Systemic immune response in young and elderly patients after traumatic brain injury

Abstract

Background Traumatic brain injury (TBI) is a leading cause of death and long-term disability worldwide. In addition to primary brain damage, systemic immune alterations occur, with evidence for dysregulated immune responses in aggravating TBI outcome and complications. However, immune dysfunction following TBI has been only partially understood, especially in the elderly who represent a substantial proportion of TBI patients and worst outcome. Therefore, we aimed to conduct an in-depth immunological characterization of TBI patients, by evaluating both adaptive (T and B lymphocytes) and innate (NK and monocytes) immune cells of peripheral blood mononuclear cells (PBMC) collected acutely (< 48 h) after TBI in young (18–45 yo) and elderly (> 65 yo) patients, compared to age-matched controls, and also the levels of inflammatory biomarkers. Results Our data show that young respond differently than elderly to TBI, highlighting the immune unfavourable status of elderly compared to young patients. While in young only CD4 T lymphocytes are activated by TBI, in elderly both CD4 and CD8 T cells are affected, and are induced to differentiate into subtypes with low cytotoxic activity, such as central memory CD4 T cells and memory precursor effector CD8 T cells. Moreover, TBI enhances the frequency of subsets that have not been previously investigated in TBI, namely the double negative CD27- IgD- and CD38-CD24- B lymphocytes, and CD56dim CD16- NK cells, both in young and elderly patients. TBI reduces the production of pro-inflammatory cytokines TNF-α and IL-6, and the expression of HLA-DM, HLA-DR, CD86/B7-2 in monocytes, suggesting a compromised ability to drive a pro-inflammatory response and to efficiently act as antigen presenting cells. Conclusions We described the acute immunological response induced by TBI and its relation with injury severity, which could contribute to pathologic evolution and possibly outcome. The focus on age-related immunological differences could help design specific therapeutic interventions based on patients’ characteristics.

High-dimensional proteomic analysis for pathophysiological classification of Traumatic Brain Injury

“…Overall, we show that studying acute patterns of plasma protein expression can help quantify focal injury and identify potential processes, including neurodegeneration and inflammation, that are important in human TBI pathophysiology. This provides a basis for more rational classification of TBI based on pathophysiology, We found acutely raised levels of inflammatory proteins IL6, IL10, IL1b, IL8, IL15, IL16, serum amyloid A (SAA1) and CCL2 after TBI, in line with prior studies 20,21,30–34,22–29 . In contrast to many prior studies, we recruited a non-TBI trauma control cohort, and thus demonstrate that changes in plasma levels of IL8, SAA1 and IL15 may actually reflect a general injury response.…”

“…IL16 is produced by CD4+ and CD8+ cells, including microglia in the brain, and acts as a chemokine and activating signal for cells expressing the CD4 receptor, such as Tlymphocytes, monocytes and macrophages [37][38][39] . Peripheral CD4+ T-lymphocyte activation is reported in acute human TBI 21 , while experimental studies have found that CD4+ T-lymphocytes can increase injury severity 40 . Increased IL16 expression is seen in experimental neuroinflammation, as a result of infiltrating immune cells and microglial activation 41 .…”

Systematic analysis of MASP-1 serves as a novel immune-related biomarker in sepsis and trauma followed by preliminary experimental validation

“…Previous research has shown that sepsis-associated apoptosis of CD8+ T cells leads to lymphopenia and immunosuppression as well as increased susceptibility to secondary infections, in late-stage sepsis patients ( 32 ). A recent study by Magatti et al ( 33 ) found that TBI affected the differentiation ability of CD8 T cells in PBMCs, which are induced to differentiate into low cytotoxicity subtypes, such as memory-precursor effector CD8 T cells, leading to additional challenges, especially in the case of infections. Altogether, these results indicate that several immune cells, especially CD8 T cells, neutrophils, and macrophages, are involved in MASP-1-mediated trauma and sepsis.…”

Translating from mice to humans: using preclinical blood-based biomarkers for the prognosis and treatment of traumatic brain injury

“…Similarly, few studies have examined circulating biomarker changes in geriatric or pediatric TBI models. This is particularly noteworthy considering that the elderly population registers the highest frequency of TBI-related hospital admissions (135) and have significantly poorer outcomes compared to young patients with similar injury severity (136). This pattern is mirrored in aged TBI mice (137).…”

“…This pattern is mirrored in aged TBI mice (137). Notably, blood NfL levels exhibit an age-related increase in TBI patients, hinting at age-linked vulnerability to neuronal damage (136). Determining whether this susceptibility is attributed to age itself or to age-related comorbidities presents challenges in the clinical context.…”