
      Hanover, New Hampshire, United States
  • 2002
    • American Society for Pharmacology and Experimental Therapeutics
      Philadelphia, Pennsylvania, United States
    • Wistar Institute
      Philadelphia, Pennsylvania, United States
  • 1995–1998
    • University of Florida
      • Department of Medicine
      Gainesville, FL, United States
  • 1980–1998
    • University of North Carolina at Chapel Hill
      • • Department of Medicine
      • • Department of Microbiology and Immunology
      • • Division of Rheumatology, Allergy and Immunology
      Chapel Hill, NC, United States
  • 1993
    • East Carolina University
      • Department of Medicine
      Greenville, NC, United States
  • 1992
    • The University of Tokyo
      • Faculty & Graduate School of Medicine
      Tokyo, Tokyo-to, Japan
  • 1990
    • Duke University
      Durham, North Carolina, United States
  • 1989
    • Johns Hopkins University
      Baltimore, Maryland, United States