Whereas the pathogenesis of some autoimmune diseases, such as rheumatoid arthritis and psoriasis, is associated with tumour-necrosis factor (TNF), other diseases such as systemic lupus erythematosus (SLE) and type 1 diabetes are thought to involve interferon-α (IFN-α). Jacques Banchereau and colleagues have studied the reciprocal relationship between these two cytokines in autoimmune disease to explain the finding that treatment of rheumatoid arthritis with TNF antagonists, although an effective therapy for many patients, can induce features of SLE, such as an increased titre of nuclear-specific antibodies.

Peripheral-blood mononuclear cells (PBMCs) isolated from paediatric patients with systemic-onset juvenile arthritis and treated with TNF-specific antibodies were shown to express a set of genes that are known to be upregulated by IFN-α. Because inhibition of TNF is associated with increased transcription of IFN-α-regulated genes, TNF might usually function to downregulate IFN-α responses. Indeed, adding TNF to PBMCs that were isolated from healthy donors and cultured with influenza virus inhibited the production of IFN-α. This was shown to be the result of targeting immature plasmacytoid dendritic cells (pDCs), which are one of the main sources of IFN-α in vivo. pDCs were cultured in vitro from CD34+ haematopoietic stem cells (HSCs) and then exposed to influenza virus; addition of TNF to the culture inhibited IFN-α production by up to 40%, by stimulating pDC maturation. Conversely, pretreatment of pDCs in vitro with TNF-specific antibody resulted in threefold higher levels of IFN-α when the pDCs were re-exposed to influenza virus, by inhibiting virus-induced pDC maturation. Finally, TNF was also shown to block the generation of pDCs, but not myeloid DCs, from HSCs.

These results led the authors to conclude that endogenous TNF controls the production of IFN-α by immature pDCs by inhibiting the generation of these cells and by stimulating their maturation. Therefore, decreased levels of TNF in patients treated with TNF antagonists will result in increased IFN-α levels. This is thought to lead to SLE-like symptoms through stimulating the maturation of myeloid DCs, which can then activate, rather than tolerize, autoreactive T and B cells. This cross-regulation between TNF and IFN-α is supported by the fact that patients with SLE have increased levels of circulating soluble TNF receptors, which correlate with disease activity.