Biomedical subjects

Jia Newcombe

Publications and source records attributed to Jia Newcombe.

7 recordsLinked to original sources

PubMed2005

Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment.

Understanding the mechanisms of immune cell migration to multiple sclerosis lesions offers significant therapeutic potential. This study focused on the chemokines CXCL12 (SDF-1) and CXCL13 (BCA-1), both of which regulate B cell migration in lymphoid tissues. We report that immunohistologically CXCL12 was constitutively expressed in CNS parenchyma on blood vessel walls. In both active and chronic inactive multiple sclerosis lesions CXCL12 protein was elevated and detected on astrocytes and blood vessels. Quantitative PCR demonstrated that CXCL13 was produced in actively demyelinating multiple sclerosis lesions, but not in chronic inactive lesions or in the CNS of subjects who had no neurological disease. CXCL13 protein was localized in perivascular infiltrates and scattered infiltrating cells in lesion parenchyma. In the CSF of relapsing-remitting multiple sclerosis patients, both CXCL12 and CXCL13 were elevated. CXCL13, but not CXCL12, levels correlated strongly with intrathecal immunoglobulin production as well as the presence of B cells, plasma blasts and T cells. About 20% of CSF CD4+ cells and almost all B cells expressed the CXCL13 receptor CXCR5. In vitro, CXCL13 was produced by monocytes and at much higher levels by macrophages. CXCL13 mRNA and protein expression was induced by TNFalpha and IL-1beta but inhibited by IL-4 and IFNgamma. Together, CXCL12 and CXCL13 are elevated in active multiple sclerosis lesions and CXCL12 also in inactive lesions. The consequences of CXCL12 up-regulation could be manifold. CXCL12 localization on blood vessels indicates a possible role in leucocyte extravasation, and CXCL12 may contribute to plasma cell persistence since its receptor CXCR4 is retained during plasma cell differentiation. CXCL12 may contribute to axonal damage as it can become a neurotoxic mediator of cleavage by metalloproteases, which are present in multiple sclerosis lesions. The strong linkage of CXCL13 to immune cells and immunoglobulin levels in CSF suggests that this is one of the factors that attract and maintain B and T cells in inflamed CNS lesions. Therefore, both CXCL13 and CXCR5 may be promising therapeutic targets in multiple sclerosis.

Acute Disease↗

PubMed2005

Exploiting genotypic differences to identify genes important for EAE development.

Experimental autoimmune encephalomyelitis (EAE) is an animal model of the human autoimmune disease multiple sclerosis (MS) and is primarily driven by T helper type 1 (Th1) cells. Interleukin (IL)-12 and interferon (IFN)-gamma are important cytokines involved in the differentiation and amplification of Th1 cells, however mice deficient in either IFN-gamma or IL-12 still develop EAE. We have used microarray analysis of EAE-affected CNS tissues in wild-type, IFN-gamma -/- and IL-12 -/- animals to identify genes critical for development of EAE. Over 500 genes were regulated in at least one genotype and over 94 genes were regulated in all three. Of those, 17 were also upregulated in spleen during the disease. We show that a majority of the genes regulated in EAE are also regulated in diseased regions of human MS tissues. The genes in the pool of 94 are more likely to be found regulated in MS patients than the genes regulated in only one or two of the mouse strains suggesting that analyzing gene expression under these multiple genetic conditions may lead to better identification of the genes critical for disease development.

Animals↗

PubMed2005

Extraction and proteomic analysis of proteins from normal and multiple sclerosis postmortem brain.

In this study, a reproducible fractionation procedure was developed to reduce levels of the abundant cytoskeletal proteins that are present in normal and pathological central nervous system (CNS) tissues. The fractionation and proteomic analysis techniques employed greatly facilitated comparison of the spectrum of proteins in normal postmortem brain with proteins in samples from patients with multiple sclerosis, an inflammatory demyelinating disease in which complex changes in protein expression occur as lesions develop. This approach may be of value for the proteomic identification and quantitation of proteins which undergo disease-related changes in CNS disorders, and also for protein expression studies on normal adult and developing CNS tissues.

Aged↗

PubMed2005

Sodium channels contribute to microglia/macrophage activation and function in EAE and MS.

Loss of axons is a major contributor to nonremitting deficits in the inflammatory demyelinating disease multiple sclerosis (MS). Based on biophysical studies showing that activity of axonal sodium channels can trigger axonal degeneration, recent studies have tested sodium channel-blocking drugs in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and have demonstrated a protective effect on axons. However, it is possible that, in addition to a direct effect on axons, sodium channel blockers may also interfere with inflammatory mechanisms. We therefore examined the novel hypothesis that sodium channels contribute to activation of microglia and macrophages in EAE and acute MS lesions. In this study, we demonstrate a robust increase of sodium channel Nav1.6 expression in activated microglia and macrophages in EAE and MS. We further demonstrate that treatment with the sodium channel blocker phenytoin ameliorates the inflammatory cell infiltrate in EAE by 75%. Supporting a role for sodium channels in microglial activation, we show that tetrodotoxin, a specific sodium channel blocker, reduces the phagocytic function of activated rat microglia by 40%. To further confirm a role of Nav1.6 in microglial activation, we examined the phagocytic capacity of microglia from med mice, which lack Nav1.6 channels, and show a 65% reduction in phagocytic capacity compared with microglia from wildtype mice. Our findings indicate that sodium channels are important for activation and phagocytosis of microglia and macrophages in EAE and MS and suggest that, in addition to a direct neuroprotective effect on axons, sodium channel blockade may ameliorate neuroinflammatory disorders via anti-inflammatory mechanisms.

Animals↗

PubMed2004

Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger.

Although voltage-gated sodium channels are known to be deployed along experimentally demyelinated axons, the molecular identities of the sodium channels expressed along axons in human demyelinating diseases such as multiple sclerosis (MS) have not been determined. Here we demonstrate changes in the expression of sodium channels in demyelinated axons in MS, with Nav1.6 confined to nodes of Ranvier in controls but with diffuse distribution of Nav1.2 and Nav1.6 along extensive regions of demyelinated axons within acute MS plaques. Using triple-labeled fluorescent immunocytochemistry, we also show that Nav1.6, which is known to produce a persistent sodium current, and the Na+/Ca2+ exchanger, which can be driven by persistent sodium current to import damaging levels of calcium into axons, are colocalized with beta-amyloid precursor protein, a marker of axonal injury, in acute MS lesions. Our results demonstrate the molecular identities of the sodium channels expressed along demyelinated and degenerating axons in MS and suggest that coexpression of Nav1.6 and Na+/Ca2+ exchanger is associated with axonal degeneration in MS.

Acute Disease↗

PubMed2004

Accumulation of Valpha7.2-Jalpha33 invariant T cells in human autoimmune inflammatory lesions in the nervous system.

T cells expressing an invariant TCR alpha chain and NK cell markers are expected to exhibit unique functions. Whereas much attention has been paid to CD1d-restricted NKT cells, a second NKT cell population bearing an invariant AV19-AJ33 TCR has recently been identified in mice and humans. Selection and/or expansion of this population require B cells, and would involve a non-classical class I-related molecule MR1. Although their preferential distribution in the gut mucosa indicates their role in the host response at the site of pathogen entry, it remains unknown whether they play an alternative role at different sites or in immunological disorders. Using single-strand conformation polymorphism clonotype analysis, we investigated the presence of the human AV19-AJ33 T cells (V(alpha)7.2-J(alpha)33 T cells) in autopsy samples from multiple sclerosis (MS) patients as well as in nerve biopsy samples from chronic inflammatory demyelinating polyneuropathy (CIDP) patients. Here we report that the V(alpha)7.2-J(alpha)33 T cells are accumulated in some of the central nervous system lesions of MS and in the majority of the peripheral nerve samples from CIDP. We have previously revealed that CD1d-restricted, V(alpha)24-J(alpha)Q NKT cells are remarkably reduced in the peripheral blood from MS. However, V(alpha)7.2-J(alpha)33 T cells are not reduced in the peripheral blood from MS and could be detected in a large majority of the cerebrospinal fluid samples obtained during relapse of MS. The present results indicate that the V(alpha)7.2-J(alpha)33 T cells are involved in the autoimmune inflammatory lesions.

Animals↗

PubMed2003

Annexin II/p11 is up-regulated in Purkinje cells in EAE and MS.

The sensory neuron specific sodium channel Na(v)1.8 is normally detectable at only very low levels within cerebellar Purkinje cells. Annexin II light chain (p11) binds to the amino terminus of Na(v)1.8 and facilitates its functional expression within the cell membrane. We previously demonstrated that expression of Na(v)1.8 is up-regulated in cerebellar Purkinje cells in experimental allergic encephalomyelitis (EAE) and multiple sclerosis (MS). In this study we demonstrate that expression of p11 is significantly up-regulated in Purkinje cells in EAE (71 +/- 9.0% vs 21.3 +/- 4.9% in controls) and in MS(65.5 +/- 1.6% vs 21.8 +/- 6.2% in controls). We also demonstrate a high degree of co-expression of p11 and Na(v)1.8 (84.8 +/- 8.9%). Together with earlier results which show that experimental expression of Na(v)1.8 within Purkinje cells perturbs the temporal pattern of impulse generation in these cells, our results extend the evidence for an acquired channelopathy which interferes with cerebellar function in MS.

Animals↗