Cerebrovascular Anomalies: Perspectives From Immunology and Cerebrospinal Fluid Flow.

Appropriate vascular function is essential for the maintenance of central nervous system homeostasis and is achieved through virtue of the blood-brain barrier; a specialized structure consisting of endothelial, mural, and astrocytic interactions. While appropriate blood-brain barrier function is typically achieved, the central nervous system vasculature is not infallible and cerebrovascular anomalies, a collective terminology for diverse vascular lesions, are present in meningeal and cerebral vasculature supplying and draining the brain. These conditions, including aneurysmal formation and rupture, arteriovenous malformations, dural arteriovenous fistulas, and cerebral cavernous malformations, and their associated neurological sequelae, are typically managed with neurosurgical or pharmacological approaches. However, increasing evidence implicates interacting roles for inflammatory responses and disrupted central nervous system fluid flow with respect to vascular perturbations. Here, we discuss cerebrovascular anomalies from an immunologic angle and fluid flow perspective. We describe immune contributions, both common and distinct, to the formation and progression of diverse cerebrovascular anomalies. Next, we summarize how cerebrovascular anomalies precipitate diverse neurological sequelae, including seizures, hydrocephalus, and cognitive effects and possible contributions through the recently identified lymphatic and glymphatic systems. Finally, we speculate on and provide testable hypotheses for novel nonsurgical therapeutic approaches for alleviating neurological impairments arising from cerebrovascular anomalies, with a particular emphasis on the normalization of fluid flow and alleviation of inflammation through manipulations of the lymphatic and glymphatic central nervous system clearance pathways.

Immune response in human cerebral cavernous malformations.

BACKGROUND AND PURPOSE: Preliminary observations suggesting the presence of B and plasma cells and oligoclonality of immunoglobulin (Ig) G in cerebral cavernous malformations (CCM) have motivated a systematic study correlating the infiltration of the immune cells with clinical activity and antigen-triggered immune response in surgically excised lesions. METHODS: Infiltration of plasma, B, T, and human leukocyte antigen-DR-expressing cells and macrophages within 23 excised CCM was related to clinical activity. Relative amounts of Ig isotypes were determined. IgG clonality of mRNA from CCM was assessed by spectratyping, cloning, and sequencing. RESULTS: Infiltration of the immune cells ranged widely within CCM lesions, and cells were generally coexpressed with each other. Immune cell infiltration did not associate with recent bleeding and lesion growth. Significantly more B lymphocytes in CCM lesions were associated with venous anomaly. More T cells were present in solitary lesions. More T cells and less macrophages were present in CCM from younger subjects. IgG isotype was present in all CCM lesions. Most lesions also expressed IgM and IgA, with IgM predominance over IgA correlating with recent CCM growth. Oligoclonality was shown in IgG mRNA from CCM, but not from peripheral blood lymphocytes, with only 8 complementary-determining region 3 sequences observed among 134 clones from 2 CCM lesions. CONCLUSIONS: An antigen-directed oligoclonal IgG immune response is present within CCM lesions regardless of recent clinical activity. Apparent differences in immune response in younger patients and in lesions with recent growth will need confirmation in other series. The pathogenicity of oligoclonal immune response will require systematic hypothesis testing in recently available CCM murine models.

Nestin expression in reactive astrocytes of human pathology.

There is a general agreement on the Nestin re-expression in reactive astrocytes, but its modalities differ among experimental animal species and between the latter and human material. In a series of 40 surgical specimens, including gliomas, vascular malformations, abscesses and angiomas, the glial reaction has been studied by immunohistochemistry and immunofluorescence of Nestin, GFAP and Vimentin. The observations made by immunohistochemistry were comparable with those by immunofluorescence. In some lesions, glial reaction was long-lasting and astrocytes were in the same late maturation stage. In other lesions, such as invading malignant gliomas, astrocytes occurred in different maturation stages. In comparison with GFAP, Nestin was poorly expressed in mature astrocytes and more expressed in developing reactive astrocytes, mainly in the cytoplasms, with a great variability, and much less in the processes. In the invading tumor, developing positive astrocytes were hardly distinguishable from tumor invading astrocytes that, interestingly, were much more Nestin- than GFAP-positive. In the deep tumor reactive astrocytes were no more visible. The interpretation of the findings was based on what is known on the reciprocal behavior of the three antigens in maturing astrocytes during embryogenesis and on the hypothesis of an embryonic regression of reactive astrocytes. The impossibility to distinguish them from tumor cells in the deep tumor legitimates the suspicion of their recruitment among tumor cells.