Elsevier

Journal of Autoimmunity

Volume 28, Issues 2–3, March–May 2007, Pages 114-121
Journal of Autoimmunity

Clearance deficiency and systemic lupus erythematosus (SLE)

https://doi.org/10.1016/j.jaut.2007.02.005Get rights and content

Abstract

Systemic lupus erythematosus (SLE) is a fairly heterogeneous autoimmune disease. Impaired clearance functions for dying cells may explain accumulation of nuclear autoantigens in various tissues of SLE patients.

Our data show that in a subgroup of patients with SLE, apoptotic cells accumulated in the germinal centres of the lymph nodes. Apoptotic material was attached to the surfaces of follicular dendritic cells. Furthermore, we found an accumulation of apoptotic cells in the skin of patients with cutaneous lupus after UV exposure.

Granulocytes and monocytes in whole blood of SLE patients showed a reduced uptake of albumin- and polyglobin-coated beads. Furthermore, we analysed sera from SLE patients in migration assays and observed that the attraction signals for macrophages were reduced by sera of approximately 25% of the SLE patients.

Analyses of high-affinity DNA binding IgG autoantibodies of SLE patients revealed that those antibodies had gained their DNA reactivity in a germinal centre reaction. We suggest a stepwise maturation from a non-anti-DNA reactive B cell to an anti-dsDNA autoreactive B cell.

We conclude that impaired clearance in early phases of apoptosis leads to a secondary necrotic status of the cells. Danger signals are released; modified autoantigens are accessible, favouring an autoimmune reaction.

Introduction

Transient autoimmunity is a natural feature present in all human beings. We are hit by environmental factors and infections and also have several genetic predispositions. However, autoimmunity only gets chronic when a certain threshold of activation of the immune system is achieved. The precise development of the chronic autoimmune disease systemic lupus erythematosus (SLE) is still unclear; however, the aetiopathogenesis has been shown to be a multifactorial event (reviewed in [1]). Genetic predisposition and the influence of female sex hormones as well as environmental factors, like infections and UV exposition, are assumed to contribute to the aetiology of this multisystem disease [2], [3], [4]. Autoantibody synthesis against nuclear constituents is the main immunological characteristic of SLE [5]. Increased apoptosis and impaired clearance functions for dying cells may explain accumulation of nuclear autoantigens in various tissues of a subgroup of patients with SLE. We analysed the presence of apoptotic material in lymph nodes from SLE patients and in the skin of patients with cutaneous lupus erythematosus (CLE).

An impaired phagocytic activity for yeast of macrophages from about 50% of patients with SLE was observed many years ago [6]. We described that the phagocytosis of autologous apoptotic material was also disturbed in approximately half of the peripheral blood mononuclear cell (PBMC) cultures form patients with SLE [7]. Monocytes isolated from SLE patients also showed alterations involving increased apoptosis rates and reduced expression of surface molecules participating in the uptake process [8], [9]. A further hint that cellular defects contribute to impaired clearance is given by macrophages differentiated from CD34 positive stem cells of the peripheral blood from SLE patients [10]. Most of the SLE stem cell-derived macrophages showed a different morphology than those generated from healthy donors; they were smaller, and died early (L.E. Munoz et al., submitted for publication).

In addition to the cellular components, serum has an important impact on the phagocytic process [11]. Complement factors are known to act as strong promoters of phagocytosis by macrophages of late apoptotic cells [12], [13], [14]. The complement component C1q was found to be necessary for an effective uptake of degraded chromatin by monocyte-derived phagocytes [15] and acts together with soluble IgM in the clearance of dying cells [16]. Further factors that have a phagocytosis promoting potential are e.g. α2-HS glycoprotein, histidine-rich glycoprotein, and the pentraxin C-reactive protein [17], [18], [19]. Prostaglandins lead to a rapid activation of cAMP signalling pathways and thereby could have a decreasing influence on the phagocytosis of dying cells [20]. We found that sera from patients with SLE exert a broad range of phagocytosis promoting activities on macrophages from healthy donors (Grossmayer at al., under review).

The results presented in this article give important hints that persisting clearance defects are very closely associated with the development of chronic nuclear autoimmunity. Apoptosis can progress in the body and the cells enter late stages of apoptotic cell death, including secondary necrosis. Due to the loss of membrane integrity, potential intracellular autoantigens become accessible. The immunological consequence of the deficient clearance is the challenge of B and T cell tolerance in the body [21].

Section snippets

Patients

All patients fulfilled the American College of Rheumatology 1997 revised criteria for the classification of SLE [22], [23]. The diagnosis and subclassification of CLE were based on clinical and histological criteria and on phototesting results as well as on serologic abnormalities [24]. Institutional guidelines on the use of human subjects were followed. Twenty millilitres of heparinised whole blood was collected by venipuncture and processed within 2 h after collection for the phagocytosis

Phagocytic cells in whole blood of SLE patients show a decreased engulfment of polystyrene beads

In order to get close to the in vivo situation in examining clearance defects we established a whole blood phagocytosis assay where cellular as well as humoral components are present. Fresh blood from SLE patients was incubated with various particulate targets. After a fixation step, the uptake was monitored by flow cytometry. Specific engulfment of albumin- and polyglobin-coated beads was detectable for the granulocyte as well as for the monocyte population at 37 °C. Granulocytes in about 60%

Discussion

SLE is a very heterogeneous autoimmune disease. Shortage of serum constituents or the presence of pathologic factors possibly contributes to the development of SLE. Relative deficiency of pentraxin proteins like C-reactive protein (CRP) [31], reduced activity and levels of DNase I in serum [32] and complement defects [33], [34] are implicated in the pathogenesis of SLE. C1q and DNase I cooperate in the degradation of chromatin derived from necrotic cells [15]. A large amount of chromosomal DNA

Acknowledgements

This work was supported by Deutsche Forschungsgemeinschaft SFB 643 (project B5), by the Interdisciplinary Centre for Clinical Research (IZKF) (project numbers A4 and N2) at the University Hospital of the University of Erlangen-Nuremberg, by the Programme Alban, the European Union Program of High Level Scholarships for Latin America, scholarship no. E04D047956VE to L.E.M., and by the European Commissions [E.U. (QLK3-CT-2002-02017_APOCLEAR)]. S.F. and K.S. are supported by the DFG research

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