Treatment of Relapsing Paralysis in Experimental Encephalomyelitis by Targeting Th1 Cells through AtorvastatinAktas, Orhan; Waiczies, Sonia; Smorodchenko, Alina; Dörr, Jan; Seeger, Bibiane; Prozorovski, Timour; Sallach, Stephanie; Endres, Matthias; Brocke, Stefan; Nitsch, Robert; Zipp, Frauke
doi: 10.1084/jem.20021425pmid: 12629065
Statins, known as inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, exhibit numerous functions related to inflammation, such as MHC class II down-regulation, interference with T cell adhesion, and induction of apoptosis. Here we demonstrate that both subcutaneous and oral administration of atorvastatin inhibit the development of actively induced chronic experimental autoimmune encephalomyelitis in SJL/J mice and significantly reduce the inflammatory infiltration into the central nervous system (CNS). When treatment was started after disease onset, atorvastatin reduced the incidence of relapses and protected from the development of further disability. Both the reduced autoreactive T cell response measured by proliferation toward the encephalitogenic peptide PLP139–151 and the cytokine profile indicate a potent blockade of T helper cell type 1 immune response. In in vitro assays atorvastatin not only inhibited antigen-specific responses, but also decreased T cell proliferation mediated by direct TCR engagement independently of MHC class II and LFA-1. Inhibition of proliferation was not due to apoptosis induction, but linked to a negative regulation on cell cycle progression. However, early T cell activation was unaffected, as reflected by unaltered calcium fluxes. Thus, our results provide evidence for a beneficial role of statins in the treatment of autoimmune attack on the CNS. EAE multiple sclerosis HMG-CoA reductase T cell autoimmunity Footnotes ↵ * Abbreviations used in this paper: BP, birch pollen; CDK, cyclin-dependent kinase; CNS, central nervous system; EAE, encephalomyelitis; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; ICAM-1, intercellular adhesion molecule-1; MBP, myelin basic protein; MS, multiple sclerosis; PLP, proteolipid protein; TCL, T cell line. Submitted: 15 August 2002 Accepted: 21 January 2003 Revision received 6 January 2003
Interferon and Granulopoiesis Signatures in Systemic Lupus Erythematosus BloodBennett, Lynda; Palucka, A. Karolina; Arce, Edsel; Cantrell, Victoria; Borvak, Josef; Banchereau, Jacques; Pascual, Virginia
doi: 10.1084/jem.20021553pmid: 12642603
Systemic lupus erythematosus (SLE) is a prototype systemic autoimmune disease characterized by flares of high morbidity. Using oligonucleotide microarrays, we now show that active SLE can be distinguished by a remarkably homogeneous gene expression pattern with overexpression of granulopoiesis-related and interferon (IFN)-induced genes. Using the most stringent statistical analysis (Bonferroni correction), 15 genes were found highly up-regulated in SLE patients, 14 of which are targets of IFN and one, defensin DEFA-3, a major product of immature granulocytes. A more liberal correction (Benjamini and Hochberg correction) yielded 18 additional genes, 12 of which are IFN-regulated and 4 granulocyte-specific. Indeed immature neutrophils were identified in a large fraction of SLE patients white blood cells. High dose glucocorticoids, a standard treatment of disease flares, shuts down the interferon signature, further supporting the role of this cytokine in SLE. The expression of 10 genes correlated with disease activity according to the SLEDAI. The most striking correlation (P < 0.001, r = 0.55) was found with the formyl peptide receptor-like 1 protein that mediates chemotactic activities of defensins. Therefore, while the IFN signature confirms the central role of this cytokine in SLE, microarray analysis of blood cells reveals that immature granulocytes may be involved in SLE pathogenesis. microarray immature granulocytes glucocorticoid leukocytes autoimmunity Footnotes ↵ * Abbreviations used in this paper: DC, dendritic cell; JCA, juvenile chronic arthritis; SLE, systemic lupus erythematosus. J. Banchereau and V. Pascual codirected the work. Submitted: 3 September 2002 Accepted: 14 November 2002 Revision received 11 November 2002
Role of Adhesin Release for Mucosal Colonization by a Bacterial PathogenCoutte, Loïc; Alonso, Sylvie; Reveneau, Nathalie; Willery, Eve; Quatannens, Brigitte; Locht, Camille; Jacob-Dubuisson, Françoise
doi: 10.1084/jem.20021153pmid: 12629063
Pathogen attachment is a crucial early step in mucosal infections. This step is mediated by important virulence factors called adhesins. To exert these functions, adhesins are typically surface-exposed, although, surprisingly, some are also released into the extracellular milieu, the relevance of which has previously not been studied. To address the role of adhesin release in pathogenesis, we used Bordetella pertussis as a model, since its major adhesin, filamentous hemagglutinin (FHA), partitions between the bacterial surface and the extracellular milieu. FHA release depends on its maturation by the specific B. pertussis protease SphB1. We constructed SphB1-deficient mutants and found that they were strongly affected in their ability to colonize the mouse respiratory tract, although they adhered even better to host cells in vitro than their wild-type parent strain. The defect in colonization could be overcome by prior nasal instillation of purified FHA or by coinfection with FHA-releasing B. pertussis strains, but not with SphB1-producing FHA-deficient strains, ruling out a nonspecific effect of SphB1. These results indicate that the release of FHA is important for colonization, as it may facilitate the dispersal of bacteria from microcolonies and the binding to new sites in the respiratory tract. Bordetella pertussis filamentous hemagglutinin maturation protease colonization adhesin Footnotes ↵ * Abbreviations used in this paper: BG, Bordet-Gengou; FHA, filamentous hemagglutinin; PTX, pertussis toxin, PBSG, PBS with 5% glycerol. L. Coutte and S. Alonso contributed equally to this work. S. Alonso's present address is Microbiology and Immunology, 5173 Veterinary Medical Center, Cornell University, Ithaca, NY 14853. Submitted: 10 July 2002 Accepted: 21 January 2003 Revision received 30 December 2002
Enhanced Interleukin (IL)-13 Responses in Mice Lacking IL-13 Receptor α 2Wood, Nancy; Whitters, Matthew J.; Jacobson, Bruce A.; Witek, JoAnn; Sypek, Joseph P.; Kasaian, Marion; Eppihimer, Michael J.; Unger, Michelle; Tanaka, Takashi; Goldman, Samuel J.; Collins, Mary; Donaldson, Debra D.; Grusby, Michael J.
doi: 10.1084/jem.20020906pmid: 12642602
Interleukin (IL)-13 has recently been shown to play important and unique roles in asthma, parasite immunity, and tumor recurrence. At least two distinct receptor components, IL-4 receptor (R)α and IL-13Rα1, mediate the diverse actions of IL-13. We have recently described an additional high affinity receptor for IL-13, IL-13Rα2, whose function in IL-13 signaling is unknown. To better appreciate the functional importance of IL-13Rα2, mice deficient in IL-13Rα2 were generated by gene targeting. Serum immunoglobulin E levels were increased in IL-13Rα2 −/− mice despite the fact that serum IL-13 was absent and immune interferon γ production increased compared with wild-type mice. IL-13Rα2–deficient mice display increased bone marrow macrophage progenitor frequency and decreased tissue macrophage nitric oxide and IL-12 production in response to lipopolysaccharide. These results are consistent with a phenotype of enhanced IL-13 responsiveness and demonstrate a role for endogenous IL-13 and IL-13Rα2 in regulating immune responses in wild-type mice. receptors immunoglobulin E interleukin 13 knockout mice nitric oxide Footnotes ↵ * Abbreviations used in this paper: EMSA, electrophoretic mobility shift assay; MLF, murine lung fibroblasts; NO, nitric oxide; RPA, RNase protection assay; RPM, resident peritoneal macrophages; STAT, signal transducer and activator of transcription. Submitted: 4 June 2002 Accepted: 23 January 2003 Revision received 23 January 2003
Regulation and Function of the Interleukin 13 Receptor α 2 During a T Helper Cell Type 2–dominant Immune ResponseChiaramonte, Monica G.; Mentink-Kane, Margaret; Jacobson, Bruce A.; Cheever, Allen W.; Whitters, Matthew J.; Goad, Mary E.P.; Wong, Anthony; Collins, Mary; Donaldson, Debra D.; Grusby, Michael J.; Wynn, Thomas A.
doi: 10.1084/jem.20020903pmid: 12642601
Highly polarized type 2 cytokine responses can be harmful and even lethal to the host if they are too vigorous or persist too long. Therefore, it is important to elucidate the mechanisms that down-regulate these reactions. Interleukin (IL)-13 has emerged as a central mediator of T helper cell (Th)2-dominant immune responses, exhibiting a diverse array of functional activities including regulation of airway hyperreactivity, resistance to nematode parasites, and tissue remodeling and fibrosis. Here, we show that IL-13 receptor (R)α2 is a critical down-regulatory factor of IL-13–mediated tissue fibrosis induced by the parasitic helminth Schistosoma mansoni . IL-13Rα2 expression was induced after the onset of the fibrotic response, IL-10, IL-13, and Stat6 dependent, and inhibited by the Th1-inducing adjuvant IL-12. Strikingly, schistosome-infected C57BL/6 and BALB/c IL-13Rα2–deficient mice showed a marked exacerbation in hepatic fibrosis, despite displaying no change in granuloma size, tissue eosinophilia, or mastocytosis. Fibrosis increased despite the fact that IL-13 levels decreased significantly in the liver and serum. Importantly, pathology was prevented when IL-13Rα2–deficient mice were treated with a soluble IL-13Rα2-Fc construct, formally demonstrating that their exacerbated fibrotic response was due to heightened IL-13 activity. Together, these studies illustrate the central role played by the IL-13Rα2 in the down-regulation of a chronic and pathogenic Th2-mediated immune response. fibrosis inflammation liver granuloma mouse Footnotes ↵ * Abbreviations used in this paper: CCCA, Cincinnati cytokine capture assay; HPRT, hypoxanthine-guanine phosphoribosyl transferase; SEA, soluble egg antigen; sIL-13Rα2-Fc, soluble IL-13Rα2-Fc. M.G. Chiaramonte and M. Mentink-Kane contributed equally to this work. M.G. Chiaramonte's present address is Division of Immunobiology, The Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229. Submitted: 4 June 2002 Accepted: 22 January 2003 Revision received 20 January 2003
Type-I Interferon Receptor Deficiency Reduces Lupus-like Disease in NZB MiceSantiago-Raber, Marie-Laure; Baccala, Roberto; Haraldsson, Katarina M.; Choubey, Divaker; Stewart, Timothy A.; Kono, Dwight H.; Theofilopoulos, Argyrios N.
doi: 10.1084/jem.20021996pmid: 12642605
Indirect evidence suggests that type-I interferons (IFN-α/β) play a significant role in the pathogenesis of lupus. To directly examine the contribution of these pleiotropic molecules, we created congenic NZB mice lacking the α-chain of IFN-α/βR, the common receptor for the multiple IFN-α/β species. Compared with littermate controls, homozygous IFN-α/βR-deleted NZB mice had significantly reduced anti-erythrocyte autoantibodies, erythroblastosis, hemolytic anemia, anti-DNA autoantibodies, kidney disease, and mortality. These reductions were intermediate in the heterozygous-deleted mice. The disease-ameliorating effects were accompanied by reductions in splenomegaly and in several immune cell subsets, including B-1 cells, the major producers of anti-erythrocyte autoantibodies. Decreases of B and T cell proliferation in vitro and in vivo, and of dendritic cell maturation and T cell stimulatory activity in vitro were also detected. Absence of signaling through the IFN-α/βR, however, did not affect increased basal levels of the IFN-responsive p202 phosphoprotein, encoded by a polymorphic variant of the Ifi202 gene associated with the Nba2 predisposing locus in NZB mice. The data indicate that type-I IFNs are important mediators in the pathogenesis of murine lupus, and that reducing their activity in the human counterpart may be beneficial. autoimmunity hemolytic anemia ifi202 B-1 cells dendritic cells Footnotes ↵ * Abbreviations used in this paper: AFC, Ab forming cell; BM, bone marrow; CFSE, carboxyfluorescein-diacetate-succinimidyl-ester; DC, dendritic cell; IRF-1, IFN regulatory transcription factor-1; PAS, periodic acid-Schiff; SLE, systemic lupus erythematosus. Submitted: 18 November 2002 Accepted: 30 January 2003 Revision received 24 January 2003
Preferential Accumulation of Antigen-specific Effector CD4 T Cells at an Antigen Injection Site Involves CD62E-dependent Migration but Not Local ProliferationReinhardt, R. Lee; Bullard, Daniel C.; Weaver, Casey T.; Jenkins, Marc K.
doi: 10.1084/jem.20021690pmid: 12629067
The migration of antigen-specific T cells to nonlymphoid tissues is thought to be important for the elimination of foreign antigens from the body. However, recent results showing the migration of activated T cells into many nonlymphoid tissues raised the possibility that antigen-specific T cells do not migrate preferentially to nonlymphoid tissues containing antigen. We addressed this question by tracking antigen-specific CD4 T cells in the whole body after a localized subcutaneous antigen injection. Antigen-specific CD4 T cells proliferated in the skin-draining lymph nodes and the cells that underwent the most cell divisions acquired the ability to bind to CD62P. As time passed, CD62P-binding antigen-specific CD4 T cells with interferon γ production potential accumulated preferentially at the site of antigen injection but only in recipients that expressed CD62E. Surprisingly, these T cells did not proliferate in the injection site despite showing evidence of more cell divisions than the T cells in the draining lymph nodes. The results suggest that the most divided effector CD4 T cells from the lymph nodes enter the site of antigen deposition via recognition of CD62E on blood vessels and are retained there in a nonproliferative state via recognition of peptide–major histocompatibility complex II molecules. antigen-specific CD4 T cell migration selectin Footnotes ↵ * Abbreviations used in this paper: B6, C57BL/6; CD62P-Ig, fusion protein consisting of the extracellular domain of CD62P and human Ig Fc; CFSE, 5- and 6-carboxy-fluorescein succinimidyl ester; DAPI, 4′,6-diamidine-2′-phenylindole dihydrochloride; PSGL-1, CD62P glycoprotein ligand-1. Submitted: 25 September 2002 Accepted: 27 January 2003 Revision received 12 December 2002