The Immune System's Role in the Consequences of Mild Traumatic Brain Injury (Concussion)

Abstract

Mild traumatic brain injury (mild TBI), often referred to as concussion, is the most common form of TBI and affects millions of people each year. A history of mild TBI increases the risk of developing emotional and neurocognitive disorders later in life that can impact on day to day living. These include anxiety and depression, as well as neurodegenerative conditions such as chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD). Actions of brain resident or peripherally recruited immune cells are proposed to be key regulators across these diseases and mood disorders. Here, we will assess the impact of mild TBI on brain and patient health, and evaluate the recent evidence for immune cell involvement in its pathogenesis.

Keywords: concussion; inflammation; microglia; mild TBI; neurodegenenerative diseases; neuroimmunology.

Figure 1

Diagnostic criteria, symptoms and immune cell involvement in moderate to severe traumatic Brain Injury (TBI) in comparison with mild TBI. Commonly used diagnostic criteria in moderate to severe TBI compared to mild TBI shows the major clinical difference between the two reflects hemorrhage or clear contusion in the brain. Symptoms are shared across mild, moderate and severe TBI with increasing likelihood of symptom occurrence and severity with increasing injury. Schematics represent immune response in moderate to severe TBI (left) and mild TBI (right). In moderate to severe TBI in humans and animal models, there is clear evidence for resident microglia activation and recruitment of macrophages, dendritic cells, neutrophils, B cells and T cells, and meningeal inflammation. In addition to active recruitment mechanisms, peripheral immune cells can infiltrate with frank hemorrhage alongside red blood cells (RBCs) and the release of hemoglobin (Hgb), Haem, and other damage associated molecular patterns (DAMPs), which are one set of initiators of the immune response. In contrast, in mild TBI there is little evidence of infiltrating immune cells to the brain tissue in humans or animal models that do not produce hemorrhage or skull opening. In mild TBI, there is evidence of meningeal inflammation, microglial activation, and some monocyte/macrophage recruitment to the cerebrovasculature.

Figure 2

Potential triggers of the immune response in mild TBI. (A) Physical forces lead to stretching of axons, axonal injury and glial activation. (i) Schematic representing a neuron with its myelinated axon surrounded by glia in the healthy brain. (ii) Represents the stretching of axons due to physical forces during mild TBI and the subsequent glial activation (iii) Key–indicates glial subtypes hypothesized to be activated after axonal stretching. (B) Diffuse blood-brain barrier (BBB) in the brain after concussion leads to extravasation of harmful molecules to the parenchyma. (i) Schematic shows a coronal section of a human brain with representations of diffuse BBB breakdown after mild TBI (brown areas). (ii) Enlarged image shows compromised cerebral blood vessel leaking molecules that may trigger inflammation and glial activation.