Role of TNF/TNFR in autoimmunity: specific TNF receptor blockade may be advantageous to anti-TNF treatments.

Deregulated TNF production, be it low or high, characterizes many autoimmune diseases. Recent evidence supports a dualistic, pro-inflammatory and immune- or disease-suppressive role for TNF in these conditions. Blocking TNF in autoimmune-prone chronic inflammatory diseases may, therefore, lead to unpredictable outcomes, depending on timing and duration of treatment. Indeed, blockade of TNF in human rheumatoid arthritis or inflammatory bowel disease patients, although so far impressively beneficial for the majority of patients, it has also led to a significant incidence of drug induced anti-dsDNA production or even in manifestations of lupus and neuro-inflammatory disease. Notably, anti-TNF treatment of multiple sclerosis patients has led almost exclusively to immune activation and disease exacerbation. We discuss here recent evidence in murine disease models, indicating an heterogeneity of TNF receptor usage in autoimmune suppression versus inflammatory tissue damage, and put forward a rationale for a predictably beneficial effect of 'anti-TNFR' instead of 'anti-TNF' treatment in human chronic inflammatory and autoimmune conditions.