Chronic inflammation as a manifestation of defects in immunoregulatory networks: implications for novel therapies based on microbial products.

Based on a unifying theory presented here, it is predicted that the immune defects resulting in chronic inflammation rather than effective immune responses could be rectified by the therapeutic use of agents prepared from micro-organisms. With appropriate molecular patterns, these should be able to induce protective immunoregulatory networks or to reprogramme defective ones. In contrast to acute inflammation, chronic inflammation appears to have no beneficial role, but is a state of sustained immune reactivity in the presence or progression of a disease process. This results in an escalating cycle of tissue damage followed by unproductive tissue repair, breaks in self-tolerance, malignant transformation or deleterious changes in tissue morphology and function. Such inappropriate immune reactivity is an underlying characteristic, either in initiation or maintenance, of a diverse range of disease states including chronic infection, autoimmunity, allergy, cancer, vascular disease and metabolic alterations. Evidence is presented that the inappropriate immune reactivity is due, at least to some extent, to failures in the establishment of immunoregulatory networks as a result of hygiene-related factors. Such networks are the result of activation of antigen-presenting cells, principally dendritic cells, by molecular patterns of micro-organisms encountered sequentially during life and establishing the 'biography' of the immune system.