title: Inhibition of protein geranylgeranylation specifically interferes with CD40-dependent B cell activation, resulting in a reduced capacity to induce T cell immunity.
abstract: Ab-independent effector functions of B cells, such as Ag presentation and cytokine production, have been shown to play an important role in a variety of immune-mediated conditions such as autoimmune diseases, transplant rejection, and graft-versus-host disease. Most current immunosuppressive treatments target T cells, are relatively unspecific, and result in profound immunosuppression that places patients at an increased risk of developing severe infections and cancer. Therapeutic strategies, which interfere with B cell activation, could therefore be a useful addition to the current immunosuppressive armamentarium. Using a transcriptomic approach, we identified upregulation of genes that belong to the mevalonate pathway as a key molecular event following CD40-mediated activation of B cells. Inhibition of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of the mevalonate pathway, by lipophilic statins such as simvastatin and atorvastatin resulted in a specific inhibition of B cell activation via CD40 and impaired their ability to act as stimulatory APCs for allospecific T cells. Mechanistically, the inhibitory effect resulted from the inhibition of protein geranylgeranylation subsequent to the depletion of mevalonate, the metabolic precursor for geranylgeranyl. Thus, inhibition of geranylgeranylation either directly through geranylgeranyl transferase inhibitors or indirectly through statins represents a promising therapeutic approach for the treatment of diseases in which Ag presentation by B cells plays a role.
authors.affiliation: Cologne Interventional Immunology, University Hospital of Cologne, 50924 Cologne, Germany; Stem Cell Transplantation Program, University Hospital of Cologne, 50924 Cologne, Germany; Intensive Care Unit and Laboratory for Department I of Internal Medicine, University Hospital of Cologne, 50924 Cologne, Germany; shima@uk-koeln.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Shimabukuro-Vornhagen
authors.affiliation: Cologne Interventional Immunology, University Hospital of Cologne, 50924 Cologne, Germany;
authors.forename: Shahram
authors.initials: S
authors.lastname: Zoghi
authors.affiliation: Cologne Interventional Immunology, University Hospital of Cologne, 50924 Cologne, Germany;
authors.forename: Tanja M
authors.initials: TM
authors.lastname: Liebig
authors.affiliation: Cologne Interventional Immunology, University Hospital of Cologne, 50924 Cologne, Germany;
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wennhold
authors.affiliation: Stem Cell Transplantation Program, University Hospital of Cologne, 50924 Cologne, Germany;
authors.forename: Jens
authors.initials: J
authors.lastname: Chemitz
authors.affiliation: Cologne Interventional Immunology, University Hospital of Cologne, 50924 Cologne, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Draube
authors.affiliation: Stem Cell Transplantation Program, University Hospital of Cologne, 50924 Cologne, Germany; Intensive Care Unit and Laboratory for Department I of Internal Medicine, University Hospital of Cologne, 50924 Cologne, Germany;
authors.forename: Matthias
authors.initials: M
authors.lastname: Kochanek
authors.affiliation: Department of Cardiology, Charité Campus Virchow-Klinikum, 13353 Berlin, Germany; and Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Blaschke
authors.affiliation: Stem Cell Transplantation Program, University Hospital of Cologne, 50924 Cologne, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Pallasch
authors.affiliation: Cologne Interventional Immunology, University Hospital of Cologne, 50924 Cologne, Germany; Stem Cell Transplantation Program, University Hospital of Cologne, 50924 Cologne, Germany;
authors.forename: Udo
authors.initials: U
authors.lastname: Holtick
authors.affiliation: Stem Cell Transplantation Program, University Hospital of Cologne, 50924 Cologne, Germany;
authors.forename: Christof
authors.initials: C
authors.lastname: Scheid
authors.affiliation: Cologne Interventional Immunology, University Hospital of Cologne, 50924 Cologne, Germany; Stem Cell Transplantation Program, University Hospital of Cologne, 50924 Cologne, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Theurich
authors.affiliation: Stem Cell Transplantation Program, University Hospital of Cologne, 50924 Cologne, Germany; Intensive Care Unit and Laboratory for Department I of Internal Medicine, University Hospital of Cologne, 50924 Cologne, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.affiliation: Cologne Interventional Immunology, University Hospital of Cologne, 50924 Cologne, Germany; Stem Cell Transplantation Program, University Hospital of Cologne, 50924 Cologne, Germany; Intensive Care Unit and Laboratory for Department I of Internal Medicine, University Hospital of Cologne, 50924 Cologne, Germany;
authors.forename: Michael S
authors.initials: MS
authors.lastname: von Bergwelt-Baildon
mesh_terms: D017951:Antigen Presentation / Q000187:drug effects; D000069059:Atorvastatin; D001402:B-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D019013:CD40 Antigens / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000276:immunology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007111:Immunity, Cellular / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects; D008798:Mevalonic Acid / Q000378:metabolism; D061251:Primary Cell Culture; D017368:Protein Prenylation / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction; D019821:Simvastatin / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D059467:Transcriptome / Q000276:immunology*
chemical_list: D019013:CD40 Antigens; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid