Iris Vallavanatt

Background: Traumatic brain injury (TBI) is mechanical damage to brain parenchyma that causes neuronal death, axonal damage, ischemia, and hemorrhage and can result in secondary injury. This secondary injury results from chronic activation of the inflammatory immune cascade necessary for debris clearance and regeneration and can persist for months to years following TBI. ^1,2 Chronic secondary injury is correlated with increased incidence of neural protein accumulation diseases, traumatic encephalopathies, psychiatric disorders, and multiorgan dysfunction, among other outcomes.^3,4 In America, an estimated 1.7 million people experience TBI, however, these numbers underestimate the real magnitude of TBI and TBI-related injuries because mild to moderate cases often go unreported.² Outcomes of individuals that suffer from TBI vary widely based on mechanism and degree of initial injury as well as patient age, sex, genetic variability, and therapeutic interventions.¹ Therapeutic investigations aim to restrict acute neuroinflammatory responses to the extent needed for debris clearance, promote an anti-inflammatory, regenerative immune state, and prevent chronic neuroinflammation.^1,3

Objective: The progression of the adaptive immune response following TBI is investigated in this review to distinguish between the beneficial and detrimental effects and delineate a potential timeline for therapeutic interventions.

Search Methods: An online inquiry in the PubMed database was conducted from 2017-2023 with the following keywords: “traumatic brain injury”, “adaptive immunity”, “T-cells”, and “B-cells”.

Results: Increased expression of CD8+ T-cells were found to contribute to deleterious neurological and motor effects at various time points post-TBI. Also seen in post-TBI mice was a decrease in CD4+ T-cells, a significant increase in pro-inflammatory cytokine IL-17A, and a decrease in the anti-inflammatory cytokine IL-13.⁵ Macrophages were found to polarize into an M1 phenotype which promotes a pro-inflammatory T1/T17 phenotype post-TBI.⁶ Post-TBI rats that were co-administered brain proteins and probiotics demonstrated decreased CD4+/CD8+ T-cells and an increase in Treg cells, which maintain immune homeostasis and prevent excessive immune responses.⁷ Breach of the blood brain barrier following TBI results in the release of cerebral antigens into circulation. Meningeal lymphatic vessels (mLVs) link the peripheral immune system with the CNS and can prime the adaptive immune response towards an anti-inflammatory state.⁸ Autoantibody production post-TBI requires further investigation but is known to vary between individuals and is associated with worse outcomes.⁹

Conclusion: Th1 and Th17 T-cell polarization as well as the increased proliferation of CD8+ T-cells over CD4+ T-cells create a pro-inflammatory environment that is associated with poor neurological and motor outcomes.^5-7 A preferential shift in T-cell polarization to Treg cells may prevent excessive immune responses and prevent chronic secondary injury.⁶ Therapeutic approaches that downregulate the adaptive immune response after TBI show no improvement in outcomes.⁸ However, potential therapeutics exist in attenuating the pro-inflammatory immune response and promoting an anti-inflammatory immune state. To do this, further studies are needed to precisely delineate the role of the adaptive immune response in post-TBI and account for the highly variable individual response.

Works cited:

1. Needham EJ, Helmy A, Zanier ER, Jones JL, Coles AJ, Menon DK. The immunological response to traumatic brain injury. J Neuroimmunol. Jul 15 2019;332:112-125. doi:10.1016/j.jneuroim.2019.04.005
2. Simon DW, McGeachy MJ, Bayir H, Clark RSB, Loane DJ, Kochanek PM. The far-reaching scope of neuroinflammation after traumatic brain injury. Nat Rev Neurol. Sep 2017;13(9):572. doi:10.1038/nrneurol.2017.116
3. Pearn ML, Niesman IR, Egawa J, et al. Pathophysiology Associated with Traumatic Brain Injury: Current Treatments and Potential Novel Therapeutics. Cell Mol Neurobiol. May 2017;37(4):571-585. doi:10.1007/s10571-016-0400-1
4. Bao W, Lin Y, Chen Z. The Peripheral Immune System and Traumatic Brain Injury: Insight into the role of T-helper cells. Int J Med Sci. 2021;18(16):3644-3651. doi:10.7150/ijms.46834
5. Daglas M, Draxler DF, Ho H, et al. Activated CD8(+) T Cells Cause Long-Term Neurological Impairment after Traumatic Brain Injury in Mice. Cell Rep. Oct 29 2019;29(5):1178-1191 e6. doi:10.1016/j.celrep.2019.09.046
6. Braun M, Vaibhav K, Saad N, et al. Activation of Myeloid TLR4 Mediates T Lymphocyte Polarization after Traumatic Brain Injury. J Immunol. 2017;198(9):3615-3626. doi:10.4049/jimmunol.1601948
7. Cui Y, Xu L, Wang F, Wang Z, Tong X, Yan H. Orally Administered Brain Protein Combined With Probiotics Increases Treg Differentiation to Reduce Secondary Inflammatory Damage Following Craniocerebral Trauma. Front Immunol. 2022;13:928343. Published 2022 Jul 6. doi:10.3389/fimmu.2022.928343
8. Wojciechowski S, Virenque A, Vihma M, et al. Developmental Dysfunction of the Central Nervous System Lymphatics Modulates the Adaptive Neuro-Immune Response in the Perilesional Cortex in a Mouse Model of Traumatic Brain Injury. Front Immunol. 2021;11:559810. Published 2021 Jan 27. doi:10.3389/fimmu.2020.559810
9. Needham EJ, Stoevesandt O, Thelin EP, et al. Complex Autoantibody Responses Occur following Moderate to Severe Traumatic Brain Injury. J Immunol. 2021;207(1):90-100. doi:10.4049/jimmunol.2001309