Comparison of the timing of acute blood‐brain barrier breakdown to rabbit immunoglobulin G in the cerebellum and spinal cord of mice with experimental autoimmune encephalomyelitis

Abstract

Experimental autoimmune encephalomyelitis (EAE) is an animal model for human multiple sclerosis (MS). Similar to MS patients, EAE animals can exhibit chronic or relapsing, remitting paralysis; leukocyte infiltration of the central nervous system (CNS); and breakdown of the blood-brain barrier (BBB), allowing access to serum components. EAE pathology in rodents is generally thought to progress from the spinal cord to the more rostral brain. This common notion is based on numerous reports on the severity and progression of cellular infiltration and BBB breakdown during the course of disease. We studied opening of the BBB in EAE mice immunized to the proteolipid protein (PLP) peptide, PLP 139-151, with or without the use of pertussis toxin. Peripherally injected rabbit immunoglobulin G showed significant penetration through a compromised BBB in EAE mice and was observed throughout the parenchyma as well as intracellularly in multiple neuronal types. Results demonstrate the novel finding that the cerebellar BBB is dramatically and briefly comprised, even before breakdown of the BBB in the thoracolumbar spinal cord and prior to symptomatic disease. The demonstration of susceptibility in the cerebellum provides an important target for studying the factors predisposing certain CNS regions to autoimmune-related compromise of the BBB, such as MS.

Central histamine H3receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

“…The neurogenically controlled changes related to cerebrovascular tone, particularly at the level of the neurovascular unit (26,27), are consistent with an increasing body of evidence in both EAE (45,46) and MS (47,48) that subtle, progressive alterations in BBB integrity precede the formation of inflammatory lesions. Hrh3 is linked to Eae8.…”

Purkinje cell loss in experimental autoimmune encephalomyelitis

“…Disruption of the blood-brain barrier (BBB) at the cerebellum occurs early in disease in Lewis rats as visualized using ultra small particles of iron oxide (USPIO) in MRI (Floris et al, 2004; Rausch et al, 2003). The same has been shown in SJL/J mice with proteolipid protein (PLP) peptide 139–151-induced EAE, where cerebellar BBB breakdown was demonstrated to occur prior to disruption of the BBB in the spinal cord and prior to the development of clinical symptoms (Tonra, 2002; Tonra et al, 2001). Interestingly, this work demonstrated that the rabbit immunoglobulins used to evaluate BBB breakdown accumulated around Purkinje cells.…”

Neural precursors exhibit distinctly different patterns of cell migration upon transplantation during either the acute or chronic phase of EAE: A serial MR imaging study

“…For example, adult neurogenesis has been demonstrated along perivascular sites within the subventricular and subgranular zones of the CNS following ischemic cerebral infarct (40). Alternatively, expansions in Virchow‐Robin perivascular space have recently been demonstrated during heightened disease activity in MS (41) and these spaces may expand similarly in EAE at the peak of disability when blood‐brain barrier lesions within the mouse brain are at their peak, particularly in somatosensory regions of cortex (42, 43). Therefore, immune cell foci within enlarged perivascular spaces may release factors that compete with chemoattractive signals for NPCs that are released along fiber tracts containing demyelinated axons originating from relatively dispersed cell bodies.…”