Interferon and granulopoiesis signatures in systemic lupus erythematosus blood
Lynda Bennett, A Karolina Palucka, Edsel Arce, Victoria Cantrell, Josef Borvak, Jacques Banchereau, Virginia Pascual, Lynda Bennett, A Karolina Palucka, Edsel Arce, Victoria Cantrell, Josef Borvak, Jacques Banchereau, Virginia Pascual
Abstract
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.
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References
- Kammer, G.M., and G.C. Tsokos. 1999. Lupus: Molecular and Cellular Pathogenesis. Humana Press, Totowa, NJ. 728 pp.
- Lahita, R.G. 1999. Systemic Lupus Erythematosus. Academic Press. 3rd edition. San Diego, CA. 1051 pp.
- Wakeland, E.K., K. Liu, R.R. Graham, and T.W. Behrens. 2001. Delineating the genetic basis of systemic lupus erythematosus. Immunity. 15:397–408.
- Shlomchik, M.J., J.E. Craft, and M.J. Mamula. 2001. From T to B and back again: positive feedback in systemic autoimmune disease. Nat. Rev. Immunol. 1:147–153.
- Davidson, A., and B. Diamond. 2001. Autoimmune diseases. N. Engl. J. Med. 345:340–350.
- Freed, J.H., A. Marrs, J. VanderWall, P.L. Cohen, and R.A. Eisenberg. 2000. MHC class II-bound self peptides from autoimmune MRL/lpr mice reveal potential T cell epitopes for autoantibody production in murine systemic lupus erythematosus. J. Immunol. 164:4697–4705.
- Kaliyaperumal, A., M.A. Michaels, and S.K. Datta. 2002. Naturally processed chromatin peptides reveal a major autoepitope that primes pathogenic T and B cells of lupus. J. Immunol. 168:2530–2537.
- Lipsky, P.E. 2001. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat. Immunol. 2:764–766.
- Arce, E., D.G. Jackson, M.A. Gill, L.B. Bennett, J. Banchereau, and V. Pascual. 2001. Increased frequency of pre-germinal center b cells and plasma cell precursors in the blood of children with systemic lupus erythematosus. J. Immunol. 167:2361–2369.
- Rubin, R.L., F.L. Tang, E.K. Chan, K.M. Pollard, G. Tsay, and E.M. Tan. 1986. IgG subclasses of autoantibodies in systemic lupus erythematosus, Sjogren's syndrome, and drug-induced autoimmunity. J. Immunol. 137:2528–2534.
- Casciola-Rosen, L.A., G. Anhalt, and A. Rosen. 1994. Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J. Exp. Med. 179:1317–1330.
- Amoura, Z., J.C. Piette, H. Chabre, P. Cacoub, T. Papo, B. Wechsler, J.F. Bach, and S. Koutouzov. 1997. Circulating plasma levels of nucleosomes in patients with systemic lupus erythematosus: correlation with serum antinucleosome antibody titers and absence of clear association with disease activity. Arthritis Rheum. 40:2217–2225.
- Banchereau, J., F. Briere, C. Caux, J. Davoust, S. Lebecque, Y. Liu, B. Pulendran, and K. Palucka. 2000. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18:767–811.
- Steinman, R.M., S. Turley, I. Mellman, and K. Inaba. 2000. The induction of tolerance by dendritic cells that have captured apoptotic cells. J. Exp. Med. 191:411–416.
- Blanco, P., A.K. Palucka, M. Gill, V. Pascual, and J. Banchereau. 2001. Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science. 294:1540–1543.
- Preble, O.T., R.J. Black, R.M. Friedman, J.H. Klippel, and J. Vilcek. 1982. Systemic lupus erythematosus: presence in human serum of an unusual acid-labile leukocyte interferon. Science. 216:429–431.
- Feldmann, M., and R.N. Maini. 2001. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu. Rev. Immunol. 19:163–196.
- Shaffer, A.L., A. Rosenwald, E.M. Hurt, J.M. Giltnane, L.T. Lam, O.K. Pickeral, and L.M. Staudt. 2001. Signatures of the immune response. Immunity. 15:375–385.
- Staudt, L.M., and P.O. Brown. 2000. Genomic views of the immune system. Annu. Rev. Immunol. 18:829–859.
- Nielsen, T.O., R.B. West, S.C. Linn, O. Alter, M.A. Knowling, J.X. O'Connell, S. Zhu, M. Fero, G. Sherlock, J.R. Pollack, et al. 2002. Molecular characterisation of soft tissue tumours: a gene expression study. Lancet. 359:1301–1307.
- Hanker, J.S., J. Laszlo, and J.O. Moore. 1978. The light microscopic demonstration of hydroperoxidase-positive Phi bodies and rods in leukocytes in acute myeloid leukemia. Histochemistry. 58:241–252.
- Verhoven, B., R.A. Schlegel, and P. Williamson. 1995. Mechanisms of phosphatidylserine exposure, a phagocyte recognition signal, on apoptotic T lymphocytes. J. Exp. Med. 182:1597–1601.
- Zhou, Q., J. Zhao, T. Wiedmer, and P.J. Sims. 2002. Normal hemostasis but defective hematopoietic response to growth factors in mice deficient in phospholipid scramblase 1. Blood. 99:4030–4038.
- Griffith, T.S., S.R. Wiley, M.Z. Kubin, L.M. Sedger, C.R. Maliszewski, and N.A. Fanger. 1999. Monocyte-mediated tumoricidal activity via the tumor necrosis factor-related cytokine, TRAIL. J. Exp. Med. 189:1343–1354.
- Leaman, D.W., M. Chawla-Sarkar, K. Vyas, M. Reheman, K. Tamai, S. Toji, and E.C. Borden. 2002. Identification of X-linked inhibitor of apoptosis-associated factor-1 (XAF1) as and interferon-stimulated gene that augments TRAIL (Apo2L)-induced apoptosis. J Biol Chem. 277:28504–28511.
- de Saint-Vis, B., J. Vincent, S. Vandenabeele, B. Vanbervliet, J.J. Pin, S. Ait-Yahia, S. Patel, M.G. Mattei, J. Banchereau, S. Zurawski, et al. 1998. A novel lysosome-associated membrane glycoprotein, DC-LAMP, induced upon DC maturation, is transiently expressed in MHC class II compartment. Immunity. 9:325–336.
- Cowland, J.B., and N. Borregaard. 1999. The individual regulation of granule protein mRNA levels during neutrophil maturation explains the heterogeneity of neutrophil granules. J. Leukoc. Biol. 66:989–995.
- Niwa, Y., T. Sakane, M. Shingu, and Y. Miyachi. 1985. Role of stimulated neutrophils from patients with systemic lupus erythematosus in tissue injury, with special reference to serum factors and increased active oxygen species generated by neutrophils. Inflammation. 9:163–172.
- Yang, D., O. Chertov, and J.J. Oppenheim. 2001. Participation of mammalian defensins and cathelicidins in anti-microbial immunity: receptors and activities of human defensins and cathelicidin (LL-37). J. Leukoc. Biol. 69:691–697.
- Winoto, A., and D.R. Littman. 2002. Nuclear hormone receptors in T lymphocytes. Cell. 109(Suppl):S57–66.
- Ronnblom, L., and G.V. Alm. 2001. A pivotal role for the natural interferon alpha-producing cells (plasmacytoid dendritic cells) in the pathogenesis of lupus. J. Exp. Med. 194:F59–F63.
- Rozzo, S.J., J.D. Allard, D. Choubey, T.J. Vyse, S. Izui, G. Peltz, and B.L. Kotzin. 2001. Evidence for an interferon-inducible gene, Ifi202, in the susceptibility to systemic lupus. Immunity. 15:435–443.
- Herrmann, M., R.E. Voll, and J.R. Kalden. 2000. Etiopathogenesis of systemic lupus erythematosus. Immunol. Today. 21:424–426.
- Suit, B.E., D. Axelrod, H.M. Moutsopoulos, J.L. Decker, and J.J. Hooks. 1983. Detection of anti-interferon antibodies in systemic lupus erythematosus. Clin. Exp. Rheumatol. 1:133–135.
- Farkas, L., K. Beiske, F. Lund-Johansen, P. Brandtzaeg, and F.L. Jahnsen. 2001. Plasmacytoid dendritic cells (natural interferon-alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions. Am. J. Pathol. 159:237–243.
- Blomberg, S., M.L. Eloranta, B. Cederblad, K. Nordlin, G.V. Alm, and L. Ronnblom. 2001. Presence of cutaneous interferon-alpha producing cells in patients with systemic lupus erythematosus. Lupus. 10:484–490.
- Hacbarth, E., and A. Kajdacsy-Balla. 1986. Low density neutrophils in patients with systemic lupus erythematosus, rheumatoid arthritis, and acute rheumatic fever. Arthritis Rheum. 29:1334–1342.
- Hetherington, S.V., and P.G. Quie. 1985. Human polymorphonuclear leukocytes of the bone marrow, circulation, and marginated pool: function and granule protein content. Am. J. Hematol. 20:235–246.
- Corssmit, E.P., R. Heijligenberg, C.E. Hack, E. Endert, H.P. Sauerwein, and J.A. Romijn. 1997. Effects of interferon-alpha (IFN-alpha) administration on leucocytes in healthy humans. Clin. Exp. Immunol. 107:359–363.
- Fukuda, A., H. Kobayashi, K. Teramura, S. Yoshimoto, and N. Ohsawa. 2000. Effects of interferon-alpha on peripheral neutrophil counts and serum granulocyte colony-stimulating factor levels in chronic hepatitis C patients. Cytokines Cell. Mol. Ther. 6:149–154.
- Coxon, A., X. Cullere, S. Knight, S. Sethi, M.W. Wakelin, G. Stavrakis, F.W. Luscinskas, and T.N. Mayadas. 2001. Fc gamma RIII mediates neutrophil recruitment to immune complexes. a mechanism for neutrophil accumulation in immune-mediated inflammation. Immunity. 14:693–704.
- Hotta, O., T. Oda, Y. Taguma, H. Kitamura, S. Chiba, S. Miyazawa, and H. Nagura. 1996. Role of neutrophil elastase in the development of renal necrotizing vasculitis. Clin. Nephrol. 45:211–216.
- Qasim, F.J., P.W. Mathieson, F. Sendo, S. Thiru, and D.B. Oliveira. 1996. Role of neutrophils in the pathogenesis of experimental vasculitis. Am. J. Pathol. 149:81–89.
- Courtney, P.A., A.D. Crockard, K. Williamson, A.E. Irvine, R.J. Kennedy, and A.L. Bell. 1999. Increased apoptotic peripheral blood neutrophils in systemic lupus erythematosus: relations with disease activity, antibodies to double stranded DNA, and neutropenia. Ann. Rheum. Dis. 58:309–314.
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