REVIEW ARTICLE Mod Rheumatol (2005) 15:383–390 © Japan College of Rheumatology and Springer-Verlag Tokyo 2005 DOI 10.1007/s10165-005-0430-x Gerhard E. Grossmayer · Luis E. Munoz · Udo S. Gaipl Sandra Franz · Ahmed Sheriff · Reinhard E. Voll Joachim R. Kalden · Martin Herrmann Removal of dying cells and systemic lupus erythematosus Received: July 29, 2005 / Accepted: August 23, 2005 Abstract Systemic lupus erythematosus (SLE) is a very heterogeneous systemic autoimmune disease, in which autoantibody synthesis against nuclear constituents is the main immunological characteristic. These autoantibodies underwent affinity maturation and isotype switching. Addi- tionally, T-cell tolerance against nuclear autoantigens should be affected in these autoimmune patients. Nuclear material derived from apoptotic and/or necrotic cells may serve as an important source of autoantigens. However, dead and dying cells as well as cellular debris are rapidly removed from tissues by phagocytes without eliciting in- flammation or immune responses under healthy conditions. During apoptosis nuclear components are strongly modified through enzymatic reactions. If these cells are not timely cleared, those autoantigens may be released, taken up, and presented by dendritic cells in tissues or presented by follicular dendritic cells in lymph nodes to T and B cells, respectively. This could be a mechanism for breaking the peripheral self-tolerance. In this article we focus on the deficient clearance of apoptotic cells in SLE patients and its importance in development of this autoimmune disease. Key words Apoptosis · Autoimmunity · Clearance · Necro- sis · Systemic lupus erythematosus (SLE) G.E. Grossmayer · L.E. Munoz · U.S. Gaipl · S. Franz · A. Sheriff · J.R. Kalden · M. Herrmann (*) Institute for Clinical Immunology, Department of Medicine 3, Friedrich-Alexander University of Erlangen-Nuremberg, Glückstrasse 4a, 91054 Erlangen, Germany Tel. +49-9131-85-36345; Fax +49-9131-85-35776 e-mail: martin.herrmann@med3.imed.uni-erlangen.de R.E. Voll IZKF Research Group N2, Nikolaus-Fiebiger Center of Molecular Medicine, Erlangen, Germany G.E.G. and L.E.M. contributed equally to this work. Introduction The immune mechanisms of the pathogenesis of systemic lupus erythematosus (SLE) are still not fully understood. This disease shows a wide array of clinical manifestations resulting from inflammatory reactions in multiple organs. Immunological abnormalities observed in the autoimmune disease SLE are characterized by autoantibody synthesis against nuclear constituents, immune complex deposits in tissues, and complement activation. Antinuclear autoanti- bodies are not exclusively generated in SLE, but also in other autoimmune diseases like scleroderma, rheumatoid arthritis, and Sjögren’s syndrome. Several genetic and envi- ronmental factors as well as infections have been implicated as important elements of the disease (reviewed in Herrmann et al. 1 and Kuenkele et al. 2 ). How intracellular proteins become targets of immune responses is important in understanding the etiology of autoimmune diseases. Anti-double-stranded DNA antibodies (anti-dsDNA) are one of the most important criteria for the diagnosis of the disease. They show high-affinity binding activity in con- trast to low-affinity naturally occurring anti-dsDNA anti- bodies from normal healthy donors (NHD), which did not go through the isotype switch from IgM to IgG or IgA. Affinity maturation of immunoglobulins for the antigen and isotype switching are processes dependent on T-cell help. This takes place in the germinal centers (GCs) of lymphoid tissues. The role of T cells in the development of chronic autoimmunity in SLE is supported by the fact that patients with SLE respond to T-cell specific immunosuppressive drugs like cyclosporin A. 3 Although human DNA is known to be poorly immuno- genic and does not bear T-cell epitopes, DNA–histone com- plexes and nucleosomes are released in SLE patients in high amounts into the circulation. 4,5 The nucleosomes are targets of anti-dsDNA autoantibodies and of anti-histone autoanti- bodies, as shown by enzyme-linked immunosorbent assays with autoimmune sera and monoclonal antibodies. 6,7 Those autoantibodies are predominantly of the IgG isotype and molecular analyses revealed a high degree of somatic muta-