Although drug development has advanced for autoimmune diseases, many current therapies are hampered by adverse effects and the frequent destruction or inactivation of healthy cells in addition to pathological cells. Targeted autoimmune therapies capable of eradicating the rare autoreactive immune cells that are responsible for the attack on the body's own cells are yet to be identified. This Review presents a new emerging approach aimed at selectively destroying autoreactive immune cells by specific activation of tumour necrosis factor receptor 2 (TNFR2), which is found on autoreactive and normal T lymphocytes, with the potential of avoiding or reducing the toxicity observed with existing therapies.

The regulatory cytokine tumor necrosis factor (TNF) exerts its effects through two receptors: TNFR1 and TNFR2. Defects in TNFR2 signaling are evident in a variety of autoimmune diseases. One new treatment strategy for autoimmune disease is selective destruction of autoreactive T cells by administration of TNF, TNF inducers, or TNFR2 agonism. A related strategy is to rely on TNFR2 agonism to induce T-regulatory cells (Tregs) that suppress cytotoxic T cells. Targeting TNFR2 as a treatment strategy is likely superior to TNFR1 because of its more limited cellular distribution on T cells, subsets of neurons, and a few other cell types, whereas TNFR1 is expressed throughout the body. This review focuses on TNFR2 expression, structure, and signaling; TNFR2 signaling in autoimmune disease; treatment strategies targeting TNFR2 in autoimmunity; and the potential for TNFR2 to facilitate end organ regeneration.

Excess levels of tumor necrosis factor-alpha (TNF-alpha) have been associated with certain autoimmune diseases. Under the rationale that elevated TNF-alpha levels are deleterious, several anti-TNF-alpha therapies are now available to block the action of TNF-alpha in patients with autoimmune diseases with a chronic inflammatory component to the destructive process. TNF-alpha antagonists have provided clinical benefit to many patients, but their use also is accompanied by new or aggravated forms of autoimmunity. Here we propose a mechanistically based hypothesis for the adverse events observed with TNF-alpha antagonists, and argue for the opposite therapeutic strategy: to boost or restore TNF-alpha activity as a treatment for some forms of autoimmunity. Activation defects in the transcription factor nuclear factor kappaB leave autoreactive T cells sensitive to TNF-alpha-induced apoptosis. Treatment with TNF-alpha, by destroying autoreactive T cells, appears to be a highly targeted strategy to interrupt the pathogenesis of type 1 diabetes, lupus and certain forms of autoimmunity.

Sex hormones have long been implicated in autoimmune diseases because women account for 80% of cases. The mechanism of hormonal action in autoimmunity is unknown. Drawing on genetic studies of autoimmune disease, this article discusses how both genes and sex hormones may exert their effects through the same general mechanism, dysregulation of transcription factor NF-kappaB, an immunoregulatory protein. Gene and hormone alterations of the NF-kappaB signaling cascade provide a unifying hypothesis to explain the wide-ranging human and murine autoimmune disease phenotypes regulated by NF-kappaB, including cytokine balance, antigen presentation, lymphoid development, and lymphoid repertoire selection by apoptosis.