1.6 The Immune Risk Phenotype (IRP)

All changes that occur in immunosenescence mentioned above lead to the development of the Immune Risk Phenotype (IRP), characterized by the inversion of the proportion of CD4+/CD8+ cells (increase in CD8+ and decrease in CD8-), reduction in lymphocytes B, Cytomegalovirus (CMV) seropositivity, increased production of pro-inflammatory cytokines, decreased responsiveness to IL-2 and late differentiation of CD8+CD28-CD27- cells (WIKBY et al., 2005). IRP markers were delineated in two longitudinal studies called OCTO and NINTH (WIKBY et al., 2005), where their predictive power of survival of elderly people over the next 4 years was evaluated. Combined with cognitive impairment metrics, the IRP was able to predict 58% of observed deaths (WIKBY et al., 2005).

‌ This phenotype has a characteristic increase in the production of IL-1, IL-4, IL-6 and IFN-gamma, cytokines that regulate B cell differentiation. The increase in cytokine secretion, correlated with the impact of CMV infection, is one of the main culprits for unsuccessful ageing. In addition, a reduced proliferative capacity is observed in T cells specific for CMV infection associated with telomere shortening, which leads to genomic instability, activation of DNA damage repair processes and triggers cell cycle arrest and/or apoptosis. As a result, not all memory T cells differentiate in the same way, and there may be an expansion of a specific cell subgroup, which leads to aggravation in the clinical scenario with an increase in infectious diseases and neoplasms (WEISKOPF; WEINBERGER; GRUBECK-LOEBENSTEIN, 2009).

‌ In general, the changes observed in the immune system can cause deficiencies in innate and adaptive immunity, leading to a greater susceptibility of the elderly to autoimmunity, cancer and reducing their defensive capacity against invading microorganisms and pathogens. The fundamental role that immunosenescence plays in the ageing process is evident, making it essential to study the behaviour of the immune system throughout life to identify mechanisms underlying its remodelling which can influence the pace and quality of the ageing process. In addition, it is also important to distinguish cause-and-effect relationships between the mechanisms of the immune system that change in immunosenescence, identifying which ones reflect primary problems, that is, mechanisms that change homeostasis due to its response to some stress, and which are secondary: mechanisms that change due to an attempt to return to homeostasis, which was lost due to primary problems.

‌ By understanding the mechanisms involved in immunosenescence and the dynamics between processes that are disturbed during life, it is possible to identify biomolecular targets that can be manipulated through pharmacological interventions, which could alleviate and/or regulate the harmful characteristics of a damaged immune system. Significant improvements in the immune system could even positively influence the ageing process itself, increasing the chances of the elderly to remain autonomous for as long as possible, with quality of life and free from disease.