Laura J. Edwards

A prospective study of conditions associated with multiple sclerosis in a cohort of 658 consecutive outpatients attending a multiple sclerosis clinic

The cause of multiple sclerosis (MS) remains unknown. It is largely regarded as being an inflammatory autoimmune disease and has been reported in association with other inflammatory/autoimmune diseases. We performed a prospective study in 658 consecutive patients diagnosed with MS attending our outpatient MS management clinic between June 2002 and June 2003. Prevalence of associated conditions in these patients was calculated and compared with values from population studies using chi-square tests, odds ratios and confidence intervals. The MS population had significantly increased rates of asthma, inflammatory bowel disease, type I diabetes mellitus, pernicious anaemia, autoimmune thyroid disease, uveitis, seronegative spondyloarthropathies, bipolar disorder and melanoma compared to the general population. Both T helper type 1 (Th1)-mediated and T helper type 2 (Th2)-mediated diseases were significantly increased compared to the general population. There were also interesting associations seen with polyglandular autoimmune syndrome and rare single case associations. MS is associated with several other conditions. This work does not give evidence for the hypothesis that MS and atopy, reflecting Th1 and Th2 polarization, respectively, are mutually exclusive. Further work, ideally with a matched control population, is indicated.

Th17/Th1 phenotype in demyelinating disease

BACKGROUND Th17 cells are thought to contribute to the immunopathology of allergic and autoimmune conditions. Their role in multiple sclerosis (MS) pathology remains to be fully elucidated. OBJECTIVE To assess peripheral blood Th17 responses in patients with MS compared to controls. METHODS We isolated peripheral blood mononuclear cells from 41 MS patients and 23 healthy controls, which were then stimulated using phorbol ester and ionomycin, labelled for CD3, CD8, CD154, IL-17 and IFN-gamma and analysed using flow cytometry. RESULTS Minimal IL-17 was detectable in unstimulated cells. Following stimulation with phorbol ester and ionomycin, PBMCs taken from MS patients in relapse developed a more inflammatory profile than those taken from controls or non-relapse patients, with greater expression of CD154, IL-17 and dual expression of IL-17/IFN-gamma. CONCLUSION We suggest a greater tendency to Th17 and Th1/Th17 response to non-specific stimulation in MS patients in relapse compared to controls and non-relapse patients.

Platelet activating factor/platelet activating factor receptor pathway as a potential therapeutic target in autoimmune diseases.

Platelet activating factor (PAF) is a phospholipid mediator of inflammation that is released early in inflammation by a variety of cell types. PAF acts largely by binding to its receptor, PAF-R, a G-protein coupled receptor found on a variety of cells, including cells of the immune system. PAF has been implicated in the pathogenesis of asthma and allergic conditions, but its role in autoimmune conditions has been less extensively investigated. Here, we review the accumulating evidence for the role of PAF/PAF-R pathway in autoimmune diseases. We describe studies showing up-regulation of PAF-R in inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis and review the evidence from the use of PAF-R antagonists. We describe results of experimental models of inflammatory diseases that point to a role for PAF/PAF-R pathway including those using PAF-R antagonists and those employing PAF-R knockout mice and knockout mice for cytosolic phospholipase2. Recent experiments from our laboratory show that PAF/PAF-R pathway may influence T cell responses and favour the Th17 phenotype (in which T cells produce tissue destructive proinflammatory cytokine IL-17). The PAF/PAF-R pathway is a promising target for pharmacological intervention in autoimmune diseases.

Effects of pro-inflammatory cytokines on cannabinoid CB1 and CB2 receptors in immune cells

To investigate the regulation of cannabinoid receptors CB1 and CB2 on immune cells by pro‐inflammatory cytokines and its potential relevance to the inflammatory neurological disease, multiple sclerosis (MS).

Central inflammation versus peripheral regulation in multiple sclerosis

Th17 cells are a highly pro-inflammatory T-helper cell subset characterised by the expression of IL17. They have been implicated in a variety of allergic and autoimmune conditions. T-regulatory (Treg) cells, a subset of CD4 cells which express Foxp3, CD25, IL10 and TGFβ, can suppress the activity of Th17 cells. In this study, we show that the circulating levels of Th17 and Treg cells in peripheral blood are correlated; furthermore, the expression of the pro-inflammatory cytokine IL17 and the anti-inflammatory cytokine IL10 by CD4 cells are also correlated. However, we found no clear correlation between cerebrospinal fluid (CSF) IL10 and IL17 cytokine levels in MS, approaching a negative correlation at the time of relapse, and an overall negative correlation between CSF IL17 and TGFβ levels, suggesting a lack of central regulation of pro:anti-inflammatory balance in this demyelinating condition.

MiR-126 and miR-126* regulate shear-resistant firm leukocyte adhesion to human brain endothelium.

Leukocyte adhesion to brain endothelial cells, the blood-brain barrier main component, is a critical step in the pathogenesis of neuroinflammatory diseases such as multiple sclerosis (MS). Leukocyte adhesion is mediated mainly by selectins, cell adhesion molecules and chemokines induced by pro-inflammatory cytokines such as TNFα and IFNγ, but the regulation of this process is not fully clear. This study investigated the regulation of firm leukocyte adhesion to human brain endothelium by two different brain endothelial microRNAs (miRs), miR-126 and miR-126*, that are downregulated by TNFα and IFNγ in a human brain endothelial cell line, hCMEC/D3. Using a leukocyte adhesion in vitro assay under shear forces mimicking blood flow, we observed that reduction of endothelial miR-126 and miR-126* enhanced firm monocyte and T cell adhesion to hCMEC/D3 cells, whereas their increased expression partially prevented THP1, Jurkat and primary MS patient-derived PBMC firm adhesion. Furthermore, we observed that miR-126* and miR-126 downregulation increased E-selectin and VCAM1, respectively, while miR-126 overexpression reduced VCAM1 and CCL2 expression by hCMEC/D3 cells, suggesting that these miRs regulate leukocyte adhesion by modulating the expression of adhesion-associated endothelial mRNA targets. Hence, human brain endothelial miR-126 and miR-126* could be used as a therapeutic tool to reduce leukocyte adhesion and thus reduce neuroinflammation.

Parasite immunomodulation in autoimmune disease: focus on multiple sclerosis

There can be no argument that the past few generations have seen a marked change in the environment in the developed world; improved sanitation, access to antibiotics and vaccination are just some of the major changes that have been implemented with a view to improving health. Overall, this has been of great benefit, with the average life expectancy having increased by 32 years compared with a century ago in the UK [1,2]. One area of particular improvement has been the marked decrease in infectious diseases in the developed world, although this unfortunately seems to be being paralleled by a concomitant increase in certain allergic and autoimmune conditions [3]. This has been especially described in terms of childhood asthma [4–6] and Type I diabetes [7] but there is evidence that the incidence of multiple sclerosis (MS) is also on the increase [8,9]. This latter disease is necessarily a more contentious area, as improvements in access to neurology and imaging services over recent years confound some estimates, but it is agreed overall that the rise in the incidence of MS is real, and not only due to ascertainment bias [10]. While the etiology and immunopathogenesis of MS, like those of other autoimmune diseases, remain unclear, the disease is believed to be the end result of predisposing genetic factors inter acting with environmental factors to result in autoimmune CNS myelin damage. It would be difficult to attribute a change in the disease incidence over such a relatively short time period, such as we have seen with MS, to genetic changes. Hence, the examination of environmental factors may provide useful clues regarding the immuno pathology of this devastating neuro logical condition, and even some ideas for possible treatments.

Profiling Humoral Immune Responses to Clostridium difficile-Specific Antigens by Protein Microarray Analysis.

ABSTRACT Clostridium difficile is an anaerobic, Gram-positive, and spore-forming bacterium that is the leading worldwide infective cause of hospital-acquired and antibiotic-associated diarrhea. Several studies have reported associations between humoral immunity and the clinical course of C. difficile infection (CDI). Host humoral immune responses are determined using conventional enzyme-linked immunosorbent assay (ELISA) techniques. Herein, we report the first use of a novel protein microarray assay to determine systemic IgG antibody responses against a panel of highly purified C. difficile-specific antigens, including native toxins A and B (TcdA and TcdB, respectively), recombinant fragments of toxins A and B (TxA4 and TxB4, respectively), ribotype-specific surface layer proteins (SLPs; 001, 002, 027), and control proteins (tetanus toxoid and Candida albicans). Microarrays were probed with sera from a total of 327 individuals with CDI, cystic fibrosis without diarrhea, and healthy controls. For all antigens, precision profiles demonstrated <10% coefficient of variation (CV). Significant correlation was observed between microarray and ELISA in the quantification of antitoxin A and antitoxin B IgG. These results indicate that microarray is a suitable assay for defining humoral immune responses to C. difficile protein antigens and may have potential advantages in throughput, convenience, and cost.

Adequacy of Online Patient Information Resources on Gout and Potentially Curative Urate-Lowering Treatment

To assess the content and readability of online patient information resources against the current understanding of gout.

Online patient information resources on gout provide inadequate information and minimal emphasis on potentially curative urate lowering treatment.

To assess the content and readability of online patient information resources against the current understanding of gout.