Rheumatologic diseases display a multi causal etiology influenced by genetic and environmental factors. All diseases have been defined clinically and often the organ specific pathology of the patient determines the name of the disease. Therefore, the many rheumatologic diseases must be considered as a variety of different conditions leading to a more or less unified pathology. Many roads lead to Rome. In the last years of research it became increasingly clear that a long-lasting production of a single particular cytokine drives the rheumatologic pathologies of arthritis tumor necrosis factor-α (TNF-α) or systemic lupus erythematosus (SLE) [alpha-interferon (αIFN)]. The reason of the induction turned out to be less important since transgenic expression or TNF-α and injection of αIFN in otherwise healthy mice led to arthritis and glomerulonephritis, respectively. Most importantly, even very low levels of the cytokines suffice in causing pathology, if they are permanently present in the animal. This is in discordance with the thesis of Paracelsus “the dose makes the poison” and more reflects the aphorism “constant dripping wears away the stone!” In the case of a long-lasting low-level threat the body seems to be unable to completely shut down the inflammation and go into a normal state, in which tissue repair is usually performed. Tissue destruction and repair may become balance causing pathologic damage. Even small amounts of waste can cause spurious rotten stench, if they persist permanently.
There are many conditions leading to chronic stress. Among them is the problem of how to properly cope with infectious agents and with waste disposal in general and with clearance of apoptotic or necrotic cells in particular. What does it mean “the clearance of dying or dead cells?” This term not only refer to proper phagocytosis, but also means that the removal process is not accompanied by inflammation. The permanent presence of cellular debris even in small amounts may be able to cause the chronic production of inflammatory mediators that initiate and maintain the devastating pathology of rheumatologic diseases. A similar effect of small quantities can be observed when a few drops of milk were spilled on the seat of a car, cause a nasal attack for an almost unlimited time.
The need for pathwayomics or functiomics
Although, as pointed out in the first paragraph, TNF-α or αIFN are able to induce arthritis and glomerulonephritis in healthy mice, respectively, rheumatoid arthritis and SLE are not monogenetic diseases with just the aberrant expression of a single cytokine. Indeed, as shown by genomics and proteomics, in most patients both cytokines are properly regulated. But the patients display disease conditions aberrantly inducing these cytokines by a plethora of often-unknown reasons. I shall discuss this issue exemplarily for the case of an impaired clearance of dying and dead cells.
Any defects affecting the phagocytic receptors, the adaptor proteins or the number of phagocytic cells, the proteins involved in cytoskeletal rearrangement, intracellular signalling, adhesion or membrane stability and many others bear the risk of impairing the function of phagocytosis and consequently, clearance. This is a typical task for the future technical platforms of functiomics.