Background/Purpose: There is an association between natural antibodies, such as anti-phospholipid antibodies, and vasculature injury in stroke and in SLE models of systemic ischemic damage.   There is also a correlation between chronic inflammatory micro-environments and long term neuro-degeneration.  Preliminary data in our mild traumatic brain injury model demonstrated the development of long term inflammation at the Blood Brain Barrier (BBB) and mild neurocognitive memory defects.  The objective of this study is to determine if the chronic inflammatory microenvironment produced in the BBB in our model, was correlated with increasing preferential association between complement and natural antibodies to mediated vascular damage.   We utilized a long-term longitudinal study to explore this relationship. 

Methods:  Multiple HIFU exposure was used to induce cerebral vascular injury.  Briefly, the animals were anesthetized with 5% Isoflurane and the scalp region was cleared of fur using Nair. Animals assigned to the HIFU-exposure (3 exposures 24 hours apart) experienced a one-millisecond pulse while sham animals did not.  Animals were harvested at a series of time points 2 hours to 30 days post injury. Immunocytochemistry and Immunofluorescence analysis of brain slices was performed to assess vascular integrity and injury.

Results: In the immune competent (C57Bl/6) strain HIFU injury resulted in the activation of the endothelium of the BBB, increased permeability of the BBB to low molecular weight molecules, and deposition of complement C3b, all of which support disruption of endothelial integrity.  In longitudinal studies, a sustained neuro-inflammation was evident 30 days after injury and correlated with neuro-cognitive deficits.   Initial data has demonstrated increased IgG deposition on the luminal surface of the BBB endothelium immediately after injury and at 30 days post injury.  At the 30 day post injury time point there is an increased susceptibility to vascular injury as evidenced by Ferritin deposits within the Virchow-Robin space of the BBB structural unit, specifically in the hippocampus.  At early time points, IgG was associated with complement at the BBB, but epitopes associated with natural antibodies were not dominant.  By 30 days, there was a preferential association between natural antibodies and complement deposition.  Specifically, anti-phospholipid type epitopes were detected.    

Conclusion: Preliminary data suggest that anti-phospholipid type natural antibodies have a stronger association with vascular damage at the 30 day time point than other pathogenic type antibodies. We are currently assessing if the anti-phospholipid antibodies are co-localized with ferritin breaches of the BBB.  Elucidating the mechanics of vascular injury which results in both sustained neuro-pathology and neuro-cognitive decline would provide insight into the emergence and progression in vascular associated neuro-degeneration.  These finding may illuminate a mechanism in Neuropsychiatric Systemic Lupus Erythematous (NPSLE), although there is a correlation of NPSLE with some antibodies, a well-delineated mechanism of how antibody induced cerebral damage occurs has not been defined.  

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/characterization-of-epitopes-identified-with-cerebral-vasculature-injury/