Abstract
Recent studies have renewed the interest on the potential role that neutrophils play in the development of systemic lupus erythematosus (SLE) and other autoimmune conditions. A distinct subset of proinflammatory, low-density granulocytes (LDGs) isolated from the peripheral blood mononuclear cell fractions of patients with SLE has been described. While the origin and role of LDGs needs to be fully characterized, there is evidence that these cells may contribute to lupus pathogenesis and to the development of end-organ damage through heightened proinflammatory responses, altered phagocytic capacity, enhanced ability to synthesize type I interferons, and to kill endothelial cells. Furthermore, these cells readily form neutrophil extracellular traps, a phenomenon that may promote autoantigen externalization and organ damage. This review examines the biology and potential origin of LDGs, describes the ultrastructural characteristics of these cells, and discusses their putative pathogenic role in systemic autoimmune diseases.
Similar content being viewed by others
References
Weiss SJ, Young J, LoBuglio AF, Slivka A, Nimeh NF (1981) Role of hydrogen peroxide in neutrophil-mediated destruction of cultured endothelial cells. J Clin Invest 68:714–721
Bainton DF, Ullyot JL, Farquhar MG (1971) The development of neutrophilic polymorphonuclear leukocytes in human bone marrow. J Exp Med 134:907–934
Kyttaris VC, Juang YT, Tsokos GC (2005) Immune cells and cytokines in systemic lupus erythematosus: an update. Curr Opin Rheumatol 17:518–522
Camussi G, Cappio FC, Messina M, Coppo R, Stratta P, Vercellone A (1980) The polymorphonuclear neutrophil (PMN) immunohistological technique: detection of immune complexes bound to the PMN membrane in acute poststreptococcal and lupus nephritis. Clin Nephrol 14:280–287
Ward MM (1999) Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus. Arthritis Rheum 42:338–346
Crispin JC, Kyttaris VC, Terhorst C, Tsokos GC (2010) T cells as therapeutic targets in SLE. Nat Rev Rheumatol 6:317–325
Dorner T, Jacobi AM, Lee J, Lipsky PE (2011) Abnormalities of B cell subsets in patients with systemic lupus erythematosus. J Immunol Methods 363:187–197
Denny MF, Chandaroy P, Killen PD, Caricchio R, Lewis EE, Richardson BC, Lee KD, Gavalchin J, Kaplan MJ (2006) Accelerated macrophage apoptosis induces autoantibody formation and organ damage in systemic lupus erythematosus. J Immunol 176:2095–2104
Denny MF, Yalavarthi S, Zhao W, Thacker SG, Anderson M, Sandy AR, McCune WJ, Kaplan MJ (2010) A distinct subset of proinflammatory neutrophils isolated from patients with systemic lupus erythematosus induces vascular damage and synthesizes type I IFNs. J Immunol 184:3284–3297
Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J, Pascual V (2003) Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med 197:711–723
Banchereau J, Pascual V (2006) Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity 25:383–392
Brandt L, Hedberg H (1969) Impaired phagocytosis by peripheral blood granulocytes in systemic lupus erythematosus. Scand J Haematol 6:348–353
Courtney PA, Crockard AD, Williamson K, Irvine AE, Kennedy RJ, Bell AL (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
Hashimoto Y, Ziff M, Hurd ER (1982) Increased endothelial cell adherence, aggregation, and superoxide generation by neutrophils incubated in systemic lupus erythematosus and Felty’s syndrome sera. Arthritis Rheum 25:1409–1418
Abramson SB, Given WP, Edelson HS, Weissmann G (1983) Neutrophil aggregation induced by sera from patients with active systemic lupus erythematosus. Arthritis Rheum 26:630–636
Molad Y, Buyon J, Anderson DC, Abramson SB, Cronstein BN (1994) Intravascular neutrophil activation in systemic lupus erythematosus (SLE): dissociation between increased expression of CD11b/CD18 and diminished expression of L-selectin on neutrophils from patients with active SLE. Clin Immunol Immunopathol 71:281–286
Cochrane CG, Unanue ER, Dixon FJ (1965) A Role of Polymorphonuclear Leukocytes and Complement in Nephrotoxic Nephritis. J Exp Med 122:99–116
Hacbarth E, Kajdacsy-Balla A (1986) Low density neutrophils in patients with systemic lupus erythematosus, rheumatoid arthritis, and acute rheumatic fever. Arthritis Rheum 29:1334–1342
Nakou M, Knowlton N, Frank MB, Bertsias G, Osban J, Sandel CE, Papadaki H, Raptopoulou A, Sidiropoulos P, Kritikos I et al (2008) Gene expression in systemic lupus erythematosus: bone marrow analysis differentiates active from inactive disease and reveals apoptosis and granulopoiesis signatures. Arthritis Rheum 58:3541–3549
Villanueva E, Yalavarthi S, Berthier CC, Hodgin JB, Khandpur R, Lin AM, Rubin CJ, Zhao W, Olsen SH, Klinker M et al (2011) Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol 187:538–552
Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A (2004) Neutrophil extracellular traps kill bacteria. Science 303:1532–1535
Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, Weinrauch Y, Brinkmann V, Zychlinsky A (2007) Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 176:231–241
Saffarzadeh M, Juenemann C, Queisser MA, Lochnit G, Barreto G, Galuska SP, Lohmeyer J, Preissner KT (2012) Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones. PLoS One 7:e32366
Mollinedo F, Borregaard N, Boxer LA (1999) Novel trends in neutrophil structure, function and development. Immunol Today 20:535–537
Cowland JB, Borregaard N (1999) The individual regulation of granule protein mRNA levels during neutrophil maturation explains the heterogeneity of neutrophil granules. J Leukoc Biol 66:989–995
Pavon EJ, Garcia-Rodriguez S, Zumaquero E, Perandres-Lopez R, Rosal-Vela A, Lario A, Longobardo V, Carrascal M, Abian J, Callejas-Rubio JL et al (2012) Increased expression and phosphorylation of the two S100A9 isoforms in mononuclear cells from patients with systemic lupus erythematosus: a proteomic signature for circulating low-density granulocytes. J Proteomics 75:1778–1791
Fiehn C, Wermann M, Pezzutto A, Hufner M, Heilig B (1992) Plasma GM-CSF concentrations in rheumatoid arthritis, systemic lupus erythematosus and spondyloarthropathy. Z Rheumatol 51:121–126
Willeke P, Schluter B, Schotte H, Erren M, Mickholz E, Domschke W, Gaubitz M (2004) Increased frequency of GM-CSF secreting PBMC in patients with active systemic lupus erythematosus can be reduced by immunoadsorption. Lupus 13:257–262
Ramos-Kichik V, Mondragon-Flores R, Mondragon-Castelan M, Gonzalez-Pozos S, Muniz-Hernandez S, Rojas-Espinosa O, Chacon-Salinas R, Estrada-Parra S, Estrada-Garcia I (2009) Neutrophil extracellular traps are induced by Mycobacterium tuberculosis. Tuberculosis (Edinb) 89:29–37
Popova EY, Claxton DF, Lukasova E, Bird PI, Grigoryev SA (2006) Epigenetic heterochromatin markers distinguish terminally differentiated leukocytes from incompletely differentiated leukemia cells in human blood. Exp Hematol 34:453–462
Lukasova E, Koristek Z, Falk M, Kozubek S, Grigoryev S, Kozubek M, Ondrej V, Kroupova I (2005) Methylation of histones in myeloid leukemias as a potential marker of granulocyte abnormalities. J Leukoc Biol 77:100–111
Lindemann A, Riedel D, Oster W, Ziegler-Heitbrock HW, Mertelsmann R, Herrmann F (1989) Granulocyte-macrophage colony-stimulating factor induces cytokine secretion by human polymorphonuclear leukocytes. J Clin Invest 83:1308–1312
Studnicka-Benke A, Steiner G, Petera P, Smolen JS (1996) Tumour necrosis factor alpha and its soluble receptors parallel clinical disease and autoimmune activity in systemic lupus erythematosus. Br J Rheumatol 35:1067–1074
Gabay C, Cakir N, Moral F, Roux-Lombard P, Meyer O, Dayer JM, Vischer T, Yazici H, Guerne PA (1997) Circulating levels of tumor necrosis factor soluble receptors in systemic lupus erythematosus are significantly higher than in other rheumatic diseases and correlate with disease activity. J Rheumatol 24:303–308
Malide D, Russo P, Bendayan M (1995) Presence of tumor necrosis factor alpha and interleukin-6 in renal mesangial cells of lupus nephritis patients. Hum Pathol 26:558–564
Edwards CK 3rd, Zhou T, Zhang J, Baker TJ, De M, Long RE, Borcherding DR, Bowlin TL, Bluethmann H, Mountz JD (1996) Inhibition of superantigen-induced proinflammatory cytokine production and inflammatory arthritis in MRL-lpr/lpr mice by a transcriptional inhibitor of TNF-alpha. J Immunol 157:1758–1772
Shirafuji N, Matsuda S, Ogura H, Tani K, Kodo H, Ozawa K, Nagata S, Asano S, Takaku F (1990) Granulocyte colony-stimulating factor stimulates human mature neutrophilic granulocytes to produce interferon-alpha. Blood 75:17–19
Tamassia N, Le Moigne V, Rossato M, Donini M, McCartney S, Calzetti F, Colonna M, Bazzoni F, Cassatella MA (2008) Activation of an immunoregulatory and antiviral gene expression program in poly(I:C)-transfected human neutrophils. J Immunol 181:6563–6573
Kaplan MJ, Salmon JE (2011) How does interferon-α insult the vasculature? Let me count the ways. Arthritis Rheum 63:334–336
Urban CF, Ermert D, Schmid M, Abu-Abed U, Goosmann C, Nacken W, Brinkmann V, Jungblut PR, Zychlinsky A (2009) Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog 5:e1000639
Urban CF, Reichard U, Brinkmann V, Zychlinsky A (2006) Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell Microbiol 8:668–676
Cogen AL, Yamasaki K, Muto J, Sanchez KM, Crotty Alexander L, Tanios J, Lai Y, Kim JE, Nizet V, Gallo RL (2010) Staphylococcus epidermidis antimicrobial delta-toxin (phenol-soluble modulin-gamma) cooperates with host antimicrobial peptides to kill group A Streptococcus. PLoS One 5:e8557
Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, Patel KD, Chakrabarti S, McAvoy E, Sinclair GD et al (2007) Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 13:463–469
Juneau RA, Pang B, Weimer KE, Armbruster CE, Swords WE (2011) Nontypeable Haemophilus influenzae initiates formation of neutrophil extracellular traps. Infect Immun 79:431–438
Pilsczek FH, Salina D, Poon KK, Fahey C, Yipp BG, Sibley CD, Robbins SM, Green FH, Surette MG, Sugai M et al (2010) A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus. J Immunol 185:7413–7425
Martinelli S, Urosevic M, Daryadel A, Oberholzer PA, Baumann C, Fey MF, Dummer R, Simon HU, Yousefi S (2004) Induction of genes mediating interferon-dependent extracellular trap formation during neutrophil differentiation. J Biol Chem 279:44123–44132
Gupta AK, Hasler P, Holzgreve W, Gebhardt S, Hahn S (2005) Induction of neutrophil extracellular DNA lattices by placental microparticles and IL-8 and their presence in preeclampsia. Hum Immunol 66:1146–1154
Garcia-Romo GS, Caielli S, Vega B, Connolly J, Allantaz F, Xu Z, Punaro M, Baisch J, Guiducci C, Coffman RL et al (2011) Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med 3:73ra20
Lande R, Ganguly D, Facchinetti V, Frasca L, Conrad C, Gregorio J, Meller S, Chamilos G, Sebasigari R, Riccieri V et al (2011) Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci Transl Med 3:73ra19
Kahlenberg JM, Carmona-Rivera C, Smith CK, Kaplan MJ (2013) Neutrophil extracellular trap-associated protein activation of the NLRP3 inflammasome is enhanced in lupus macrophages. J Immunol 190:1217–1226
Hakkim A, Furnrohr BG, Amann K, Laube B, Abed UA, Brinkmann V, Herrmann M, Voll RE, Zychlinsky A (2010) Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci U S A 107:9813–9818
Yasutomo K, Horiuchi T, Kagami S, Tsukamoto H, Hashimura C, Urushihara M, Kuroda Y (2001) Mutation of DNASE1 in people with systemic lupus erythematosus. Nat Genet 28:313–314
Shin HD, Park BL, Kim LH, Lee HS, Kim TY, Bae SC (2004) Common DNase I polymorphism associated with autoantibody production among systemic lupus erythematosus patients. Hum Mol Genet 13:2343–2350
Leffler J, Martin M, Gullstrand B, Tyden H, Lood C, Truedsson L, Bengtsson AA, Blom AM (2012) Neutrophil extracellular traps that are not degraded in systemic lupus erythematosus activate complement exacerbating the disease. J Immunol 188:3522–3531
Liu CL, Tangsombatvisit S, Rosenberg JM, Mandelbaum G, Gillespie EC, Gozani OP, Alizadeh AA, Utz PJ (2012) Specific post-translational histone modifications of neutrophil extracellular traps as immunogens and potential targets of lupus autoantibodies. Arthritis Res Ther 14:R25
Caudrillier A, Kessenbrock K, Gilliss BM, Nguyen JX, Marques MB, Monestier M, Toy P, Werb Z, Looney MR (2012) Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J Clin Invest 122:2661–2671
Morisaki T, Goya T, Ishimitsu T, Torisu M (1992) The increase of low density subpopulations and CD10 (CALLA) negative neutrophils in severely infected patients. Surg Today 22:322–327
Rodriguez PC, Ernstoff MS, Hernandez C, Atkins M, Zabaleta J, Sierra R, Ochoa AC (2009) Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res 69:1553–1560
Cloke T, Munder M, Taylor G, Muller I, Kropf P (2012) Characterization of a novel population of low-density granulocytes associated with disease severity in HIV-1 infection. PLoS One 7:e48939
Lin AM, Rubin CJ, Khandpur R, Wang JY, Riblett M, Yalavarthi S, Villanueva EC, Shah P, Kaplan MJ, Bruce AT (2011) Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J Immunol 187:490–500
Hoffmann MH, Bruns H, Backdahl L, Neregard P, Niederreiter B, Herrmann M, Catrina AI, Agerberth B, Holmdahl R (2013) The cathelicidins LL-37 and rCRAMP are associated with pathogenic events of arthritis in humans and rats. Ann Rheum Dis (in press)
Porntrakulpipat S, Depner KR, Moennig V (2001) Are low-density granulocytes the major target cells of classical swine fever virus in the peripheral blood? J Vet Med B Infect Dis Vet Public Health 48:593–602
Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, Basham B, Smith K, Chen T, Morel F et al (2007) Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 8:950–957
Puga I, Cols M, Barra CM, He B, Cassis L, Gentile M, Comerma L, Chorny A, Shan M, Xu W et al (2012) B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat Immunol 13:170–180
Acknowledgments
This study is supported by the NIH through PHS grants AR007080 and HL088419.
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is a contribution to the special issue on Neutrophils - Guest Editors: Paul Hasler and Sinuhe Hahn
Rights and permissions
About this article
Cite this article
Carmona-Rivera, C., Kaplan, M.J. Low-density granulocytes: a distinct class of neutrophils in systemic autoimmunity. Semin Immunopathol 35, 455–463 (2013). https://doi.org/10.1007/s00281-013-0375-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00281-013-0375-7