Katarzyna Biernacki

Glial cell influence on the human blood-brain barrier

The blood‐brain barrier (BBB) is a specialized structure of the central nervous system (CNS) that restricts immune cell migration and soluble molecule diffusion from the systemic compartment into the CNS. Astrocytes and microglia are resident cells of the CNS that contribute to the formation of the BBB. In this article, we consider the influence of these glial cells on the immune regulatory functions of the microvascular endothelium, with special emphasis on the human BBB. A series of in vitro studies demonstrate that soluble factors produced by glial cells, under basal culture conditions, help restrict development of inflammation within the CNS. These soluble factor effects include upregulating expression of molecules including HT7, UEA‐1 lectin‐binding sites, and angiotensin receptors that help define the phenotype of endothelial cells. These factors also induce tight junction formation between brain endothelial cells, contributing to the restricted permeability of the BBB. In contrast, these factors have little effect on expression of molecules by ECs that either promote lymphocyte migration, such as chemokines and adhesion molecules or molecules that are required for competent antigen presentation, such as MHC and co‐stimulatory molecules. Glial cells that become activated in response to signals derived from the immune system or generated within the CNS, produce an array of inflammatory molecules that increase permeability and promote lymphocyte trafficking and persistence. These observations emphasize the bidirectional nature of neural‐immune interactions; this dynamic system should be amenable to therapeutic interventions. GLIA 36:145–155, 2001.

Determinants of Human B Cell Migration Across Brain Endothelial Cells

Circulating B cells enter the CNS as part of normal immune surveillance and in pathologic states, including the common and disabling illness multiple sclerosis. However, little is known about the molecular mechanisms that mediate human B cell interaction with the specialized brain endothelial cells comprising the blood-brain barrier (BBB). We studied the molecular mechanisms that regulate the migration of normal human B cells purified ex vivo, across human adult brain-derived endothelial cells (HBECs). We found that B cells migrated across HBECs more efficiently than T cells from the same individuals. B cell migration was significantly inhibited by blocking Abs to the adhesion molecules ICAM-1 and VLA-4, but not VCAM-1, similar to the results previously reported for T cells. Blockade of the chemokines monocyte chemoattractant protein-1 and IL-8, but not RANTES or IFN-γ-inducible protein-10, significantly inhibited B cell migration, and these results were correlated with the chemokine receptor expression of B cells measured by flow cytometry and by RNase protection assay. Tissue inhibitor of metalloproteinase-1, a natural inhibitor of matrix metalloproteinases, significantly decreased B cell migration across the HBECs. A comprehensive RT-PCR comparative analysis of all known matrix metalloproteinases and tissue inhibitors of metalloproteinases in human B and T cells revealed distinct profiles of expression of these molecules in the different cell subsets. Our results provide insights into the molecular mechanisms that underlie human B cell migration across the BBB. Furthermore, they identify potential common, and unique, therapeutic targets for limiting CNS B cell infiltration and predict how therapies currently developed to target T cell migration, such as anti-VLA-4 Abs, may impact on B cell trafficking.

Differential effects of Th1 and Th2 lymphocyte supernatants on human microglia

We assessed the effects of soluble molecules (supernatants) produced by pro‐ (Th1) and anti‐ (Th2) inflammatory T‐cell lines on the capacity of adult human CNS‐derived microglia to express or produce selected cell surface and soluble molecules that regulate immune reactivity or impact on tissue protection/repair within the CNS. Treatment of microglia with supernatants from allo‐antigen and myelin basic protein‐specific Th1 cell lines augmented expression of cell surface molecules MHC class II, CD80, CD86, CD40, and CD54, enhanced the functional antigen‐presenting cell capacity of microglia in a mixed lymphocyte reaction, and increased cytokine/chemokine secretion (TNFα, IL‐6, and CXCL10/IP‐10). These Th1‐induced effects were not reproduced by interferon‐γ (IFNγ) alone and were only incompletely blocked by anti‐IFNγ antibody. Th2 cell supernatant treatments did not alter costimulatory/adhesion molecule expression or induce cytokine/chemokine production by microglia. Th2 treatment, furthermore, failed to reduce the induction observed in response to Th1 supernatants. Neither Th1 nor Th2 supernatants induced production of the neurotrophin molecules, nerve growth factor, or brain‐derived neurotrophic factor. Our results suggest that soluble molecules released by Th1 and not Th2 cells that infiltrate the CNS can stimulate resident microglia to acquire enhanced effector and accessory cell functions; the Th1‐induced effects were not downregulated by Th2 supernatant‐mediated bystander suppression. GLIA 42:36–45, 2003.

Human brain endothelial cells supply support for monocyte immunoregulatory functions

Blood-derived monocytic cells comprise a significant component of most inflammatory responses that occur in the CNS. We utilized human brain-derived endothelial cells (HBECs) coated membranes in Boyden chambers to assess immune function related properties of human blood-derived monocytes following interaction with HBECs. Monocytes in contact with HBECs maintained functional antigen-presenting capacity and chemokine/cytokine production in contrast to monocytes that migrated through the HBEC barrier. These results indicate that HBECs, although themselves incapable of serving as competent antigen-presenting cells during the course of inflammatory CNS disorders, supply support needed for infiltrating perivascular monocytes to maintain their functions. Monocyte migration across HBECs was inhibited by interferon-beta.

Multiple sclerosis-associated uveitis

ABSTRACT Introduction: Multiple sclerosis (MS)-associated uveitis is an uncommon ocular manifestation of the systemic neurological disease. A wide range of ocular findings has been described including uveitis from every anatomical location. Most commonly, MS-associated uveitis presents as a chronic bilateral intermediate type of uveitis. Although the underlying mechanism remains unknown, a relationship between MS and uveitis suggests autoimmune and genetic predispositions. This manuscript aims to update the clinician on the multiple clinical portraits as well as the latest therapeutic advances in the field. Areas covered: The authors systematically describe the epidemiology, the pathophysiological hypotheses, the clinical manifestations, and the treatment options of MS-associated uveitis. A thorough literature review of the last 10 years was conducted using PubMed. Expert commentary: Limited literature is currently available on MS-associated uveitis. To date, the presence of MS-associated uveitis is not considered a sign of MS disease activity nor severity. While the actual treatment of MS-associated uveitis is similar to other noninfectious uveitic entities, future research avenues could lead to potential combined treatment of both neurologic and ophthalmologic disease.