Novel aspects of defensins’ involvement in virus-induced autoimmunity in the central nervous system

Abstract

Recent research on re-circulation of interstitial fluid from the brain parenchyma to the periphery and its inferred importance in immune surveillance dysregulation are changing our conceptualization of the pathophysiology of virus-induced autoimmunity. In this context, it is necessary to reassess the immunomodulatory properties of human defensins that are variably expressed by cerebral microglia, astrocytes and choroid plexus epithelial cells and exhibit complex and often confounding roles in neuroinflammatory processes. Therefore, in this review we describe current contributions in this field and we propose novel hypotheses regarding the potential impact of defensin-related pathways on virus-driven autoimmune neurodegeneration. In this regard, we have previously proposed that abnormal expression of defensins by penetrating the blood-brain barrier (BBB) may contribute to the pathophysiology of Helicobacter pylori-related brain neurodegenerative disorders through variable modulations of innate and adaptive immune responses. We hereby propose that impaired expression of defensins by structural components of the BBB may impede glymphatic circulation and disrupt receptor signalling in pericytes that is essential for microvascular stability, thereby retaining blood-derived toxins and bystander activated T-cells in the brain and further impairing BBB integrity and hampering viral clearance. Autoreactive T-cell infiltrates in neuronaxonal lesions characteristic of chronic central nervous system diseases, such as multiple sclerosis, are directed against both, myelin and non-myelin, antigens the precise nature of which remains enigmatic. Inadequate expression of the autoimmune regulator (AIRE), a gene expressed in medullary thymic epithelial cells, induces the recruitment of defensin-specific T-cells. These cells may access the brain, thereby causing a decrease in defensin expression and subsequent down-regulation of CD91/LRP1-mediated clearance of amyloid-β that ultimately accumulates as protein deposits. It should be highlighted that β-amyloid brain deposits are a hallmark of many neurodegenerative diseases. During human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections, selective elicitation of the VH1-69 antibody subfamily directed against specific, viral glycoprotein epitopes, often correlates with a higher likelihood of developing autoimmune disorders. In addition, we propose that recently described defensin affinity towards the same epitopes may prevent proper viral fusion, but at the expense of augmenting autoimmune reactivity. Moreover, in the context of complex and largely unknown symbiotic relations between host microbiota and pathogenic viruses, we propose that co-stimulation of defensin expression may modulate adaptive immune responses thereby enhancing inflammatory cascades responsible for autoimmunity. Finally, we describe current evidence that supports the hypothesis of a possible involvement of defensins in HCV-related autoimmunity. Exploring further potential implications of human defensins in virus-related autoimmunity may lead to improved strategies for the treatment of neurodegenerative disorders.