George C Tsokos is a professor of medicine and molecular cell biology, and Director of the Division of Immunology and Rheumatology at the Uniformed Services University of the Health Sciences in Bethesda, MD, USA. He is also Chief of the Department of Cellular Injury at the Walter Reed Army Institute of Research in Silver Spring. Systemic lupus erythematosus (SLE) is an autoimmune disorder that mainly affects women of childbearing age. The disease is a heterogeneous syndrome with a complex pathogenesis. Clinically, many organs can be affected, including the skin and kidneys, and the central nervous, musculoskeletal, and haematopoietic systems. Genetic, environmental, hormonal, and immunoregulatory factors are involved in its pathogenesis. Various genes contribute to the expression of SLE and most are clustered in the 1q and 6p chromosomes. Environmental factors include ultraviolet light, certain medications, and infections. Hormonal factors (oestrogens) are important too and are probably involved in regulation of the transcription of genes central to the expression of SLE. Immune system abnormalities seen in SLE are multiple and diverse (figure). Central among them is the presence of overactive B lymphocytes, which are responsible for the production of autoantibodies. Some of these autoantibodies contribute to abnormalities associated with SLE, whereas others are disease markers. B lymphocytes are controlled by T cells, which provide cognate help by engaging co-stimulatory pairs of molecules on the surface of interacting immune cells. Increased production of cytokines 6 and 10 further enhances B-cell function. Simultaneously, in response to antigens such as tetanus toxoid and viruses, the T cells display decreased cellular cytotoxic responses and decreased production of interleukin 2. These latter defects might account for the high rate of infections. Secreted autoantibodies can be deposited in tissues, instigating inflammation. They might also form immune complexes with nuclear antigens, which are released in excess because of abnormal apoptosis of various cell types. Because of defects in the receptors for complement and the Fc portion of immunoglobulin, the complexes formed are not cleared. Instead, they are deposited in tissues—ie, kidneys and nervous system—resulting in inflammation. Immunocompetent cells respond to external antigens through a series of biochemical processes, known as cell signalling. After engagement of the antigen receptor, T and B lymphocytes from SLE patients respond briskly by hyperphosphorylating many cytosolic components and raising their concentration of free calcium. These reactions arise despite the low concentrations of the T-cell receptor ζ chain, whose function seems to be taken over by another member of the ζ chain group of proteins, the γ chain of the Fc receptor. Furthermore, concentrations of some proteins and the function of certain kinases, such as protein kinase A, are decreased, whereas the activity of others such as protein kinase PKR, which is involved in the phosphorylation of translation initiation factors, is increased. Early signalling abnormalities are followed by altered activation of transcription factors and abnormal gene transcription. Certain genes are transcribed at low rates (the T-cell receptor ζ chain and interleukin-2 genes) and others are transcribed at increased rates (the genes for the γ chain of the Fc receptor for IgE and the CD40 ligand). Defects have been identified in the expression or activation of transcription enhancers and repressors—ie, the concentration of the transcription enhancer nuclear factor kB is decreased, whereas concentrations of the transcription repressor cyclic AMP-responsive element modulator are increased. Characterisation of early and late signalling aberrations is important to understand the abnormal function of SLE lymphocytes and to develop specific therapeutic strategies to normalise cell biochemistry and function. Some of the molecular abnormalities in patients can be linked to known defects. For instance, heightened calcium responses can explain the increased expression of CD40 ligand and other molecules whose expression depends on calcium-controlled transcription factors. Increased expression of CD40 ligand on the surface of T cells is apparently responsible for the increased interaction between T cells and B cells that readily express CD40. Corticosteroids and cytotoxic drugs are used to treat SLE. These, along with improvements in patient care and ability to treat infections, have increased life expectancy. Advances in our understanding of the deregulated immune system might lead to treatments that will further decrease SLE mortality and morbidity. These efforts include: (1) disruption of the increased cooperation between immune cells and, therefore, suppression of production of autoantibodies; (2) blocking the action of cytokines such as interleukin 10, to promote B cell overactivity; (3) restoring anergy to self-antigens by modulating the antigen receptors of the surface of anti-double stranded DNA producing B cells; (4) controlling increased complement activation, to limit organ injury mediated by the process; and (5) restoring a normal immune system by reinfusing autologous stem cells after ablation of the existing immune system.