The picture of immune senescence in inflammatory diseases

Abstract

The immune system, as complex and plastic as it is, requires adequate cooperation between multiple internal and external cofactors with respect to each immune cell-subset. Consistent with chronic inflammation, immune cells undergo various challenges in attempt to dispose and neutralize pathogens and inflammatory triggers. In the meanwhile, immune cells secrete pro-inflammatory mediators and cytokines. Also, the immune cells undergo damage on account of i.a. phagocytosis of the pathogens. Not to forget, immune cells are contrived to adapt upon varying tissues and organ substances while migrating to reach the site of inflammation. These circumstances force the immune cells to proliferation c.q. cell division and DNA/cellular repair. Like all dividing eukaryotic cells with end replication limitation, immune cells also have a restricted number of cell divisions that they can undergo in order to proliferate and or repair. With each cycle of cell division, DNA loses parts of its protecting telomeres eventuating in completely eroded telomeres that leave the coding DNA unprotected and eventuates DNA loss. Critically eroded telomeres initiate a sustained form of signalling with respect to the damaged DNA that will predict the faith of the cell depending on its characteristics and type. Finally, increased cell-turnover that accelerates telomere erosion, enhances the state of immune senescence. The main hypothesis of this thesis is that patients with chronic immune mediated diseases have an “aged immune system” in terms of replicative senescence. In other words, we hypothesize that chronic inflammation paints the phenomenon of inflamm-ageing. The picture of an aged immune system however, demonstrates cells with multiple morphological and behavioural deviations that are incapable of adequate and appropriate functioning. Consequently, inflamm-ageing and immune deficiencies could eventuate in the development of various systemic and local disorders with a chronic inflammatory signature. We elaborated on some of the chronic inflammatory disorders, with respect to inflamm-ageing. This thesis touches upon Birdshot uveitis, Fibromyalgia, Systemic Sclerosis, RA and Gout. The main future perspective of this thesis relies on the detailed insights on potential biomarkers such as telomere length that could potentially be applied as a laboratory test for patients with inflammatory disorders and could indicate an enhanced state of immune senescence, or a marker for cumulative inflammation over time. Accordingly, individuals with an aged immune biology that are more susceptible to develop senescence-associated disease, can receive adequate and prelude directions and treatment. The necessity to gain a better understanding on the available indications might unravel potential novel targeting possibilities. Even the research in this regard is quite young and in early stages. Although the gained knowledge could be translated in treatment strategies that might diminish the prevalence of ageing associated diseases, prolong healthy ageing and increase the quality of life in ageing individuals and concomitant burden of economic health costs.