Falk Nimmerjahn

Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Bavaria, Germany

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Publications (112)940.95 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Although well-designed prospective trials are generally lacking, intravenous immunoglobulins (IVIG) seem an effective adjuvant treatment for autoimmune bullous skin diseases. Here, efficacy of IVIG monotherapy was compared with corticosteroid treatment in mice with immunization-induced experimental epidermolysis bullosa acquisita (EBA), an autoimmune bullous skin disease characterized by autoantibodies against type VII collagen. We found that IVIG significantly ameliorated clinical disease severity and skin neutrophil infiltration compared to vehicle-treated mice, whereas methylprednisolone showed comparatively less pronounced effects. Efficacy of IVIG was accompanied by reduced levels of autoantibodies, a shift towards non-complement-fixing autoantibodies, and lower complement deposition at the dermal-epidermal junction. Additionally, peripheral Gr-1-positive cells of IVIG-treated animals showed reduced expression of the activating Fcγ receptor IV, which we recently described as a major mediator of tissue injury in experimental EBA. These data show that treatment with IVIG is superior to systemic corticosteroids in experimental EBA and that the effects of IVIG are pleiotropic involving modulation of both the adaptive and innate immune response, although the detailed mode of action of IVIG in this model remains in need of further elucidation.Journal of Investigative Dermatology accepted article preview online, 20 October 2014. doi:10.1038/jid.2014.453.
    The Journal of investigative dermatology. 10/2014;
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    ABSTRACT: Bullous pemphigoid (BP) and epidermolysis bullosa acquisita are subepidermal autoimmune blistering diseases mediated by autoantibodies against type XVII collagen (Col17) and Col7, respectively. For blister formation, Fc-mediated events, such as infiltration of inflammatory cells in the skin, complement activation, and release of proteases at the dermal-epidermal junction, are essential. Although in the neonatal passive transfer mouse model of BP, tissue destruction is mediated by Fcγ receptors (FcγRs) I and III, the passive transfer model of epidermolysis bullosa acquisita completely depends on FcγRIV. To clarify this discrepancy, we developed a novel experimental model for BP using adult mice. Lesion formation was Fc mediated because γ-chain–deficient mice and mice treated with anti-Col17 IgG, depleted from its sugar moiety at the Fc portion, were resistant to disease induction. By the use of various FcγR-deficient mouse strains, tissue destruction was shown to be mediated by FcγRIV, FcγRIII, and FcγRIIB, whereas FcγRI was not essential. Furthermore, anti-inflammatory mediators in already clinically diseased mice can be explored in the novel BP model, because the pharmacological inhibition of FcγRIV and depletion of granulocytes abolished skin blisters. Herein, we extended our knowledge about the importance of FcγRs in experimental BP and established a novel BP mouse model suitable to study disease development over a longer time period and explore novel treatment strategies in a quasi-therapeutic setting.
    The American Journal of Pathology. 08/2014; 184(8):2185–2196.
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    ABSTRACT: Dendritic cells (DCs) are central modulators of immune responses and, therefore, interesting target cells for the induction of antitumor immune responses. Ag delivery to select DC subpopulations via targeting Abs to DC inhibitory receptor 2 (DCIR2, clone 33D1) or to DEC205 was shown to direct Ags specifically to CD11c(+)CD8(-) or CD11c(+)CD8(+) DCs, respectively, in vivo. In contrast to the increasing knowledge about the induction of immune responses by efficiently cross-presenting CD11c(+)CD8(+) DCs, little is known about the functional role of Ag-presenting CD11c(+)CD8(-) DCs with regard to the initiation of protective immune responses. In this study, we demonstrate that Ag targeting to the CD11c(+)CD8(-) DC subpopulation in the presence of stimulating anti-CD40 Ab and TLR3 ligand polyinosinic-polycytidylic acid induces protective responses against rapidly growing tumor cells in naive animals under preventive and therapeutic treatment regimens in vivo. Of note, this immunization protocol induced a mixed Th1/Th2-driven immune response, irrespective of which DC subpopulation initially presented the Ag. Our results provide important information about the role of CD11c(+)CD8(-) DCs, which have been considered to be less efficient at cross-presenting Ags, in the induction of protective antitumor immune responses.
    The Journal of Immunology 05/2014; · 5.52 Impact Factor
  • Daniela Kao, Anja Lux, Inessa Schwab, Falk Nimmerjahn
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    ABSTRACT: B cells and B cell-derived autoantibodies play a central role in the pathogenesis of many autoimmune diseases. Thus, depletion of B cells via monoclonal antibodies such as Rituximab is an obvious therapeutic intervention and has been used successfully in many instances. More recently, novel therapeutic options targeting either the autoantibody itself or resetting the threshold for B cell activation have become available and show promising immunomodulatory and anti-inflammatory effects in a variety of animal models. The aim of this review is to summarize these results and to provide an insight into the underlying molecular and cellular pathways of these novel therapeutic interventions targeting autoantibodies and B cells and to discuss their value for human therapy.
    Seminars in Immunopathology 04/2014; · 5.38 Impact Factor
  • Inessa Schwab, Anja Lux, Falk Nimmerjahn
    Nature Reviews Immunology 04/2014; 14(5):349. · 32.25 Impact Factor
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    ABSTRACT: Genetic differences between humans and in vivo model systems, including mice and nonhuman primates, make it difficult to predict the efficacy of immunoglobulin G (IgG) activity in humans and understand the molecular and cellular mechanisms underlying that activity. To bridge this gap, we established a small-animal model system that allowed us to study human IgG effector functions in the context of an intact human immune system without the interference of murine Fcγ receptors expressed on mouse innate immune effector cells in vivo. Using a model of B cell depletion with different human IgG variants that recognize CD20, we show that this humanized mouse model can provide unique insights into the mechanism of human IgG activity in vivo. Importantly, these studies identify the bone marrow as a niche with low therapeutic IgG activity.
    Cell Reports 03/2014; · 7.21 Impact Factor
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    ABSTRACT: Objective: The colony stimulating factor 1 receptor (CSF-1R) essentially modulates monocyte proliferation, migration and activation, which are considered important for the pathogenesis of rheumatoid arthritis (RA). We therefore determined CSF-1R expression in human RA and the efficacy of a specific CSF-1R antibody in two different animal models of RA. Methods: CSF-1R expression was examined in the blood, synovium and bone of RA patients, osteoarthritis (OA) patients and healthy subjects. The efficacy of CSF-1R monoclonal antibody (mAb, AFS98) neutralization was examined by clinical assessment, histology and bone histomorphometry in collagen-induced (CIA) and serum transfer arthritis. Results: In humans, CSF-1R expression was increased in the synovium of RA compared to OA and healthy controls in fibroblast-like synoviocytes (FLS), follicular dendritic cells, macrophages and osteoclasts. Circulating RA monocytes and neutrophils but not lymphocytes were CSF-1R positive. In mice, blockade of CSF-1R abrogated cartilage damage, bone erosion and systemic bone loss associated with the depletion of osteoclasts in both models. Whereas blockade of CSF-1R did not affect inflammation in the passive serum transfer arthritis, it significantly reduced inflammation in CIA, associated with absent synovial macrophages and reduced splenic CD11b+Gr-1- monocytes. Conclusion: CSF-1R was broadly expressed in human RA. In the mouse model, blockade of anti-CSF-R protected against bone and cartilage destruction and also showed significant anti-inflammatory effects in the CIA arthritis model. These data supports evidence for CSF-1R as a therapeutic target in RA, combining anti.-inflammatory effect and protecting from bone and cartilage damage. © 2014 American College of Rheumatology.
    Arthritis & Rheumatology. 03/2014;
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    ABSTRACT: Intravenous immunoglobulin (IVIg) therapy is widely used to treat a variety of autoimmune diseases including immunothrombocytopenia, chronic inflammatory demyelinating polyneuropathy and more recently autoimmune skin blistering diseases. Despite this well documented clinical success the precise molecular and cellular mechanisms underlying this immunomodulatory activity are discussed controversially. In particular, the clinically relevant therapeutic pathway of IVIg-mediated immune modulation has not been studied in detail. In the present study we use four independent in vivo model systems of autoantibody-mediated autoimmune disease to identify a common pathway explaining IVIg activity under therapeutic conditions in vivo. We show that irrespective of the in vivo model system, IVIg activity is strictly dependent on the presence of terminal sialic acid residues and the inhibitory FcγRIIB under preventive as well as therapeutic treatment conditions. In contrast, SIGNR1, previously demonstrated to be essential under preventative treatment conditions, showed a disease-specific impact on IVIg-mediated resolution of established autoimmune disease. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 02/2014; · 4.97 Impact Factor
  • Falk Nimmerjahn, Anja Lux
    Proceedings of the National Academy of Sciences 02/2014; · 9.81 Impact Factor
  • Sybille Böhm, Daniela Kao, Falk Nimmerjahn
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    ABSTRACT: The importance of immunoglobulin G (IgG) molecules for providing long-term sterile immunity as well as their major contribution to tissue inflammation during autoimmune diseases is generally accepted. In a similar manner, studies over the last years have elucidated many details of the molecular and cellular pathways underlying this protective activity in vivo, emphasizing the role of cellular recognizing the constant antibody fragment. In contrast, the active anti-inflammatory activity of IgG, despite being known and actually identified in human autoimmune patients more than 30 years ago, is much less defined. Recent evidence from several independent model systems suggests that IgG glycosylation is critical for the immunomodulatory activity of IgG and that both monomeric IgG as well as IgG immune complexes can diminish Fc receptor and complement dependent inflammatory processes. Moreover, there is increasing evidence that IgG molecules also modulate B and T cell responses, which may suggest that IgG is centrally involved in the establishment and maintenance of immune homeostasis.
    Current topics in microbiology and immunology 01/2014; 382:393-417. · 4.86 Impact Factor
  • Markus Biburger, Anja Lux, Falk Nimmerjahn
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    ABSTRACT: The capacity of immunoglobulin G (IgG) antibodies to eliminate virtually any target cell has resulted in the widespread introduction of cytotoxic antibodies into the clinic in settings of cancer therapy, autoimmunity, and transplantation, for example. More recently, it has become apparent that also the protection from viral infection via IgG antibodies may require cytotoxic effector functions, suggesting that antibody-dependent cellular cytotoxicity (ADCC) directed against malignant or virally infected cells is one of the most essential effector mechanisms triggered by IgG antibodies to protect the host. A detailed understanding of the underlying molecular and cellular pathways is critical, therefore, to make full use of this antibody effector function. Several studies over the last years have provided novel insights into the effector pathways and innate immune effector cells responsible for ADCC reactions. One of the most notable outcomes of many of these reports is that cells of the mononuclear phagocytic system rather than natural killer cells are critical for removal of IgG opsonized target cells in vivo.
    Advances in Immunology 01/2014; 124C:67-94. · 7.26 Impact Factor
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    ABSTRACT: Impaired regulatory T-cell function results in a severe chronic autoimmune disease affecting multiple organs in Scurfy mice and humans with the immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Previous studies have shown that T helper cells but not cytotoxic T cells are critical for the disease pathology. Whether this T-cell subset is responsible directly for tissue inflammation or rather indirectly via the interaction with B cells or myeloid cells is largely unknown. To study this and to identify potential therapeutic targets for this lethal disease we investigated the contribution of B cells to this complex autoimmune phenotype. We show that B cells and the production of autoantibodies plays a major role for skin, liver, lung, and kidney inflammation and therapeutic depletion of B cells resulted in reduced tissue pathology and in prolonged survival. In contrast, the absence of B cells did not impact systemic T-cell activation and hyperreactivity, indicating that autoantibody production by B cells may be a major factor for the autoimmune pathology in mice deficient for regulatory T cells.
    Proceedings of the National Academy of Sciences 11/2013; · 9.81 Impact Factor
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    ABSTRACT: Activation of the nuclear transcription factor κB (NF-κB) regulates the expression of inflammatory genes crucially involved in the pathogenesis of inflammatory diseases. NF-κB governs the expression of adhesion molecules that play a pivotal role in leukocyte-endothelium interactions. We uncovered the crucial role of NF-κB activation within endothelial cells in models of immune-mediated diseases using a "sneaking ligand construct" (SLC) selectively inhibiting NF-κB in the activated endothelium. The recombinant SLC1 consists of three modules: (i) an E-selectin targeting domain, (ii) a Pseudomonas exotoxin A translocation domain, and (iii) a NF-κB Essential Modifier-binding effector domain interfering with NF-κB activation. The E-selectin-specific SLC1 inhibited NF-κB by interfering with endothelial IκB kinase 2 activity in vitro and in vivo. In murine experimental peritonitis, the application of SLC1 drastically reduced the extravasation of inflammatory cells. Furthermore, SLC1 treatment significantly ameliorated the disease course in murine models of rheumatoid arthritis. Our data establish that endothelial NF-κB activation is critically involved in the pathogenesis of arthritis and can be selectively inhibited in a cell type- and activation stage-dependent manner by the SLC approach. Moreover, our strategy is applicable to delineating other pathogenic signaling pathways in a cell type-specific manner and enables selective targeting of distinct cell populations to improve effectiveness and risk-benefit ratios of therapeutic interventions.
    Proceedings of the National Academy of Sciences 09/2013; · 9.81 Impact Factor
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    ABSTRACT: CD8(+) T cells have an essential role in controlling LCMV infection in mice. Here, we examined the contribution of humoral immunity, including non-neutralizing antibodies (Abs), in this infection induced by low virus inoculation doses. Mice with impaired humoral immunity readily terminated infection with the slowly replicating LCMV strain Armstrong but showed delayed virus elimination after inoculation with the faster replicating LCMV strain WE and failed to clear the rapidly replicating LCMV strain Docile, which is in contrast to the results obtained with wild-type mice. Thus, the requirement for adaptive humoral immunity to control the infection was dependent on the replication speed of the LCMV strains used. Ab transfers further showed that LCMV-specific IgG Abs isolated from LCMV immune serum accelerated virus elimination. These Abs were mainly directed against the viral nucleoprotein and completely lacked virus neutralizing activity. Moreover, mAbs specific for the LCMV nucleoprotein were also able to decrease viral titers after transfer into infected hosts. Intriguingly, neither C3 nor FcγR were required for the antiviral activity of the transferred Abs. In conclusion, our study suggests that rapidly generated non-neutralizing Ab specific for the viral nucleoprotein speed up virus elimination and thereby may counteract T-cell exhaustion. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 06/2013; · 4.97 Impact Factor
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    ABSTRACT: Destruction of bone tissue by osteoclasts represents a severe pathological phenotype during inflammatory arthritis and results in joint pain and bone malformations. Previous studies have established the essential role of cytokines including TNFα and receptor-ligand interactions, such as the receptor activator of nuclear factor-kappa B-receptor activator of nuclear factor-kappa B ligand interaction for osteoclast formation during joint inflammation. Moreover, autoantibodies contribute to joint inflammation in inflammatory arthritis by triggering cellular fragment crystallizable (Fc)γ receptors (FcγR), resulting in the release of proinflammatory cytokines and chemokines essential for recruitment and activation of innate immune effector cells. In contrast, little is known about the expression pattern and function of different FcγRs during osteoclast differentiation. This would allow osteoclasts to directly interact with autoantibody immune complexes, rather than being influenced indirectly via proinflammatory cytokines released upon immune complex binding to other FcγR-expressing innate immune cells. To address this question, we studied FcγR expression and function on osteoclasts during the steady state and during acute joint inflammation in a model of inflammatory arthritis. Our results suggest that osteoclastogenesis is directly influenced by IgG autoantibody binding to select activating FcγRs on immature osteoclasts, resulting in enhanced osteoclast generation and, ultimately, bone destruction.
    Proceedings of the National Academy of Sciences 06/2013; · 9.81 Impact Factor
  • Sidonia Mihai, Falk Nimmerjahn
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    ABSTRACT: Autoantibodies interact with the innate immune system, including the complement network and Fc receptors (FcRs) bearing effector cells, resulting in the induction of tissue injury. It was suggested that these two pro-inflammatory pathways might mediate distinct effector responses, and that only one or the other effector arm may usually dominate an inflammatory response. Recent studies, however, support the notion that autoantibody-induced tissue injury may depend on both, FcRs and selected pathways of the complement network. This review summarizes our current knowledge on the interactions between autoantibodies, FcRs and complement components as essential triggers of tissue injury in autoimmune diseases like rheumatoid arthritis, anti-glomerular basement membrane glomerulonephritis and subepidermal blistering diseases. Manipulation of these connective pathways might be of therapeutic use to control antibody-mediated autoimmune diseases.
    Autoimmunity reviews 04/2013; 12(6):657–660. · 6.37 Impact Factor
  • Anja Lux, Xiaojie Yu, Chris N Scanlan, Falk Nimmerjahn
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    ABSTRACT: IgG molecules are widely used as therapeutic agents either in the form of intact Abs or as Fc fusion proteins. Although efficient binding of the IgG Fc fragment to cellular FcγRs may be essential to achieve a high cytolytic activity, it may be advantageous for other applications to limit or abolish this interaction. Genetic or biochemical approaches have been used to generate these non-FcγR-binding IgG variants. By using soluble versions of FcγRs and monomeric versions of these altered IgG molecules, it was demonstrated that these IgG variants no longer bind to FcγRs. Importantly, however, these assays do not reflect the physiologic interaction of IgG with low-affinity cellular FcγRs occurring in the form of multimeric immune complexes. In this study, we investigated how the size of an immune complex can affect the interaction of normal and various versions of potentially non-FcγR-binding IgG variants with cellular FcγRs. We show that neither the D265A mutation nor EndoS treatment resulting in IgG molecules with only one N-acetylglucosamine and a fucose residue was fully able to abolish the interaction of all IgG subclasses with cellular FcγRs, suggesting that IgG subclass-specific strategies are essential to fully interfere with human FcγR binding.
    The Journal of Immunology 03/2013; · 5.52 Impact Factor
  • Inessa Schwab, Falk Nimmerjahn
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    ABSTRACT: Intravenous immunoglobulin (IVIG) preparations comprise pooled IgG antibodies from the serum of thousands of donors and were initially used as an IgG replacement therapy in immunocompromised patients. Since the discovery, more than 30 years ago, that IVIG therapy can ameliorate immune thrombocytopenia, the use of IVIG preparations has been extended to a wide range of autoimmune and inflammatory diseases. Despite the broad efficacy of IVIG therapy, its modes of action remain unclear. In this Review, we cover the recent insights into the molecular and cellular pathways that are involved in IVIG-mediated immunosuppression, with a particular focus on IVIG as a therapy for IgG-dependent autoimmune diseases.
    Nature Reviews Immunology 03/2013; 13(3):176-89. · 32.25 Impact Factor
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    Journal of Translational Medicine 11/2012; 10(3). · 3.46 Impact Factor
  • Source
    Inessa Schwab, Falk Nimmerjahn
    Journal of Translational Medicine 11/2012; 10(3). · 3.46 Impact Factor

Publication Stats

5k Citations
940.95 Total Impact Points


  • 2008–2014
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      • • Department of Biology
      • • Department of Biology (Medicine)
      • • Chair of Genetics
      • • Nikolaus-Fiebiger-Center of Molecular Medicine (NFZ)
      Erlangen, Bavaria, Germany
  • 2012
    • Kyowa Hakko Kirin
      Edo, Tōkyō, Japan
  • 2008–2011
    • University of Geneva
      • Department of Pathology and Immunology (PATIM)
      Genève, GE, Switzerland
  • 2010
    • University Hospital Vall d'Hebron
      Barcino, Catalonia, Spain
  • 2009–2010
    • Philipps University of Marburg
      Marburg, Hesse, Germany
  • 2008–2010
    • Universitätsklinikum Erlangen
      • Department of Dermatology
      Erlangen, Bavaria, Germany
  • 2005–2010
    • The Rockefeller University
      • Laboratory of Cellular Physiology and Immunology
      New York City, New York, United States
  • 2006
    • Institute of Molecular Biology
      Mayence, Rheinland-Pfalz, Germany