Abstract
BackgroundInappropriate contact between the immune system and the central nervous system is thought to be a cause of demyelination. We previously reported the ability of the class IV semaphorin, Semaphorin4A (Sema4A), to induce apoptosis in human oligodendrocytes; however, these results have yet to be translated to an in vivo setting. Importantly, HIV-associated neurocognitive disorder remains a significant complication for patients on combined anti-retroviral therapy, with white matter damage seen on MRI.MethodsHuman cerebrospinal fluid and serum was assayed for Sema4A using a Sema4A-specific ELISA. Wild-type mice were injected with Sema4A via stereotaxic infusion. Data was assessed for significance using unpaired t tests, comparing the corpus callosum of PBS-injected mice versus Sema4A-injected mice.ResultsHere, we demonstrate elevated levels of Sema4A in the cerebrospinal fluid and serum of people with HIV infection. Furthermore, we demonstrate that direct injection of Sema4A into the corpus callosum of mice results in loss of myelin architecture and decreased myelin, concomitant with apoptosis of mature myelinating oligodendrocytes. Sema4A injection also causes increased activation of microglia.ConclusionsTaken together, our data further establish Sema4A as a potentially significant mediator of demyelinating diseases and a direct connection between the immune system and oligodendrocytes.
Highlights
Inappropriate contact between the immune system and the central nervous system is thought to be a cause of demyelination
Sema4A is elevated in the Cerebrospinal fluid (CSF) and serum of Human immunodeficiency virus (HIV)+ individuals The levels of Sema4A were measured in 50 HIV+ individuals who consented to have lumbar punctures and blood measurements as part of previously conducted studies at the University of California-San Diego HIV Neurobehavioral Research Center (HNRC)
Using a Sema4A-specific Enzyme-linked immunosorbent assay (ELISA), we determined that Sema4A levels are higher in individuals with HIV infection (53.72 ± 14.37 ng/mL)
Summary
Inappropriate contact between the immune system and the central nervous system is thought to be a cause of demyelination. Demyelination in the central nervous system (CNS) has long been thought to be a result of inappropriate immune activation, leading to targeted destruction of the myelin sheath, as well as a loss of mature myelinating oligodendrocytes [1, 2]. Previous studies by our laboratory have demonstrated that exposure to Semaphorin4A (Sema4A), an immune trophic factor required for T cell activation [3], is implicated in the death of oligodendrocytes [4, 5]. Previous studies have demonstrated that Sema4A aids in T cell maturation by binding to the T cell immunoglobulin and mucin domain 2 (Tim-2) receptor in rodents [3] and to Tim-1 in humans [5]. We have previously demonstrated that Tim-1 and Tim-2 are present on oligodendrocytes in humans and rodents, respectively, and that this receptor binds to and mediates the uptake of H-ferritin [5, 13,14,15]
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