Soluble peptide-MHC monomers cause activation of CD8+ T cells through transfer of the peptide to T cell MHC molecules

T cell receptor (TCR)-mediated activation of CD4(+) T cells is known to require multivalent engagement of the TCR by, for example, oligomeric peptide-MHC complexes. In contrast, for CD8(+) T cells, there is evidence for TCR-mediated activation by univalent engagement of the TCR. We have here compared oligomeric and monomeric L(d) and K(b) peptide-MHC complexes and free peptide as stimulators of CD8(+) T cells expressing the 2C TCR. We found that the monomers are indeed effective in activating naive and effector CD8(+) T cells, but through an unexpected mechanism that involves transfer of peptide from soluble monomers to T cell endogenous MHC (K(b)) molecules. The result is that T cells, acting as antigen-presenting cells, are able to activate other naive T cells.     

Mutated VH genes and preferential VH3-21 use define new subsets of mantle cell lymphoma

Mantle cell lymphoma (MCL) is believed to originate from a naive B cell. However, we recently demonstrated that a subset of MCL displayed mutated V(H) genes. We also reported restricted use of certain V(H) genes. To assess the prognostic impact of these new findings, we performed V(H) gene analysis of 110 patients, revealing that 18 (16%) patients had mutated and 92 (84%) patients had unmutated V(H) genes. Because the mutation rate was low in the mutated group (2.2%-6.7%), further investigation of the germline V(H) gene in T cells from 5 patients with mutated V(H) genes was carried out; results showed that the unrearranged V(H) gene was identical to the published sequence. These data confirm that the base pair substitutions within the rearranged V(H) genes represent hypermutations, and indicate germinal center exposure. However, V(H) gene mutation status did not correlate with prognosis because there was no difference in clinical outcome between the unmutated and mutated groups. The most frequently used V(H) genes were V(H)3-21 (21 patients) and V(H)4-34 (19 patients). A novel finding was that V(H)3-21(+) MCL almost exclusively expressed lambda light chains and displayed highly restricted use of the V(lambda)3-19 gene. V(H)3-21(+) patients had longer median survival than the remaining patients (53 vs 34 months; P =.03), but they tended to be younger at diagnosis. The combined use of V(H)3-21/V(lambda)3-19 suggests a possible role for antigen(s) in the pathogenesis of these tumors and indicates that V(H)3-21(+) patients constitute a new MCL entity.     

Association Between Vitamin D Status and COPD Phenotypes

Background

It has been suggested that identifying phenotypes in chronic obstructive pulmonary disease (COPD) might improve treatment outcome and the accuracy of prediction of prognosis. In observational studies vitamin D deficiency has been associated with decreased pulmonary function, presence of emphysema and osteoporosis, upper respiratory tract infections, and systemic inflammation. This could indicate a relationship between vitamin D status and COPD phenotypes. The aim of this study was to assess the association between vitamin D levels and COPD phenotypes. In addition, seasonality of vitamin D levels was examined.

Methods

A total of 91 patients from a Danish subpopulation of the “Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points” cohort took part in a biomarker substudy. Vitamin D concentration was measured from blood samples taken at two visits, approximately 6 months apart. The participants were 40–75-year-old patients with COPD and had a smoking history of >10 pack-years.

Results

Fifty-six patients had 25-hydroxyvitamin D measured from blood samples from both visits. In the final model of the multivariate analyses, the factors that were associated with vitamin D deficiency at the first visit were age (OR: 0.89, p = 0.02) and summer season (OR: 3.3, p = 0.03). Factors associated with vitamin D level also at the first visit were age (B: 0.9, p = 0.02) and 6 min walking distance (B: 0.05, p = 0.01).

Conclusion

Vitamin D was not associated with COPD phenotypes and season did not seem to be a determinant of vitamin D levels in patients with moderate to severe COPD.     

Survey of County-Level Heat Preparedness and Response to the 2011 Summer Heat in 30 U.S. States

Background: Adapting to extreme heat is becoming more critical as our climate changes. Previous research reveals that very few communities in the United States have programs to sufficiently prevent health problems during hot weather.Objective: Our goal was to examine county-level local heat preparedness and response in 30 U.S. states following the unusually hot summer of 2011.Methods: Using a multimodal survey approach, we invited local health and emergency response departments from 586 counties to participate in the largest survey to date of heat preparedness and response in the United States. County-level responses were pooled into national and regional-level summaries. Logistic regressions modeled associations between heat planning/response and county characteristics, including population, poverty rates, typical summer weather, and 2011 summer weather.Results: Of 586 counties, 190 (32%) responded to the survey. Only 40% of these counties had existing heat plans. The most common heat responses were communication about heat, outreach, and collaborations with other organizations. Both heat preparedness and heat response were, on average, more extensive in counties with higher populations, lower poverty rates, and lower percentages of older people. Heat response was generally more extensive in counties with heat plans.Conclusions: Most responding counties were underprepared for extreme heat in 2011 and lacked a formal response plan. Because counties with heat plans were more likely to act to prevent adverse heat impacts to residents, local health departments should consider adopting such plans, especially because increased extreme heat is anticipated with further climate change.Citation: White-Newsome JL, Ekwurzel B, Baer-Schultz M, Ebi KL, O’Neill MS, Anderson GB. 2014. Survey of county-level heat preparedness and response to the 2011 summer heat in 30 U.S. States. Environ Health Perspect 122:573–579; http://dx.doi.org/10.1289/ehp.1306693     

First assessment of classical swine fever marker vaccine candidate CP7_E2alf for oral immunization of wild boar under field conditions

Oral vaccination against classical swine fever (CSF) is a potent tool to control disease outbreaks in wild boar. So far, vaccination campaigns have been carried out using live attenuated vaccines that do not allow serological differentiation of infected from vaccinated animals (DIVA). Although this drawback is acceptable for wild boar, the use of marker vaccines would facilitate studies on disease and vaccination dynamics. Recently, the CSF marker vaccine candidate CP7_E2alf was assessed for oral immunization under laboratory conditions. Promising results prompted efforts to study the vaccine candidate under field conditions and in bait formulation. In this context, two oral vaccination campaigns were carried out with CP7_E2alf bait vaccines in two areas called ‘faunistic-hunting farms’ in the region of Umbria, Italy. One campaign was conducted using single vaccination, the second with the routinely employed double vaccination strategy. Both campaigns were carried out before concerted hunting actions were performed. Bait uptake, vaccine virus detection and antibody responses were assessed along with inspections upon gutting. As a comparator, seven wild boar were hand-fed with baits under laboratory conditions. In the field, bait uptake ranged from 63.7% to 98.7%, whereas antibody prevalence reached only 33.3–35.1%. The marker serology showed a strong influence of sample quality on the test outcome with a total of 85% of samples being classified correctly. Vaccine virus was not detectable. Under hand feeding conditions, six out of seven wild boar took up at least one bait, and five of them showed detectable antibody levels seven weeks after vaccination. These results were supplemented by stability tests. Appropriate stability of vaccine virus was shown both under field and laboratory conditions. In total, most results were in line with our expectations. However, optimization of the DIVA assay has to be attempted in the future.     

Salmonid alphavirus glycoprotein E2 requires low temperature and E1 for virion formation and induction of protective immunity

Salmonid alphavirus (SAV; also known as Salmon pancreas disease virus; family Togaviridae) causes pancreas disease and sleeping disease in Atlantic salmon and rainbow trout, respectively, and poses a major burden to the aquaculture industry. SAV infection in vivo is temperature-restricted and progeny virus is only produced at low temperatures (10–15 °C). Using engineered SAV replicons we show that viral RNA replication is not temperature-restricted suggesting that the viral structural proteins determine low-temperature dependency. The processing/trafficking of SAV glycoproteins E1 and E2 as a function of temperature was investigated via baculovirus vectors in Sf9 insect cells and by transfection of CHSE-214 fish cells with DNA constructs expressing E1 and E2. We identified SAV E2 as the temperature determinant by demonstrating that membrane trafficking and surface expression of E2 occurs only at low temperature and only in the presence of E1. Finally, a vaccination-challenge model in Atlantic salmon demonstrates the biological significance of our findings and shows that SAV replicon DNA vaccines encoding E2 elicit protective immunity only when E1 is co-expressed. This is the first study that identifies E2 as the critical determinant of SAV low-temperature dependent virion formation and defines the prerequisites for induction of a potent immune response in Atlantic salmon by DNA vaccination.     

ACEP Guidelines on Acute Nontraumatic Headache Diagnosis and Management in the Emergency Department,Commentary on Behalf of the Refractory,Inpatient, Emergency Care Section of the American Headache Society

The American College of Emergency Physicians (ACEP) published guidelines in July 2019 on the diagnosis and management of acute nontraumatic headaches in the emergency department, focusing predominantly on the diagnosis of subarachnoid hemorrhage and the role of imaging and lumbar puncture in diagnosis. The ACEP Clinical Policies document is intended to aide Emergency Physicians in their approach to patients presenting with acute headache and to improve the accuracy of diagnosis, while promoting safe patient care practices. The Clinical Policies document also highlights the need for future research into best practices to distinguish primary from secondary headaches and the efficacy and safety of current treatment options for acute headaches. The following commentary on these guidelines is intended to support and expand on these guidelines from the Headache specialists’ perspective, written on behalf of the Refractory, Inpatient, Emergency Care section of the American Headache Society (AHS). The commentary have been reviewed and approved by Board of Directors of the AHS.     

A familial frontotemporal dementia associated with C9orf72 repeat expansion and dysplastic gangliocytoma

A hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 gene (C9orf72) was recently identified as the most common genetic cause of frontotemporal dementia/amyotrophic lateral sclerosis. Here we describe the clinical, pathologic, and genetic features of a Finnish C9orf72 expansion carrier, who developed a dysplastic gangliocytoma (Lhermitte-Duclos disease), a rare hamartoma/overgrowth syndrome of cerebellar granule cells associated with mutations in the phosphatase and tensin homolog gene. In addition to the dysplastic gangliocytoma, the patient showed typical transactive response DNA-binding protein with M_r 43 kD (TDP-43) pathology mainly in the cortex and the substantia nigra and numerous p62-positive/TDP-43-negative inclusions in the cerebellar granule cells. His sister carried the same gene defect and showed a similar type of TDP-43/p62 pathology in her brain. Our findings confirm that the clinical and pathologic picture of C9orf72 mutation carriers is more heterogeneous than originally thought and warrants further studies on the possible involvement of phosphatase and tensin homolog gene pathway in the specific cerebellar granule cell pathology associated with C9orf72 expansion.