Adaptive Immunity Regulation and Cerebral Ischemia

Abstract

Stroke is a disease that occurs due to a sudden interruption of the blood supply to the brain. It is a leading cause of death and disability worldwide. It is well-known that the immune system drives brain injury following an episode of ischemic stroke. The innate system and the adaptive system play distinct but synergistic roles following ischemia. The innate system can be activated by damage-associated molecular patterns (DAMPs), which are released from cells in the ischemic region. Damaged cells also release various other mediators that serve to increase inflammation and compromise the integrity of the blood-brain barrier (BBB). Within 24 h of an ischemic insult, the adaptive immune system is activated. This involves T cell and B cell-mediated inflammatory and humoral effects. These cells also stimulate the release of various interleukins and cytokines, which can modulate the inflammatory response. The adaptive immune system has been shown to contribute to a state of immunodepression following an ischemic episode, and this can increase the risk of infections. However, this phenomenon is equally important in preventing autoimmunity of the body to brain antigens that are released into the peripheral system as a result of BBB compromise. In this review, we highlight the key components of the adaptive immune system that are activated following cerebral ischemia.

Keywords: adaptive immunity; cerebral ischemia; immune response; innate immunity; stroke.

Figure 1

Timeline of immune response in ischemic stroke. Ischemic stroke begins with a cascade of events as a result of arterial occlusion leading to hypoxia accompanied by ROS production within minutes and glucose deprivation. The integrity of the BBB is compromised leading to increased permeability within 1–2 h, allowing infiltration of circulatory cells which contribute to the inflammatory process and exacerbate neuronal death. BBB, blood–brain barrier; ROS, reactive oxygen species; MMPs, matrix metalloproteinases; DAMPs, damage-associated molecular patterns; ECM, extracellular matrix.

Figure 2

Innate immunity in ischemic stroke. Immediately following an episode of stroke, the innate immune system is activated. It is characterized by the presence of various mediators such as DAMPs that have been released from the injured neurons and which induce the secondary activation of microglia via TLRs signaling and NLRP3 activity. TLR, Toll-like receptors; NLRP3, nod-like receptor pyrin domain-containing 3; APC, antigen-presenting cell; DAMPs, damage-associated molecular patterns.

Figure 3

Adaptive immunity in ischemic stroke. Within 1 day of the ischemic event, there is infiltration of system cells such as CD4+ T and CD8+ T cells. CD4 cell cells differentiate into Th1, Th2, Th17, or Tregs to produce pro-inflammatory or anti-inflammatory effects. CD8+ T cells lead to neuronal death by release of perforin and granzyme. B cells produce anti-inflammatory effects via the release of interleukins such as IL-10. TLR, Toll-like receptors; NLRP3, nod-like receptor pyrin domain-containing 3; APC, antigen-presenting cell; CD4+, cluster of differentiation 4+; Th, T helper; Treg, regulatory T cell.

Figure 4

Immunodepression after ischemic stroke. Stroke-induced immunodepression leads to an increased incidence of infections. HPA, hypothalamic–pituitary–adrenal axis; SNS, sympathetic nervous system; PNS, parasympathetic nervous system; Treg, regulatory T cell.