Abstract
IntroductionPolymorphonuclear leukocytes (PMN) are main effector cells in the acute immune response. While the specific role of PMN in systemic lupus erythematosus (SLE) and autoimmunity is still unclear, their importance in chronic inflammation is gaining more attention. Here we investigate aspects of function, bone marrow release and activation of PMN in patients with SLE.MethodsThe following PMN functions and subsets were evaluated using flow cytometry; (a) production of reactive 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 bone marrow, defined as percentage of CD10−D16low in peripheral blood, and (d) PMN activation markers; CD11b, CD62L and C5aR.ResultsSLE patients (n = 92) showed lower ROS production compared with healthy controls (n = 38) after activation ex vivo. The ROS production was not associated with corticosteroid dose or other immunotherapies. PMA induced ROS production was significantly reduced in patients with severe disease. In contrast, neither ROS levels after E. coli activation, nor the capacity to phagocytose were associated with disease severity. This suggests that decreased ROS production after PMA activation is a sign of changed PMN behaviour rather than generally impaired functions. The CD10−CD16low phenotype constitute 2% of PMN in peripheral blood of SLE patients compared with 6.4% in controls, indicating a decreased release of PMN from the bone marrow in SLE. A decreased expression of C5aR on PMN was observed in SLE patients, pointing towards in vivo activation.ConclusionsOur results indicate that PMN from SLE patients have altered function, are partly activated and are released abnormally from bone marrow. The association between low ROS formation in PMN and disease severity is consistent with findings in other autoimmune diseases and might be considered as a risk factor.
Highlights
Polymorphonuclear leukocytes (PMN) are main effector cells in the acute immune response
Perazzio et al have previously shown an increased reactive oxygen species (ROS) production in systemic lupus erythematosus (SLE)-PMN after in vitro activation with S. aureus or P. aeruginosa using DCFH-DA as fluorochrome [23]. To evaluate whether this discrepancy was due to experimental procedure or differences in patient population, patients (n = 15) and controls (n = 15) were analysed in parallel with both methods, using S. aureus, P. aeruginosa, phorbol 12-myristate 13-acetate (PMA) and E. coli as stimuli
PMN from SLE patients (SLE-PMN) showed a decreased intracellular ROS formation after PMA activation compared with controls (PhagoBurst test: P = 0.0394 and DCFH-DA: P = 0.0146) whereas no significant difference was observed with the other stimuli
Summary
Polymorphonuclear leukocytes (PMN) are main effector cells in the acute immune response. While the specific role of PMN in systemic lupus erythematosus (SLE) and autoimmunity is still unclear, their importance in chronic inflammation is gaining more attention. We investigate aspects of function, bone marrow release and activation of PMN in patients with SLE. Apoptotic cells are thought to be a Polymorphonuclear leukocytes (PMN), such as neutrophils, are produced in the bone marrow and released to circulation. The role of PMN in chronic inflammation and autoimmunity is coming into focus, and neutrophils have been suggested to be the primary mediators of end organ-damage responding to deposited immune complexes [8,9]. In addition to the changing expression of surface proteins, activated PMN are primed to release granules and produce reactive oxygen species (ROS) by the nicotinamide adenine dinucleotide phosphateoxidase (NADPH) complex [12]. Patients with chronic granulomatous disease, lacking a functional NADPH oxidase complex, show autoimmune features such as high levels of immunoglobulins and autoantibodies, as well as an increased risk of Crohn’s disease and discoid lupus [18,19]
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