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Select CMV epitopes drive life-long CD8 T cell memory inflation, but the extent of CD4 memory inflation is poorly studied. CD4 T cells specific for human CMV (HCMV) are elevated in HIV HCMV subjects. To determine whether HCMV epitope-specific CD4 T cell memory inflation occurs during HIV infection, we used HLA-DR7 (DRB1*07:01) tetramers loaded with the glycoprotein B DYSNTHSTRYV (DYS) epitope to characterize circulating CD4 T cells in coinfected HLA-DR7 long-term nonprogressor HIV subjects with undetectable HCMV plasma viremia. DYS-specific CD4 T cells were inflated among these HIV subjects compared with those from an HIV HCMV HLA-DR7 cohort or with HLA-DR7-restricted CD4 T cells from the HIV-coinfected cohort that were specific for epitopes of HCMV phosphoprotein-65, tetanus toxoid precursor, EBV nuclear Ag 2, or HIV gag protein. Inflated DYS-specific CD4 T cells consisted of effector memory or effector memory-RA subsets with restricted TCRβ usage and nearly monoclonal CDR3 containing novel conserved amino acids. Expression of this near-monoclonal TCR in a Jurkat cell-transfection system validated fine DYS specificity. Inflated cells were polyfunctional, not senescent, and displayed high ex vivo levels of granzyme B, CXCR1, CD38, or HLA-DR but less often coexpressed CD38 and HLA-DR The inflation mechanism did not involve apoptosis suppression, increased proliferation, or HIV gag cross-reactivity. Instead, the findings suggest that intermittent or chronic expression of epitopes, such as DYS, drive inflation of activated CD4 T cells that home to endothelial cells and have the potential to mediate cytotoxicity and vascular disease.
Copyright © 2017 by The American Association of Immunologists, Inc.
Cytomegalovirus (CMV) causes significant morbidity and mortality in congenitally infected children and immunocompromised hosts. Among healthy individuals, CMV is generally thought to cause mild, self-limited illness. CMV enterocolitis, in particular, is rarely considered among immunocompetent children presenting with diarrhea. We describe 2 cases of invasive CMV colitis in immunocompetent infants presenting with diarrhea and review the literature to date on this topic. Although invasive CMV enterocolitis has been sporadically reported among immunocompetent children, it remains an underrecognized cause of infectious diarrhea in this population and indications for antiviral therapy are lacking. We propose that CMV should be included in the differential diagnosis of intractable diarrhea in immunocompetent children.
Drug hypersensitivity syndromes such as abacavir hypersensitivity and the severe cutaneous adverse drug reactions have been associated with significant short- and long-term morbidity and mortality. More recently, these immunologically mediated and previously unpredictable diseases have been shown to be associated with primarily class I but also class II HLA alleles. The case of the association of HLA-B*57:01 and abacavir hypersensitivity has created a translational roadmap for how this knowledge can be used in the clinic to prevent severe reactions. Although many hurdles exist to the widespread translation of such HLA screening approaches, our understanding of how drugs interact with the major histocompatibility complex has contributed to the discovery of new models that have provided considerable insights into the immunopathogenesis of severe cutaneous adverse drug reactions and other T-cell-mediated drug hypersensitivity syndromes. Future translation of this knowledge will facilitate the development of preclinical toxicity screening to significantly improve efficacy and safety of drug development and design.
Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Although commonly asymptomatic, congenital CMV infection is the leading cause of nonhereditary SNHL. Other sequelae that may be evident only after the neonatal period can include chorioretinitis, neurodevelopmental delay with mental or motor impairment, and microcephaly. (13) • Congenital CMV infection is confirmed by detection of the virus in urine, blood, or saliva within the first 3 weeks of life by culture or polymerase chain reaction. A positive test does not necessarily confirm symptomatic CMV disease or need for treatment. (13) • Postnatal CMV infections transmitted through human milk have been reported and may be clinically relevant in extremely premature infants; however, the risk-benefit ratio of pasteurizing human milk for the prevention of postnatal CMV infection is unclear. • Ganciclovir, valganciclovir, foscarnet, cidofovir, and CMV hyperimmune globulin are effective in treating or preventing CMV infections in the immunocompromised host, but require close monitoring for associated toxicities. Treatment for congenital CMV is associated with significant toxicity and uncertain effectiveness. • Based on strong evidence, anticipatory guidance for congenital CMV infection should include hearing tests and neurodevelopmental assessments until school age. (3) In patients with symptomatic congenital CMV infection, lifelong ophthalmologic screening should be included. (4) • Based primarily on consensus, owing to lack of relevant clinical studies, it is not recommended to withhold human milk produced by CMV-seropositive mothers from healthy term infants. (5)(6) • Based on some research evidence, as well as consensus, treatment for congenital CMV is recommended only in symptomatic infants with central nervous system involvement. (9)
The goal of the present study was to determine the minimum concentration of systemic erythropoietin-R76E required for neuroprotection in the retina. Erythropoietin (EPO) exhibits neuroprotective effects in both in vitro and in vivo models of neuronal cell death although its classical function is the regulation of red blood cell production. It can cross the blood brain barrier and therefore can be delivered systemically to affect the retina. However, long-term treatment with exogenous erythropoietin causes polycythemia. To decrease this potentially lethal effect, we generated and tested a modified form that contains a single arginine to glutamate mutation at the 76th position (EPO-R76E). In previous studies, this mutant protected retinal neurons in mouse models of retinal degeneration and glaucoma with similar efficacy as wild-type EPO. However, EPO-R76E has attenuated erythropoietic activity, therefore, neuroprotection can be achieved without causing a significant rise in hematocrit. BALB/cByJ mice received a single intramuscular injection of recombinant adeno-associated virus carrying enhanced green fluorescent protein, Epo, or Epo-R76E. To result in continuous production of four different doses of EPO-R76E, two doses of two different serotypes (2/5 and 2/8) were used. Mice were subjected to optic nerve crush and analysis was performed thirty days later. EPO-R76E showed dose-dependent protection of the retinal ganglion cell bodies, but was unable to prevent axonal degeneration. Furthermore, EPO-R76E induced a dose-dependent rise in the hematocrit that was still attenuated as compared to wild-type EPO.
Copyright Â© 2012 Elsevier Ltd. All rights reserved.
Human cytomegalovirus induces and requires fatty acid synthesis. This suggests an essential role for lipidome remodeling in viral replication. We used mass spectrometry to quantify glycerophospholipids in mock-infected and virus-infected fibroblasts, as well as in virions. Although the lipid composition of mock-infected and virus-infected fibroblasts was similar, virions were markedly different. The virion envelope contained twofold more phosphatidylethanolamines and threefold less phosphatidylserines than the host cell. This indicates that the virus buds from a membrane with a different lipid composition from the host cell as a whole. Compared with published datasets, the virion envelope showed the greatest similarity to the synaptic vesicle lipidome. Synaptosome-associated protein of 25 kDa (SNAP-25) is a component of the complex that mediates exocytosis of synaptic vesicles in neurons; and its homolog, SNAP-23, functions in exocytosis in many other cell types. Infection induced the relocation of SNAP-23 to the cytoplasmic viral assembly zone, and knockdown of SNAP-23 inhibited the production of virus. We propose that cytomegalovirus capsids acquire their envelope by budding into vesicles with a lipid composition similar to that of synaptic vesicles, which subsequently fuse with the plasma membrane to release virions from the cell.
RATIONALE - Although airway inflammation can persist for years after smoking cessation in patients with chronic obstructive pulmonary disease (COPD), the mechanisms of persistent inflammation are largely unknown.
OBJECTIVES - We investigated relationships between bronchial epithelial remodeling, polymeric immunoglobulin receptor (pIgR) expression, secretory IgA (SIgA), airway inflammation, and mural remodeling in COPD.
METHODS - Lung tissue specimens and bronchoalveolar lavage were obtained from lifetime nonsmokers and former smokers with or without COPD. Epithelial structural changes were quantified by morphometric analysis. Expression of pIgR was determined by immunostaining and real-time polymerase chain reaction. Immunohistochemistry was performed for IgA, CD4 and CD8 lymphocytes, and cytomegalovirus and Epstein-Barr virus antigens. Total IgA and SIgA were measured by ELISA and IgA transcytosis was studied using cultured human bronchial epithelial cells.
MEASUREMENTS AND MAIN RESULTS - Areas of bronchial mucosa covered by normal pseudostratified ciliated epithelium were characterized by pIgR expression with SIgA present on the mucosal surface. In contrast, areas of bronchial epithelial remodeling had reduced pIgR expression, localized SIgA deficiency, and increased CD4(+) and CD8(+) lymphocyte infiltration. In small airways (<2 mm), these changes were associated with presence of herpesvirus antigens, airway wall remodeling, and airflow limitation in patients with COPD. Patients with COPD had reduced SIgA in bronchoalveolar lavage. Air-liquid interface epithelial cell cultures revealed that complete epithelial differentiation was required for normal pIgR expression and IgA transcytosis.
CONCLUSIONS - Our findings indicate that epithelial structural abnormalities lead to localized SIgA deficiency in COPD airways. Impaired mucosal immunity may contribute to persistent airway inflammation and progressive airway remodeling in COPD.
BACKGROUND - Information is limited on long-term outcomes after preemptive use of ganciclovir to control cytomegalovirus (CMV) infection in lung transplantation.
METHODS - We studied 78 lung recipients who received antithymocyte globulin induction from 1994 to 2000. All patients received six months of oral acyclovir (800 mg TID). This was interrupted three wk post transplantation for a two-wk course of IV ganciclovir. Additional courses of ganciclovir were administered based on serial virological monitoring. CMV-mismatched patients (R-D+) also received four doses of CMV immunoglobulin between weeks 2 and 8.
RESULTS - The one yr cumulative risk of CMV disease was 2% (1/61) in CMV seropositive (R+) patients, but was 37% (6/17) in R-D+ patients (p < 0.0001). Over 4.3 yr of follow-up, patients with CMV infection developed more chronic graft dysfunction caused by bronchiolitis obliterans or bronchiolitis obliterans syndrome than patients without CMV infection (p = 0.012). This effect was also apparent in the subgroup of R+ recipients (p = 0.043). Acute rejection and overall survival were not associated with CMV infection.
CONCLUSIONS - The use of prophylactic acyclovir and short preemptive courses of ganciclovir effectively controlled CMV disease in R+ patients, but was a relative failure in R-D+ patients. CMV infection was significantly associated with chronic graft dysfunction, even in R+ recipients who had good control of CMV symptoms.
ADAR2 is a double-stranded RNA-specific adenosine deaminase involved in the editing of mammalian RNAs by the site-specific conversion of adenosine to inosine. To examine the physiologic consequences resulting from ADAR2 misexpression, we have generated mutant mice expressing either wild-type or deaminase-deficient ADAR2 transgenes under the control of the human cytomegalovirus promoter. Transgenic mice expressing either wild-type or inactive ADAR2 isoforms demonstrated adult onset obesity characterized by hyperglycemia, hyperleptinemia, and increased adiposity. Paired feeding analysis revealed that mutant mice on caloric restriction had a growth rate and body composition indistinguishable from wild-type littermates, indicating that the observed obesity predominantly results from hyperphagia rather than a metabolic derangement. The observation that expression of catalytically inactive ADAR2 also is capable of producing an obese phenotype in mutant animals suggests that ADAR2 may possess additional biological activities beyond those required for the site-selective deamination of adenosine or may interfere with the actions of other double-stranded RNA-specific binding proteins in the cell.