Emerging Role of Immunity in Cerebral Small Vessel Disease

Abstract

Cerebral small vessel disease (CSVD) is one of the main causes of vascular dementia in older individuals. Apart from risk containment, efforts to prevent or treat CSVD are ineffective due to the unknown pathogenesis of the disease. CSVD, a subtype of stroke, is characterized by recurrent strokes and neurodegeneration. Blood-brain barrier (BBB) impairment, chronic inflammatory responses, and leukocyte infiltration are classical pathological features of CSVD. Understanding how BBB disruption instigates inflammatory and degenerative processes may be informative for CSVD therapy. Antigens derived from the brain are found in the peripheral blood of lacunar stroke patients, and antibodies and sensitized T cells against brain antigens are also detected in patients with leukoaraiosis. These findings suggest that antigen-specific immune responses could occur in CSVD. This review describes the neurovascular unit features of CSVD, the immune responses to specific neuronal and glial processes that may be involved in a distinct mechanism of CSVD, and the current evidence of the association between mechanisms of inflammation and interventions in CSVD. We suggest that autoimmune activity should be assessed in future studies; this knowledge would benefit the development of effective therapeutic interventions in CSVD.

Keywords: autoimmune response; cerebral small vessel disease; degeneration; inflammation; pathogenesis.

Figure 1

Proposed autoimmunity mechanism in the development of neurodegeneration in CSVD. CSVD is a cerebral vascular disorder characterized by recurrent strokes with sustainable BBB disruption as well as a chronic inflammatory response at the neurovascular unit. Autoimmunity could be generated in acute stroke under certain brain chronic inflammatory circumstances with damaged immune tolerance in CSVD. Blood proteins at the neurovascular unit play an important role in the communication between the brain and the immune system. During BBB disruption, fibrinogen extravagates into the CNS and is converted to fibrin upon activation of coagulation. Fibrin, the high-affinity plasma-derived ligand for CD11b/CD18, activates CNS-resident innate immune cells (microglia and perivascular macrophages) to stimulate cytokine release, thus sustaining antigen-presenting properties by providing instructive signals (such asIL-12, IL-1, and TNFα) to promote antigen-specific (neuron or oligodendrocyte) Th1-cell or Th2-cell differentiation following a stroke. The cellular immune response or humoral immune response leads to neuron and oligodendrocyte injury. APC, antigen-presenting cells; LI, lacunar infarct; CH, cerebral hemorrhage; EPVS, enlarged perivascular space; MBs, microbleeds; CSVD, cerebral small vessel disease; BBB, blood–brain barrier. The original data were acquired in the YPY group.