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Ian Galea

Publications and source records attributed to Ian Galea.

7 recordsLinked to original sources
PubMed2006

What is the blood-brain barrier (not)?

In 1900, summarizing his experiments with toxins and Ehrlich's earlier observations with intravital dyes, the Berlin physician Lewandowski concluded that "brain capillaries must hold back certain molecules". Illustrating this phenomenon with persuasive beauty, the subsequently evolving metaphor of a 'Bluthirnschranke' (blood-brain barrier, BBB) gained wide acceptance, but the extension of its meaning into the context of inhibiting leukocyte recruitment into the brain is imprecise. On the basis of the original work by Ehrlich, Lewandowski and Goldmann we re-define the BBB as a capillary barrier for solutes, and clarify that leukocyte recruitment requires two differentially regulated steps: (i) passage across postcapillary venules into Virchow-Robin spaces, and (ii) subsequent progression across the glia limitans into the neuropil. We propose that the second step frequently involves perivascular antigen-recognition and the induction of ectoenzymes, for example matrix metalloproteinases (MMPs).

Blood-Brain Barrier↗
PubMed2006

What is immune privilege (not)?

The 'immune privilege' of the central nervous system (CNS) is indispensable for damage limitation during inflammation in a sensitive organ with poor regenerative capacity. It is a longstanding notion which, over time, has acquired several misconceptions and a lack of precision in its definition. In this article, we address these issues and re-define CNS immune privilege in the light of recent data. We show how it is far from absolute, and how it varies with age and brain region. Immune privilege in the CNS is often mis-attributed wholly to the blood-brain barrier. We discuss the pivotal role of the specialization of the afferent arm of adaptive immunity in the brain, which results in a lack of cell-mediated antigen drainage to the cervical lymph nodes although soluble drainage to these nodes is well described. It is now increasingly recognized how immune privilege is maintained actively as a result of the immunoregulatory characteristics of the CNS-resident cells and their microenvironment.

Animals↗
PubMed2005

Mannose receptor expression specifically reveals perivascular macrophages in normal, injured, and diseased mouse brain.

Perivascular macrophages are believed to have a significant role in inflammation in the central nervous system (CNS). They express a number of different receptors that point toward functions in both innate immunity, through pathogen-associated molecular pattern recognition, phagocytosis, and cytokine responsiveness, and acquired immunity, through antigen presentation and co-stimulation. We are interested in the receptors that are differentially expressed by perivascular macrophages and microglia in both the normal CNS as well as in neuroinflammation and neurodegeneration. In this article we report the use of a well-characterized monoclonal antibody, 5D3, to localize the expression of the mannose receptor to perivascular macrophages in the normal CNS and in various models of brain pathology. Mannose receptor expression was limited to perivascular, meningeal, and choroid plexus macrophages in normal, inflamed, injured, and diseased CNS. In particular, activated microglia and invading hematogenous leukocytes were mannose receptor negative while expressing the F4/80 antigen, macrosialin (CD68), FcRII (CD32), scavenger receptor (CD204), and CR3 (CD11b/CD18). Since the perivascular macrophages expressing the mannose receptor are known to be the only constitutively phagocytic cells in the normal CNS, we injected clodronate-loaded liposomes intracerebroventricularly in control mice to deplete these cells. In these mice, there was no detectable mannose receptor expression in perivascular spaces after immunocytochemistry with the 5D3 monoclonal antibody. This finding underlines the value of the monoclonal antibody 5D3 as a tool to study murine perivascular macrophages selectively. Mannose receptor expression by macrophages located at blood-brain (perivascular), brain-cerebrospinal fluid (CSF) (meningeal), and CSF-blood (choroid plexus) interfaces supports a functional role of these cells in responding to external stimuli such as infection.

Animals↗
PubMed2005

CD163-positive perivascular macrophages in the human CNS express molecules for antigen recognition and presentation.

Perivascular macrophages (PVM) constitute a subpopulation of resident macrophages in the central nervous system (CNS) that by virtue of their strategic location at the blood-brain barrier potentially lend themselves to a variety of important functions in both health and disease. Functional evidence suggests that PVM play a supportive role during experimental autoimmune encephalomyelitis in rodents. However, the function of PVM in the human CNS remains poorly characterized. We first set out to investigate the validity of the antibody EDhu1, which recognizes human CD163, to specifically identify human PVM. Second, we wanted to gain insight into the function of PVM in antigen recognition and presentation and therefore we studied the expression of DC-SIGN, mannose receptor, MHC class II, and several costimulatory molecules by PVM in the normal and inflamed human CNS (multiple sclerosis (MS) brain lesions). Conventional immunohistochemistry and double-labeled immunofluorescence techniques were used. We show that CD163 specifically reveals PVM in the normal human CNS. In MS lesions, CD163 staining reveals expression on foamy macrophages and microglia, besides an upregulation of the amount of PVM stained. In contrast, mannose receptor expression is restricted to PVM in both normal and inflamed brain tissue. Furthermore, we show that a subpopulation of PVM in the human brain express several molecules involved in antigen recognition, presentation, and costimulation. Therefore PVM, which occupy a strategic location at the BBB, are equipped to recognize antigen and present it to T cells, supporting a role in the regulation of perivascular inflammation in the human CNS.

Aged↗
PubMed2005

Biochemical indices of renal osteodystrophy in dialysis patients on the island of Malta.

OBJECTIVES: Renal osteodystrophy (ROD) has never been studied on the small Mediterranean island of Malta, which has a largely inbred population. The genetic contribution to the pattern of renal osteodystrophy is being increasingly recognized. We were, thus, interested in studying indices of bone turnover in Maltese end stage renal failure patients. MATERIALS AND METHODS: Sixty unselected patients, representing 65% of all patients undergoing dialysis in the island's renal unit, were prospectively investigated over a period of 5 months with respect to symptoms, calcium/phosphate chemistry, intact parathyroid hormone (iPTH) and bone alkaline phosphatase (bAP). Bone histomorphometry, which is the gold standard in the diagnosis of ROD, was not within the reach of our small unit. Biochemical markers may not be as sensitive and specific as bone biopsy for individual patient diagnosis of ROD sub-type but they can give a fairly good indication of the spectrum of bone turnover on a population basis. The optimum combination of biochemical marker cut-offs available from studies in the literature was then employed to estimate bone turnover. RESULTS: The following biochemical picture emerged: 42% had iPTH < 79.7 pg/ml (which cut off has a reported specificity of 93.7% for low turnover bone disease), 45% had iPTH > 100 pg/ml and bAP > 10 ng/ml (which combined cut off has a reported specificity of 100% for high turnover bone disease), while 13% could not be classified (ie had intermediate values). CONCLUSIONS: Based on biochemical data, the pattern of bone turnover seems to be comparable to the European average. Further indepth study using bone histomorphometry is warranted.

Alkaline Phosphatase↗
PubMed2005

Blood-derived dendritic cells in an acute brain injury.

Dendritic cells (DC), while absent from the normal CNS parenchyma, have been demonstrated in delayed type hypersensitivity (DTH), experimental allergic encephalomyelitis (EAE), and some MS lesions. We demonstrate that an acute excitotoxic lesion results in DC recruitment to the brain, with maximal cells between days 3 and 5. Clodronate liposome-mediated depletion of cerebral perivascular macrophages does not prevent recruitment of DC; however, a lesion in a whole-body irradiated animal does not show evidence of DC recruitment. We conclude that DC are recruited to an excitotoxic lesion from a blood-derived cell population. This may have implications for neuropathologies involving DC recruitment.

Acute Disease↗