Microparticles as biomarkers in autoimmunity: from dust bin to center stage

Microparticles are small membrane-bound vesicles released from activated and dying cells. As shown in a study of primary Sjogren's syndrome, systemic lupus erythematosus and rheumatoid arthritis, levels of microparticles in the blood, as measured by a solid-phase prothrombinase assay or flow cytometry, are increased with autoimmunity. Among patients with these conditions, however, particle numbers were inversely related to disease activity and levels of the enzyme secretory phospholipase A2 that can digest membrane lipids and perhaps cause particle loss. These findings suggest microparticles as novel biomarkers for autoimmunity, with levels reflecting events leading to their loss as well as production

Antinuclear antibodies in healthy people: the tip of autoimmunity's iceberg?

Antinuclear antibodies (ANAs) are venerable biomarkers for assessing the diagnosis and prognosis of patients with autoimmunity. While closely associated with diseases such as systemic lupus erythematosus, ANA expression occurs commonly in healthy people. The basis for this expression is unknown, although it may reflect features of the assays for antibody detection or intrinsic immunological disturbances in otherwise normal individuals. Like autoimmunity itself, ANA expression is more common among women than men, pointing to an important determinant of these responses. Future research will clarify the mechanisms of ANA expression and the utility of current assays as antecedent and screening biomarkers

Developments in the scientific understanding of lupus

Systemic lupus erythematosus is a systemic autoimmune disease characterized by the production of antinuclear antibodies (ANAs). Recent research into human and murine lupus suggests that disease susceptibility results from genetic polymorphisms regulating immune responses as well as impairing the clearance of apoptotic cells. Because the products of dead cells, including nucleic acids, have immunologic activity, this situation can promote antigen-driven ANA responses. Furthermore, immune complexes of ANAs can drive the production of proinflammatory cytokines, inducing the 'interferon signature', and intensifying disease. Together, these findings point to new genetic and immunologic markers of disease as well as targets for new therapies

The central role of nucleic acids in the pathogenesis of systemic lupus erythematosus [version 1; peer review: 3 approved]

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease whose pathogenesis can be conceptualized by a model based on a central role for immune complexes (ICs) between antinuclear antibodies and nucleic acids. According to this model, ICs can promote pathogenesis by two main mechanisms: deposition in the tissue to incite local inflammation and interaction with cells of the innate immune system to stimulate the production of cytokines, most prominently type 1 interferon. The latter stimulation results from the uptake of DNA and RNA in the form of ICs into cells and subsequent signaling by internal nucleic acid sensors for DNA and RNA. These sensors are likely important for the response to intracellular infection, although they may also be triggered during cell stress or injury by DNA or RNA aberrantly present in the cytoplasm. For IC formation, a source of extracellular DNA and RNA is essential. The current model of SLE posits that cell death is the origin of the nucleic acids in the ICs and that impairment of clearance mechanisms increases the amount of nuclear material in the extracellular space. This model of SLE is important since it points to new approaches to therapy; agents targeting interferon or the interferon receptor are examples of therapeutic approaches derived from this model. Future studies will explore novel biomarkers to monitor the operation of these mechanisms and to elucidate other steps in pathogenesis that can be targeted for therapy

The role of innate immunity in the induction of autoimmunity,”

The autoimmune diseases are a diverse group of conditions characterized by abnormal B and Tcell reactivity in association with autoantibody production. Among these diseases, systemic lupus erythematosus (SLE) is notable for the expression of antibodies to DNA, with these antibodies representing diagnostic markers. While mammalian DNA is immunologically inert, DNA from bacteria can potently stimulate the innate immune system, activating both toll-like receptors (TLRs) as well as non-TLR internal receptors. Since the sera of normal humans contain antibodies specific for bacterial DNA, this molecule appears to be immunogenic during infection. In pre-autoimmune mice, immunization with bacterial DNA can induce anti-DNA autoantibody production, suggesting a role in initiating this response. The immune properties of DNA are mutable, however, since mammalian DNA can acquire immunological activity when bound to certain proteins or anti-DNA antibodies to form immune complexes. In SLE, these immune complexes can drive the production of interferon by plasmacytoid dendritic cells, thereby intensifying autoimmunity. Together, these observations suggest that DNA can induce innate as well as adaptive immune responses and promote the pathogenesis of SLE because of its intrinsic immunostimulatory activity