Cross-regulation between type I IFN and TNFα. (a) The original hypothesis proposes that both cytokines can be regarded as opposite vectors. Whereas the sum of both vectors normally yields an equilibrium point allowing protective immunity, disturbance of this balance beyond a certain threshold may contribute to a pathological state promoting autoimmunity, allergy, or inflammation. A shift towards the TNFα arm may create a permissive environment for TNF-mediated autoimmunity in rheumatoid arthritis (RA). In contrast, when the type I IFN arm prevails, IFN-driven autoimmunity as observed in systemic lupus erythematosus (SLE) may occur. (b) An alternative hypothesis: in homeostatic conditions, type I IFN and TNFα are influencing each other's levels but this balance is lost in a pathological condition. (c) An alternative hypothesis: type I IFN plays an important role in the initiation of autoimmunity, while the role of TNFα increases during the secondary inflammatory phase.