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Low production of reactive oxygen species in granulocytes is associated with organ damage in systemic lupus erythematosus

Bengtsson et al. Arthritis Research & Therapy 2014, 16:R120 Low production of reactive oxygen species ingranulocytes is associated with organ damage insystemic lupus erythematosus Anders A Bengtsson1, Åsa Pettersson2, Stina Wichert3, Birgitta Gullstrand4, Markus Hansson3,Thomas Hellmark2 and Åsa CM Johansson3,5* Introduction: Polymorphonuclear leukocytes (PMN) are main effector cells in the acute immune response. Whilethe specific role of PMN in systemic lupus erythematosus (SLE) and autoimmunity is still unclear, their importancein chronic inflammation is gaining more attention. Here we investigate aspects of function, bone marrow releaseand activation of PMN in patients with SLE.
Methods: The following PMN functions and subsets were evaluated using flow cytometry; (a) production ofreactive oxygen species (ROS) after ex vivo stimulation with phorbol 12-myristate 13-acetate (PMA) or Escherichia coli(E. coli); (b) capacity to phagocytose antibody-coated necrotic cell material; (c) PMN recently released from bonemarrow, defined as percentage of CD10−D16low in peripheral blood, and (d) PMN activation markers; CD11b, CD62Land C5aR.
Results: SLE patients (n = 92) showed lower ROS production compared with healthy controls (n = 38) afteractivation ex vivo. The ROS production was not associated with corticosteroid dose or other immunotherapies. PMAinduced ROS production was significantly reduced in patients with severe disease. In contrast, neither ROS levelsafter E. coli activation, nor the capacity to phagocytose were associated with disease severity. This suggests thatdecreased ROS production after PMA activation is a sign of changed PMN behaviour rather than generally impairedfunctions. The CD10−CD16low phenotype constitute 2% of PMN in peripheral blood of SLE patients compared with6.4% in controls, indicating a decreased release of PMN from the bone marrow in SLE. A decreased expression ofC5aR on PMN was observed in SLE patients, pointing towards in vivo activation.
Conclusions: Our results indicate that PMN from SLE patients have altered function, are partly activated and arereleased abnormally from bone marrow. The association between low ROS formation in PMN and disease severity isconsistent with findings in other autoimmune diseases and might be considered as a risk factor.
major source of auto-antigens in SLE, partly because of Systemic lupus erythematosus (SLE) is a chronic systemic impaired clearance . Another potential antigen source autoimmune disease affecting several organ systems such is the neutrophil extracellular traps (NETs) that consist of as skin, joints, kidneys and central nervous system. Many chromatin and antimicrobial enzymes released from neu- of the disease manifestations in SLE are related to immune trophils to trap and kill pathogens. Serum from some SLE complexes, consisting of autoantibodies and remnants of patients have a reduced ability to degrade NETs .
apoptotic cells ]. Apoptotic cells are thought to be a Polymorphonuclear leukocytes (PMN), such as neu- trophils, are produced in the bone marrow and releasedto circulation. During acute inflammation an increased * Correspondence: 3Department of Haematology, Lund University, BMC B13, 221 84 Lund, mobilization of neutrophils from the bone marrow oc- curs, which can be observed as increased percentage of 5Clinical Immunology and Transfusion Medicine, University and Regional CD10−CD16low neutrophils in peripheral blood []. The Laboratories Region Skåne, 221 85 Lund, SwedenFull list of author information is available at the end of the article role of PMN in chronic inflammation and autoimmunity 2014 Bengtsson et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of theCreative Commons Attribution License which permits unrestricted use,distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons PublicDomain Dedication waiver applies to the data made available in thisarticle, unless otherwise stated.
Bengtsson et al. Arthritis Research & Therapy 2014, 16:R120 is coming into focus, and neutrophils have been suggested patients with chronic granulomatous disease, lacking a to be the primary mediators of end organ-damage res- functional NADPH oxidase complex, show autoimmune ponding to deposited immune complexes PMN are features such as high levels of immunoglobulins and auto- recruited to inflammatory sites, and activated by pro- antibodies, as well as an increased risk of Crohn's disease inflammatory mediators like complement factors, cytokines and discoid lupus .
and chemokines. Upon activation the expression of various This study aims at characterizing PMN from SLE pa- surface proteins changes; for example, C5aR and CD62L tients (SLE-PMN), in regard to function, bone marrow are down regulated whereas an increase in CD11b expres- release and activation to gain knowledge of the role of sion is observed [In addition to the changing expres- PMN in SLE and autoimmunity.
sion of surface proteins, activated PMN are primed torelease granules and produce reactive oxygen species (ROS) by the nicotinamide adenine dinucleotide phosphate- Patients and controls oxidase (NADPH) complex []. ROS are major effector SLE patients (n = 107) were recruited to the study, when molecules in inflammatory processes and tightly linked to coming to their scheduled visit at the Department of NETs formation. During the last decade, an increasing Rheumatology, Skåne University Hospital, Lund, Sweden.
amount of data support a T-cell regulating role for mono- All patients fulfilled at least four American College of cyte and PMN-produced ROS [–]. Furthermore, the Rheumatology classification criteria for SLE Disease association of SLE to polymorphism in NCF2, encoding a activity was assessed using the systemic lupus erythemato- protein in the NADPH oxidase complex, adds support for sus disease activity index 2000 (SLEDAI-2 K) , and the importance of ROS in this disease Of note, organ damage was evaluated according to the Systemic Table 1 Patients characteristics and demographics SLICC/ACR-DI = 0 (n = 42) SLICC/ACR-DI ≥1 (n = 50) Age, median (range) years Female gender, n (%) Disease duration, median (range) years SLEDAI, median (range) SLICC/ACR-DI median (range) PMN 109/L median (range) 4.0 (<0.1 to 11) 4.7 (<0.1 to 11) Disease manifestations at time of sampling, n Kidney involvement (urinary cast, hematuria, proteinuria, or pyuria) Low complement (C3 or C4) Anti-double stranded DNA antibodies Prednisone, % (median dose of treated patients) Hydroxychloroquine, % (n) Chloroquine phosphate, % (n) Azathioprine, % (n) Mycophenolate mofetil%, (n) Methotrexates, % (n) Cyclosporine A, % (n) SLICC/ACR-DI, Systemic Lupus International Collaborative Clinics/American College of Rheumatology (ACR) damage index; SLEDAI-2 K, Systemic lupus erythematosusdisease activity index 2000; PMN, polymorphonuclear leukocytes.
Bengtsson et al. Arthritis Research & Therapy 2014, 16:R120 Lupus International Collaborative Clinics/American Col- Poc AS, Norway). To obtain necrotic cell material, mono- lege of Rheumatology damage index (SLICC/ACR-DI) ].
nuclear cells were incubated for 10 minutes at 70°C and Demographic and clinical characteristics are shown in stained with propidium iodide (BD Bioscience). The propi- Table Healthy blood donors (n = 38, Blood centre in dium iodide-labelled necrotic cell material (4.5 × 105 cells) Lund) and healthy volunteers (n = 15) were recruited as was then incubated with or without an anti-nucleosome controls; ages 18 to 65 years. Complement proteins and antibody (clone PL2-3; gift from Marc Monestier, Temple autoantibodies were measured using routine analyses University, Philadelphia, USA) at room temperature for (Clinical Immunology and Transfusion Medicine, University 20 minutes. Normal human serum was used as the nega- and Regional laboratories, Region Skåne, Lund Sweden).
tive control. The autologous PMN were stained with anti- The study was approved by the Regional Ethics Review CD45-FITC (BD Bioscience), and then added to the nec- Board at Lund University (file number LU 2010-708) and rotic cell material, at a concentration of 1.0 × 106 cells/mL informed consent was obtained from all participants.
in a total volume of 300 μL, followed by incubation at37°C for 15 minutes. Cells were washed with phosphate- Oxidative burst and expression of surface markers buffered saline pH 7.2 containing 0.1% human serum ROS production in peripheral blood PMN was investigated albumin (Sigma-Aldrich, St. Louis, MO, USA) before ana- using the PhagoBurst assay, Glycotope Biotechnology, lysis by flow cytometry.
GmBH, Germany, according to the manufacturer's proto-col after activation with phorbol 12-myristate 13-acetate Statistical analysis (PMA) or opsonised Escherichia coli (E. coli), and analysed Correlations were determined by Spearman's correlation using flow cytometry. At least 15,000 PMN were analysed test. The Mann-Whitney U-test was used for two-group based on forward and side scatter properties. No patient comparisons and Kruskal-Wallis test with Dunn's mul- with ROS deficiency was observed.
tiple comparison test was used for three-group compari- ROS formation in peripheral blood PMN was also quan- sons. All P-values were considered significant at P <0.05.
tified by oxidation of 2,7-dichlorofluorescein-diacetate(DCFH-DA, Sigma-Aldrich®, St. Louis, MO, USA), as previ- ously described . As stimuli PMA and E. coli from the Decreased production of ROS in SLE-PMN PhagoBurst kit or Staphylococcus aureus (ATCC 25923, 1 Phagocyte-produced ROS are important effector mole- leukocyte: 2,000 bacterial cells) and Pseudomonas aerugi- cules in the defence against microbes, and could also be nosa (ATCC 27853, 1 leukocyte: 200 bacterial cells) were involved in the regulation of the adaptive immune system used. S. aureus and P. aeruginosa were grown in liquid []. To evaluate PMN function in SLE, we decided to in- Tryptic Soy Broth (TSB) medium overnight at 37°C and vestigate intracellular ROS production. PMN in peripheral killed by heat (60°C) for 2 h. To confirm bacterial inactiva- whole blood from SLE patients (n = 92, Table and tion a sample was inoculated in TSB and kept for 48 h.
healthy controls (n = 38), were stimulated with either the The bacteria were centrifuged and re-suspended in 0.8% protein kinase C activator, PMA, or with opsonised E. coli.
saline. Optical density was adjusted to 24 × 108 colony form- SLE-PMN showed a decreased capacity to produce ROS ing units/mL by comparing turbidity to a McFarland scale ex vivo after activation with both PMA (P <0.0001) and E.
number 8 BaSO4 standard solution. DCFH-DA was added coli (P = 0.0002) (Figure The decreased amount of ROS to heparinised whole blood before the various stimuli, and produced by SLE-PMN was not associated with the dose then the samples were incubated in a 37°C water bath for of prednisone or hydroxychloroquine treatment (Figure 30 minutes. Cells were analysed using flow cytometry.
and B) or other immune suppressive drugs listed in Table The expression of selected surface markers on PMN was (not shown). Perazzio et al. have previously shown an in- analysed using flow cytometry. Briefly, peripheral blood creased ROS production in SLE-PMN after in vitro activa- was lysed using 0.84% ammonium chloride. The remaining tion with S. aureus or P. aeruginosa using DCFH-DA as leukocytes were stained for surface expression of CD14 (to fluorochrome . To evaluate whether this discrepancy exclude monocytes), CD10, CD11b, CD16, CD62L, and was due to experimental procedure or differences in pa- C5aR (CD88) (BD Bioscience San Jose, CA, USA). For flow tient population, patients (n = 15) and controls (n = 15) cytometry analysis a FACSCanto II and the DIVA software were analysed in parallel with both methods, using S.
(Becton Dickinson, BD, New York, NY, USA) were used.
aureus, P. aeruginosa, PMA and E. coli as stimuli. Similarfindings where observed between the two methods Cell separation and phagocytosis of antibody-coated (Table . SLE-PMN showed a decreased intracellular necrotic cell material by PMN ROS formation after PMA activation compared with con- PMN and peripheral blood mononuclear cells were iso- trols (PhagoBurst test: P = 0.0394 and DCFH-DA: P = lated from heparinised blood of SLE patients by density 0.0146) whereas no significant difference was observed gradient centrifugation on Polymorphprep™ (Axis-Shield with the other stimuli (not shown). The decreased ROS Bengtsson et al. Arthritis Research & Therapy 2014, 16:R120 Figure 1 Polymorphonuclear leukocytes (PMN) from patients with Hydroxichloroquine systemic lupus erythematosus (SLE) produced fewer reactive oxygen species (ROS) than PMN from healthy blood donors. Thecapacities of PMN from healthy blood donors (HBD), n = 38, and SLE patients, n = 92, to produce ROS upon activation with phorbol 12-myristate 13-acetate or opsonised E. coli were investigated using flowcytometry. The amount of ROS produced is shown as geometric meanfluorescence intensity (geo mean fluorescence, MFI). The two-sided Mann-Whitney test was used to calculate the level of significance. Thehorizontal lines represent the median value of each dataset.
production in our examined SLE cohort after PMA activa- tion was consistent using both methods in contrast to thefindings of Perazzio et al., suggesting differences in patient Prednisone dose pe rday Organ damage was associated with low ROS production Figure 2 Reactive oxygen species (ROS) production in polymorphonuclear leukocytes (PMN) from systemic lupus The severity of autoimmune diseases has previously been erythematosus (SLE) patients did not correlate with associated with decreased ROS production –. Hence, Hydroxychloroquine treatment or the dose of prednisone. ROS to study if the severity of SLE was associated with changes production was measured by flow cytometry after ex vivo activationof PMN with phorbol 12-myristate 13-acetate (A) the amount ROS in ROS production, the patients were divided in two produced by SLE-PMN, treated with or without Hydroxychloroquine.
groups based on the presence of organ damage or not ac- (B) The amount of ROS produced in individual patients plotted cording to SLICC/ACR-DI (Table . PMN from patients against the dose of prednisone at the day of sampling. The amount with SLICC/ACR-DI ≥1 had decreased ROS production, ROS produced is shown as geometric mean fluorescence intensity compared with patients without organ damage (Figure ), (geo mean fluorescence, MFI). The line represents the median valueof each dataset.
when activated with PMA (P = 0.0022). No difference wasseen after activation with E. coli (not shown). Patients withorgan damage were in general older than patients without ROS production and disease activity (P = 0.0654) was ob- (Table however, the age of the patients was not cor- served (Figure B).
related with PMA-induced oxidative burst in PMN (not Phagocytosis of antibody-coated microbes and foreign material precedes ROS production in PMN. To evaluate Next, we investigated if disease activity, at the time point further the function of PMN in SLE, in particular in pa- of sampling, was associated with ROS production. The tients with organ damage, the phagocytosis capacity was patients were divided into three groups based on the investigated in 40 out of the 92 patients. Antibody-coated SLEDAI-2 K [(1) no activity, (2) laboratory parameters necrotic cells were chosen as stimuli for phagocytosis to only, such as low complement and anti-double stranded relate to lupus erythematosus cells, for example, PMN DNA antibodies; and (3) clinical manifestations, for ex- containing phagocytosed antibody-coated dead cell mate- ample, nephritis, rash and arthritis. No association between rials, a phenomenon almost pathognomonic for SLE. No Bengtsson et al. Arthritis Research & Therapy 2014, 16:R120 Table 2 Comparisons between the PhagoBurst and the DCFH-DA assay Relative reactive oxygen species formation in SLE patients as% of formation in healthy controls Comparisons of the PhagoBurst assay with the dichlorodihydrofluorescein-diacetate (DCFH-DA) assay according to Perazzio et al. [No significant differencesbetween the methods were observed. Polymorphonuclear leukocytes (PMN) from systemic lupus erythematosus (SLE) patients (n = 15) and healthy controls(n = 15) were analysed in parallel with both methods using phorbol 12-myristate 13-acetate (PMA), E. coli, S. aureus or P. aeruginosa as stimuli. ROS formation wasdefined as geometric mean fluorescence intensity. Samples from each individual patient were divided by the mean value of the controls to gain the relative ROSformation in SLE-PMN as% of ROS produced in healthy controls. Values represent mean ± standard error of the mean. The two-sided Mann-Whitney test was usedto calculate the level of significance.
differences were observed between patients with (n = conditions, including Behcet's disease [], Guillain-Barre 25; SLICC/ACR-DI ≥1), compared to patients without syndrome and multiple sclerosis , and might be a organ damage (n = 15; SLICC/ACR-DI = 0), further sug- common denominator important in the pathogenesis of gesting that the decreased ROS production in patients with severe disease is not due to a general unrespon- Interestingly, PMA-induced ROS production was signifi- siveness (Figure ). No associations between disease cantly reduced in patients with severe disease. However, activity based on SLEDAI-2 K and the ability to phago- neither ROS production after E. coli activation nor phago- cytose were observed (not shown).
cytosis of necrotic cell material were associated with organdamage, suggesting that decreased ROS levels after PMA Low numbers of CD10−CD16low SLE-PMN activation is not a sign of impaired PMN functions in gen- During acute inflammation, an increased percentage of eral but rather a sign for changed PMN behaviour. While CD10−CD16low neutrophils in peripheral blood are thought the activation and control of the NADPH oxidase in neu- to reflect an increased mobilization of cells from bone trophils (NOX2) is incompletely understood, it seems that marrow . To study the frequency of newly released different agonists encountered by the neutrophils engage CD10−CD16low PMN in peripheral blood, samples from various combinations of kinases and thereby affect the de- 73 SLE patients, and 27 healthy controls were analysed by gree of activity of the NADPH complex, and in the end flow cytometry. SLE patients showed lower percentages of the amount of ROS produced []. To some extent, this CD10−CD16low PMN (Figure ), compared with healthy could explain why ROS production after E. coli activation controls (P <0.0001). Hence, the SLE-PMN were to a high was not associated with organ damage; E. coli induced a extent CD10+CD16+ compared with controls (P <0.0001), lower degree of phosphorylation of the NADPH complex which is consistent with a decreased release of PMN from regulating subunits compared with PMA that is known to the bone marrow.
push the NADPH complex to its maximal capacity [].
To characterize the activation status of PMN in periph- Hence, PMA revealed altered behaviour in PMN from pa- eral blood the expression of C5aR, CD11b and CD62L was tients with organ damage.
investigated. SLE-PMN were to a lesser extent C5aR posi- While no association between ROS levels and current tive (P <0.0001), and the positive cells expressed less C5aR disease activity was observed, most patients were in remis- (P <0.0001) (Table . No differences in the expression of sion or had low to moderate activity based on SLEDAI- CD11b or CD62L were observed (Table , indicating that 2 K (Table . An association between disease activity and the cells were only partly activated. C5aR expression and ROS production could not be excluded based on the avail- percentage of CD10−CD16lowPMN were not correlated able data. The literature is not concurrent regarding ROS with SLICC/ACR-DI or SLEDAI-2 K (not shown).
production by SLE-PMN For example, Perazzioet al. have shown that neutrophils from SLE patients have an increased capacity to produce ROS, and they did not PMN were characterized with respect to function, bone find any correlation with organ damage or disease activity marrow release and activation to study their role in SLE, []. This discrepancy does not reflect the use of different yielding evidence for decreased ROS production in SLE methods, as we observed comparable results with both and autoimmunity. Our data support that SLE-PMN have methods. A more likely explanation is variations in patient decreased capacity to produce ROS ex vivo. The associ- cohorts. We have observed an association between de- ation with disease severity, defined as organ damage, fur- creased ROS formation and disease severity, and a ten- ther strengthened our finding. Low ROS production has dency towards increased ROS formation in SLE-PMN in been associated with disease severity of other autoimmune patients with clinical symptoms. Most patients in our Bengtsson et al. Arthritis Research & Therapy 2014, 16:R120 Figure 3 Organ damage in systemic lupus erythematosus (SLE)patients is associated with decreased reactive oxygen species (ROS) production. ROS production was measured by flow cytometry after ex vivo activation of peripheral blood polymorphonuclearleukocytes (PMN) with phorbol 12-myristate 13-acetate. (A) The amountof ROS produced by PMN from patients with organ damage (Systemic Lupus International Col aborative Clinics/ACR damage index (SLICC/ACR-DI) ≥1) was compared with PMN from patients without organdamage (SLICC/ACR-DI = 0). (B) The amount of ROS produced by PMNfrom patients with (1) inactive disease (SLE activity index 2000 (SLEDAI- 2 K) = 0) affected laboratory parameters, such as low complement andanti-double stranded DNA antibodies, but no clinical symptoms; (2) laboratory parameters only, and patients with clinical manifestations, for example, nephritis, rash and arthritis; and (3) clinical symptoms (P = 0,0654). (C) Phagocytosis of necrotic cel material, in the presenceof serum and anti-nucleosome antibodies, by purified polymorphnucleated leukocytes (n = 40), was analysed using flow cytometry. The patients were divided based on organ damage (SLICC/ACR-DI) and their phagocytosis capacity is shown as% phagocytosing cells. Thetwo-sided Mann-Whitney test was used to calculate the level of significance between two groups and Kruskal-Wallis test with Dunn'smultiple comparison test was used to calculate the level of significance between three groups. The line represents the median value of each dataset. MFI, mean fluorescence intensity.
Clinical symptoms Lab parameters only % positive granulocytes
Figure 4 Decreased numbers of CD10−CD16low polymorphonuclear leukocytes (PMN) from patients withsystemic lupus erythematosus (SLE). The frequencies of CD10+CD16+(mainly segment nucleated neutrophils) and CD10−CD16low (suggested as a marker for newly released neutrophils) PMN were investigated in healthy blood donors (HBD, n = 27) and patients (n = 73) using flowcytometry. The two-sided Mann-Whitney test was used to calculate the level of significance. The line represents the median value of eachdataset.
Bengtsson et al. Arthritis Research & Therapy 2014, 16:R120 Table 3 Decreased expression of C5aR (CD88) on was decreased, indicating that PMN are activated in per- polymorphonuclear leukocytes (PMN) from patients with ipheral blood ]. However, no increase in CD11b systemic lupus erythematosus (SLE) expression and corresponding decrease in CD62L were Healthy blood donors observed on SLE-PMN. Taken together, the observed altered PMN phenotype could be due to prolonged turn- over of SLE-PMN in the circulation that gives rise to func- tional changes such as decreased ROS production and an atypical expression of surface markers.
Our study shows an association between low ROS forma- Comparisons were done between SLE patients and healthy blood donors in tion and disease severity in SLE. This is consistent with regard of the frequency (%) and amount (geometric mean fluorescence intensity findings in other autoimmune disease, suggesting that a (geoMFI) of positive cells) of CD88, CD62L and CD11b on CD10+CD16+ PMN.
Values represent mean ± standard error of the mean. The two-sided decrease in NADPH complex-mediated ROS production Mann-Whitney test was used to calculate the level of significance; ns, not significant.
is a risk factor in autoimmunity. The phenotype observedin SLE-PMN could be due to aberrant production of leu- study were in remission and possibly our cohort contained kocytes in the bone marrow and/or in vivo activation in more patients with organ damage giving rise to the diver- the circulation. Future studies will illuminate the role of gent results. In addition, an influence of genetic factors ROS formation and PMN in SLE and autoimmunity.
could not be excluded.
Corticosteroids have been reported to affect the ROS AbbreviationsE. coli: Escherichia coli; NADPH: nicotinamide adenine dinucleotide production in PMN in a cumulative dose-dependent way phosphate-oxidase; NETs: Neutrophil extracellular traps; PMA: Phorbol [], and it is presently unclear whether this effect is due 12-myristate 13-acetate; PMN: polymorphonuclear leukocytes; ROS: reactive to increased disease severity. In our study, no correlation oxygen species; SLE: systemic lupus erythematosus; SLEDAI-2 K: systemiclupus erythematosus disease activity index 2000; SLE-PMN: PMN from SLE between corticosteroid dose and the amount of intracellu- patients; SLICC/ACR-DI: Systemic Lupus International Collaborative Clinics/ lar ROS produced was observed. The patients had rela- American College of Rheumatology damage index.
tively low doses of corticosteroids (mean = 5 mg oral Competing interests prednisone per day in treated patients) that are likely too The authors declare that they have no competing interests.
low to affect the function of PMN. This could explain whyno correlation with ROS levels was found. Moreover, other Authors' contributions forms of immune suppressive drugs did neither seem to ÅP, BG and ÅJ did the laboratory work. BG and AB gathered all clinical data.
AB, TH, MH, SW, BG and ÅJ contributed to the design of the study and affect ROS production in the current setting.
wrote the manuscript. All authors read and approved the final manuscript.
Decreased neutrophil counts occur in SLE ].
While this is partly due to autoantibodies, there is also evi- AcknowledgementsThis work was supported by grants from Alfred Österlund's Foundation, The dence for direct effects on the bone marrow production of Crafoord Foundation, Greta and Johan Kock's Foundation, King Gustaf V's PMN. Bone marrow from SLE patients has decreased 80th Birthday Foundation, Lund University Hospital, the Swedish Rheumatism granulocyte-macrophage colony-forming units ], Association, the Swedish Research council (X65X-15152) and the Foundationof the National Board of Health and Welfare.
and we show here that SLE patients have reduced num-bers of newly released CD10−CD16low neutrophils [. In agreement with earlier observations, these findings suggest Department of Clinical Sciences, Section of Rheumatology, Lund University and Skåne University Hospital, 221 85 Lund, Sweden. 2Department of an SLE-associated effect on the bone marrow with de- Nephrology, Clinical Sciences in Lund, Lund University, BMC B13, 221 84 creased release of new incompletely differentiated neutro- Lund, Sweden. 3Department of Haematology, Lund University, BMC B13, 221 phils. Hence, a decreased number of PMN will be found 84 Lund, Sweden. 4Department of Laboratory Medicine Lund. Section ofMicrobiology, Immunology and Glycobiology, Lund University, Lund, in the circulation, and with decreased numbers of PMN in Sweden. 5Clinical Immunology and Transfusion Medicine, University and the circulation, a prolonged half-life of the existing cells Regional Laboratories Region Skåne, 221 85 Lund, Sweden.
likely occur.
Received: 3 December 2013 Accepted: 29 May 2014 Another possibility is that the PMN phenotype in SLE Published: 5 June 2014 patients is altered via an as-yet unidentified mechanism.
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Microsoft word - morning mantra 24-08-201

Morning Mantra Tuesday, September 06, 2011 Indian equity indices sulked in red along with global equities on Monday after sluggish US jobs data on Friday fanned fears about the health of the world's largest economy and its fallout on ongoing global recovery amidst sustained worries about the euro zone debt crisis which prompted investors for a flight of safety from Dalal

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