Here, we will discuss the importance of the sub cellular localization of proteins (intracellular vs. extracellular) for their antigenicity.To this end, we will discuss the aberrations in protein trafficking and transport-as well as cellular damage, with regard to cell death and necrosis-that can lead to mix-ing of compartments that normally are separated in a healthy organism. Thus, we introduce a new hypothesis in biology, wherein the localization of a protein plays a causal role in its antigenicity. A change in the intracellular or extracellular localization can cause an immune reaction, which, if protein transport dysfunction or cell death is continually present over a longer time-period, it will lead to the development of an autoimmune disease.According to our hypothesis, no defect is necessary within the immune system when an autoimmune disease appears. Aspects of the pathogenetic principle presented here have already been described.