oa Editorial [Hot Topic: Aging and Immune-Mediated Diseases (Guest Editors: Christian Dejaco, Christina Duftner and Michael Schirmer)]

Due to the ‘baby boomers’ and health care advances, the aged population of Western countries is continuously growing [1]. Thus diagnosis and treatment of age-related diseases becomes an ever greater priority, for immune-mediated diseases translating into a need to better understand immunological dysfunction and its contribution to disease. The aging immune system, collectively termed immunosenescence, demonstrates a reduced capacity to mount a robust immune response and differentiate between self and foreign antigens. Immunosenescence manifests itself at several levels, from the whole organism to individual cells [2]: At the organism level, immunosenescence results in an increased susceptibility to age-related diseases including infections, cancer and autoimmune diseases. Besides, immunosenescence is associated with an impaired humoral response to vaccines, with suboptimal vaccination protection [3]. Biomarkers predicting the success of vaccination in aged individuals would improve current vaccination practice but such biomarkers have not been introduced into clinical routine yet. In this journal D. Herndler- Brandstetter et al. report that the presence of end-stage differentiated CD8+CD28- T-cells is associated with a reduced antibody production, whereas high levels of CD45RO+CD28+IL-2RαdimCD8+ T-cells may indicate preserved immuno-competence. As infectious diseases cause high morbidity and mortality in the elderly, this topic has to be considered as a major public health burden for the future [4]. At the cell population level, immune-aging is characterized by decreased function of progenitor and early differentiated cells as well as by the accumulation of highly specialized, senescent immune cells [5-7]. The involution of primary lymphoid organs and defects in the production of early lymphoid precursors contribute to these changes [8]. Other mechanisms such as lifelong encounter of the immune cells with acute and chronic pathogens further accelerate the progression of immunosenescence [4]. Age-associated thymic involution for example results in a significant loss of its capacity to generate and export new T-cells. Homeostatic equilibrium is then maintained by self-replication of T-cells in the periphery [8]. These peripheral mechanisms, however, are not unlimited: Telomere lengths decrease with each cell division and proliferative capacity of T-cells exhausts when telomere lengths are reduced to a critical level known as the “Hayflick limit” [9]. Chronic virus infections such as Human Immunodeficiency Virus (HIV) or Cytomegalovirus (CMV) accelerate peripheral proliferation of T-cells, and affected patients exhibit an aged T-cell population very early in life [4, 10]. M. Prelog and C. Duftner et al. discuss the role of early thymic failure for the development of autoimmune diseases, including juvenile idiopathic arthritis and rheumatoid arthritis [8, 11]. It is still a matter of debate, whether premature thymus dysfunction and T-cell senescence are the cause or consequence of autoimmunity. The observation that premature immune-aging also occurs in healthy individuals bearing the HLA-DR4 gene, the strongest genetic risk factor for rheumatoid arthritis, strongly supports the concept that immunosenescence precedes the onset of disease [12]. On this background immune-aging leads to phenotypical and functional changes of both, innate and adaptive immune cells. T-cell senescence for example is characterized by the down-regulation of the costimulatory molecule CD28, de-novo expression of innate immune receptors and gain of new effector functions [8]. Clinically, CD8+CD28- T-cells predict a low vaccine response (as outlined above) and are associated with an increased 2-year mortality in aged Swedish individuals [4]. Besides, higher prevalences of CD4+CD28- T-cells in the peripheral blood are linked with a worse outcome of autoimmune diseases and contribute to plaque instability in patients with coronary artery disease [8]. Concerning age-associated changes of innate immune cells, S. Mahbub et al. discuss functional changes of macrophages, neutrophils, dendritic cells, NK- and NKT-cells in aged compared to young individuals [13]. They report that aged innate immune cells have a lower capacity to clear invading pathogens as a result of lower chemotactic and phagocytosis activity. Besides, aged innate immune cells sub-optimally stimulate adaptive immune responses because of a decreased production of pro-inflammatory cytokines and defects in antigen presentation. Innate immune cells from aged individuals additionally show a lower activity after stimulation compared to young people, even though basal activation seems to be higher. The high basal activation of these cells possibly explains the common observation of high systemic levels of pro-inflammatory cytokines in the elderly. Depletion of CD28- T-cells in autoimmune diseases in order to interrupt chronic inflammation and increase homeostatic space for naive T-cells is proposed by C. Duftner et al. [8]. Such an approach, however, is critical and should be paralleled by increment of thymic output and survival of peripheral T-cells, as depletion of circulating aged T-cells drive into excessive autoproliferation aimed at re-filling-up peripheral niches. In summary, immunosenescence affects the innate and the adaptive immune system and manifests at different levels of the organism. Individuals with an aged immune system have a higher susceptibility to infections and autoimmune diseases and show a reduced immune response to vaccines. More detailed understanding of the underlying age-related alterations of the immune system should now pave the way to develop therapeutic strategies to delay, prevent or reverse immunosenescence; thereby improving quality of life in old age and new treatment regimens for patients with autoimmune diseases.