Publications by authors named "Vincent C Lombardi"

32 Publications

Genome-Wide Identification of Rare and Common Variants Driving Triglyceride Levels in a Nevada Population.

Front Genet 2021 2;12:639418. Epub 2021 Mar 2.

Center for Genomic Medicine, Desert Research Institute, Reno, NV, United States.

Clinical conditions correlated with elevated triglyceride levels are well-known: coronary heart disease, hypertension, and diabetes. Underlying genetic and phenotypic mechanisms are not fully understood, partially due to lack of coordinated genotypic-phenotypic data. Here we use a subset of the Healthy Nevada Project, a population of 9,183 sequenced participants with longitudinal electronic health records to examine consequences of altered triglyceride levels. Specifically, Healthy Nevada Project participants sequenced by the Helix Exome+ platform were cross-referenced to their electronic medical records to identify: (1) rare and common single-variant genome-wide associations; (2) gene-based associations using a Sequence Kernel Association Test; (3) phenome-wide associations with triglyceride levels; and (4) pleiotropic variants linked to triglyceride levels. The study identified 549 significant single-variant associations ( < 8.75 × 10), many in chromosome 11's triglyceride hotspot: , , , . A well-known protective loss-of-function variant in (R19X) was associated with a 51% decrease in triglyceride levels in the cohort. Sixteen gene-based triglyceride associations were identified; six of these genes surprisingly did not include a single variant with significant associations. Results at the variant and gene level were validated with the UK Biobank. The combination of a single-variant genome-wide association, a gene-based association method, and phenome wide-association studies identified rare and common variants, genes, and phenotypes associated with elevated triglyceride levels, some of which may have been overlooked with standard approaches.
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http://dx.doi.org/10.3389/fgene.2021.639418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982958PMC
March 2021

Photocytotoxicity of Oligothienyl-Functionalized Chelates That Sensitize Ln Luminescence and Generate O.

Chemistry 2020 Sep 18;26(52):12060-12066. Epub 2020 Aug 18.

Department of Chemistry, University of Nevada, Reno, Reno, NV, 89557, USA.

Three new compounds containing a heptadentate lanthanide (Ln ) ion chelator functionalized with oligothiophenes, nThept(COOH) (n=1, 2, or 3), were isolated. Their Ln complexes not only display the characteristic metal-centered emission in the visible or near-infrared (NIR) but also generate singlet oxygen ( O ). Luminescence efficiencies (ϕ ) for [Eu1Thept(COO) ] and [Eu2Thept(COO) ] are ϕ =3 % and 0.5 % in TRIS buffer and 33 % and 3 % in 95 % ethanol, respectively. 3Thept(COO) does not sensitize Eu emission due to its low-lying triplet state. Near infra-red (NIR) luminescence is observed for all NIR-emitting Ln and ligands with efficiencies of ϕ =0.002 %, 0.005 % and 0.04 % for [YbnThept(COO) ] (n=1, 2, or 3), and ϕ =0.0007 %, 0.002 % and 0.02 % for [NdnThept(COO) ] (n=1, 2, or 3) in TRIS buffer. In 95 % ethanol, quantum yields of NIR luminescence increase and are ϕ =0.5 %, 0.31 % and 0.05 % for [YbnThept(COO) ] (n=1, 2, or 3), and ϕ =0.40 %, 0.45 % and 0.12 % for [NdnThept(COO) ] (n=1, 2, or 3). All complexes are capable of generating O in 95 % ethanol with ϕ efficiencies which range from 2 % to 29 %. These complexes are toxic to HeLa cells when irradiated with UV light (λ =365 nm) for two minutes. IC values for the Ln complexes are in the range 15.2-16.2 μm; the most potent compound is [Nd2Thept(COO) ] . The cell death mechanisms are further explored using an Annexin V-propidium iodide assay which suggests that cell death occurs through both apoptosis and necrosis.
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http://dx.doi.org/10.1002/chem.202001568DOI Listing
September 2020

A Comprehensive Genome-Wide and Phenome-Wide Examination of BMI and Obesity in a Northern Nevadan Cohort.

G3 (Bethesda) 2020 02 6;10(2):645-664. Epub 2020 Feb 6.

Institute for Health Innovation, Renown Health, Reno, NV

The aggregation of Electronic Health Records (EHR) and personalized genetics leads to powerful discoveries relevant to population health. Here we perform genome-wide association studies (GWAS) and accompanying phenome-wide association studies (PheWAS) to validate phenotype-genotype associations of BMI, and to a greater extent, severe Class 2 obesity, using comprehensive diagnostic and clinical data from the EHR database of our cohort. Three GWASs of 500,000 variants on the Illumina platform of 6,645 Healthy Nevada participants identified several published and novel variants that affect BMI and obesity. Each GWAS was followed with two independent PheWASs to examine associations between extensive phenotypes (incidence of diagnoses, condition, or disease), significant SNPs, BMI, and incidence of extreme obesity. The first GWAS examines associations with BMI in a cohort with no type 2 diabetics, focusing exclusively on BMI. The second GWAS examines associations with BMI in a cohort that includes type 2 diabetics. In the second GWAS, type 2 diabetes is a comorbidity, and thus becomes a covariate in the statistical model. The intersection of significant variants of these two studies is surprising. The third GWAS is a case control study, with cases defined as extremely obese (Class 2 or 3 obesity), and controls defined as participants with BMI between 18.5 and 25. This last GWAS identifies strong associations with extreme obesity, including established variants in the and genes, as well as loci not yet linked to obesity. The PheWASs validate published associations between BMI and extreme obesity and incidence of specific diagnoses and conditions, yet also highlight novel links. This study emphasizes the importance of our extensive longitudinal EHR database to validate known associations and identify putative novel links with BMI and obesity.
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http://dx.doi.org/10.1534/g3.119.400910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003082PMC
February 2020

Evaluation of four clinical laboratory parameters for the diagnosis of myalgic encephalomyelitis.

J Transl Med 2018 11 21;16(1):322. Epub 2018 Nov 21.

Department of Microbiology and Immunology, University of Nevada, Reno, School of Medicine, Reno, NV, USA.

Background: Myalgic encephalomyelitis (ME) is a complex and debilitating disease that often initially presents with flu-like symptoms, accompanied by incapacitating fatigue. Currently, there are no objective biomarkers or laboratory tests that can be used to unequivocally diagnosis ME; therefore, a diagnosis is made when a patient meets series of a costly and subjective inclusion and exclusion criteria. The purpose of the present study was to evaluate the utility of four clinical parameters in diagnosing ME.

Methods: In the present study, we utilized logistic regression and classification and regression tree analysis to conduct a retrospective investigation of four clinical laboratory in 140 ME cases and 140 healthy controls.

Results: Correlations between the covariates ranged between [- 0.26, 0.61]. The best model included the serum levels of the soluble form of CD14 (sCD14), serum levels of prostaglandin E2 (PGE), and serum levels of interleukin 8, with coefficients 0.002, 0.249, and 0.005, respectively, and p-values of 3 × 10, 1 × 10, and 3 × 10, respectively.

Conclusions: Our findings show that these parameters may help physicians in their diagnosis of ME and may additionally shed light on the pathophysiology of this disease.
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http://dx.doi.org/10.1186/s12967-018-1696-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249861PMC
November 2018

Single-nucleotide polymorphisms in a cohort of significantly obese women without cardiometabolic diseases.

Int J Obes (Lond) 2019 02 17;43(2):253-262. Epub 2018 Aug 17.

Nevada Center for Biomedical Research, Reno, NV, USA.

Background/objectives: Obesity is an important risk factor for the development of diseases such as diabetes mellitus, hypertension, and dyslipidemia; however, a small number of individuals with long-standing obesity do not present with these cardiometabolic diseases. Such individuals are referred to as metabolically healthy obese (MHO) and potentially represent a subgroup of the general population with a protective genetic predisposition to obesity-related diseases. We hypothesized that individuals who were metabolically healthy, but significantly obese (BMI ≥ 35 kg/m) would represent a highly homogenous subgroup, with which to investigate potential genetic associations to obesity. We further hypothesized that such a cohort may lend itself well to investigate potential genotypes that are protective with respect to the development of cardiometabolic disease.

Subjects/methods: In the present study, we implemented this novel selection strategy by screening 892 individuals diagnosed as Class 2 or Class 3 obese and identified 38 who presented no manifestations of cardiometabolic disease. We then assessed these subjects for single-nucleotide polymorphisms (SNPs) that associated with this phenotype.

Results: Our analysis identified 89 SNPs that reach statistical significance (p < 1 × 10), some of which are associated with genes of biological pathways that influences dietary behavior; others are associated with genes previously linked to obesity and cardiometabolic disease as well as neuroimmune disease. This study, to the best of our knowledge, represents the first genetic screening of a cardiometabolically healthy, but significantly obese population.
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http://dx.doi.org/10.1038/s41366-018-0181-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365206PMC
February 2019

Nutritional modulation of the intestinal microbiota; future opportunities for the prevention and treatment of neuroimmune and neuroinflammatory disease.

J Nutr Biochem 2018 11 19;61:1-16. Epub 2018 Apr 19.

Kazan Federal University, Institute of Fundamental Medicine and Biology, (Volga Region) 18 Kremlyovskaya St., Kazan, 420008, Republic of Tatarstan, Russian Federation; Asklepios-Med (private medical practice and research center), Kossuth Lajos sgt. 23, Szeged, H-6722, Hungary. Electronic address:

The gut-brain axis refers to the bidirectional communication between the enteric nervous system and the central nervous system. Mounting evidence supports the premise that the intestinal microbiota plays a pivotal role in its function and has led to the more common and perhaps more accurate term gut-microbiota-brain axis. Numerous studies have identified associations between an altered microbiome and neuroimmune and neuroinflammatory diseases. In most cases, it is unknown if these associations are cause or effect; notwithstanding, maintaining or restoring homeostasis of the microbiota may represent future opportunities when treating or preventing these diseases. In recent years, several studies have identified the diet as a primary contributing factor in shaping the composition of the gut microbiota and, in turn, the mucosal and systemic immune systems. In this review, we will discuss the potential opportunities and challenges with respect to modifying and shaping the microbiota through diet and nutrition in order to treat or prevent neuroimmune and neuroinflammatory disease.
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http://dx.doi.org/10.1016/j.jnutbio.2018.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195483PMC
November 2018

Serum Cytokine Profiles Differentiating Hemorrhagic Fever with Renal Syndrome and Hantavirus Pulmonary Syndrome.

Front Immunol 2017 18;8:567. Epub 2017 May 18.

Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.

Hantavirus infection is an acute zoonosis that clinically manifests in two primary forms, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). HFRS is endemic in Europe and Russia, where the mild form of the disease is prevalent in the Tatarstan region. HPS is endemic in Argentina, as well as other countries of North and South American. HFRS and HPS are usually acquired via the upper respiratory tract by inhalation of virus-contaminated aerosol. Although the pathogenesis of HFRS and HPS remains largely unknown, postmortem tissue studies have identified endothelial cells as the primary target of infection. Importantly, cell damage due to virus replication, or subsequent tissue repair, has not been documented. Since no single factor has been identified that explains the complexity of HFRS or HPS pathogenesis, it has been suggested that a cytokine storm may play a crucial role in the manifestation of both diseases. In order to identify potential serological markers that distinguish HFRS and HPS, serum samples collected during early and late phases of the disease were analyzed for 48 analytes using multiplex magnetic bead-based assays. Overall, serum cytokine profiles associated with HPS revealed a more pro-inflammatory milieu as compared to HFRS. Furthermore, HPS was strictly characterized by the upregulation of cytokine levels, in contrast to HFRS where cases were distinguished by a dichotomy in serum cytokine levels. The severe form of hantavirus zoonosis, HPS, was characterized by the upregulation of a higher number of cytokines than HFRS (40 vs 21). In general, our analysis indicates that, although HPS and HFRS share many characteristic features, there are distinct cytokine profiles for these diseases. These profiles suggest a strong activation of an innate immune and inflammatory responses are associated with HPS, relative to HFRS, as well as a robust activation of Th1-type immune responses. Finally, the results of our analysis suggest that serum cytokines profiles of HPS and HFRS cases are consistent with the presence of extracellular matrix degradation, increased mononuclear leukocyte proliferation, and transendothelial migration.
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http://dx.doi.org/10.3389/fimmu.2017.00567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435745PMC
May 2017

The Skin-Brain Connection Hypothesis, Bringing Together CCL27-Mediated T-Cell Activation in the Skin and Neural Cell Damage in the Adult Brain.

Front Immunol 2016 16;7:683. Epub 2017 Jan 16.

Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia; Nevada Center for Biomedical Research, Reno, NV, USA.

Recent discovery of an association of low serum melatonin levels with relapse in multiple sclerosis (MS) opens a new horizon in understanding the pathogenesis of this disease. Skin is the main organ for sensing seasonal changes in duration of sunlight exposure. Level of melatonin production is dependent on light exposure. The molecular mechanisms connecting peripheral (skin) sensing of the light exposure and developing brain inflammation (MS) have not been investigated. We hypothesize that there is a connection between the reaction of skin to seasonal changes in sunlight exposure and the risk of MS and that seasonal changes in light exposure cause peripheral (skin) inflammation, the production of cytokines, and the subsequent inflammation of the brain. In skin of genetically predisposed individuals, cytokines attract memory cutaneous lymphocyte-associated antigen (CLA+) T lymphocytes, which then maintain local inflammation. Once inflammation is resolved, CLA+ lymphocytes return to the circulation, some of which eventually migrate to the brain. Once in the brain these lymphocytes may initiate an inflammatory response. Our observation of increased CC chemokine ligand 27 (CCL27) in MS sera supports the involvement of skin in the pathogenesis of MS. Further, the importance of our data is that CCL27 is a chemokine released by activated keratinocytes, which is upregulated in inflamed skin. We propose that high serum levels of CCL27 in MS are the result of skin inflammation due to exposure to seasonal changes in the sunlight. Future studies will determine whether CCL27 serum level correlates with seasonal changes in sunlight exposure, MS exacerbation, and skin inflammation.
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http://dx.doi.org/10.3389/fimmu.2016.00683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237636PMC
January 2017

Previously Unidentified Single Nucleotide Polymorphisms in HIV/AIDS Cases Associate with Clinical Parameters and Disease Progression.

Biomed Res Int 2016 5;2016:2742648. Epub 2016 Dec 5.

Kazan Federal University, 18 Kremlyovskaya St., Kazan 420008, Russia.

The genetic background of an individual plays an important role in the progression of HIV infection to AIDS. Identifying previously unknown or uncharacterized single nucleotide polymorphisms (SNPs) that associate with disease progression may reveal important therapeutic targets and provide a greater understanding of disease pathogenesis. In the present study, we employed ultra-high multiplex PCR on an Ion Torrent next-generation sequencing platform to sequence 23 innate immune genes from 94 individuals with HIV/AIDS. This data was used to identify potential associations of SNPs with clinical parameters and disease progression. SNPs that associated with an increased viral load were identified in the genes for the interleukin 15 receptor (), toll-like receptor 7 (), tripartite motif-containing protein 5 (), and two killer-cell immunoglobulin-like receptors ( and ). Additionally, SNPs that associated with progression from HIV infection to AIDS were identified in two 2'-5'-oligoadenylate synthetase genes ( and ). In contrast, other SNPs identified in and genes, as well as in the and genes, were associated with a slower progression of disease. Taken together, our data demonstrates the utility of ultra-high multiplex PCR in identifying polymorphisms of potential clinical significance and further,identifies SNPs that may play a role in HIV pathogenesis.
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http://dx.doi.org/10.1155/2016/2742648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5165134PMC
February 2017

Serum Cytokine Signature That Discriminates Positive and Negative Juvenile Gastroduodenitis.

Front Microbiol 2016 15;7:1916. Epub 2016 Dec 15.

Institute of Fundamental Medicine and Biology, Kazan Federal University Kazan, Russia.

Gastroduodenitis caused by , often acquired in early childhood, is found in about 50% of the adult population. Although infections can remain asymptomatic, its virulence factors usually trigger epithelial vacuolization and degeneration, loss of microvilli, disintegration of cytoplasm, and leukocyte accumulation. It is believed that leukocyte infiltration is driven by cytokines produced locally in infected tissue. However, so far little is known about changes in serum cytokines in juvenile patients infected with . Serum cytokine profiles were analyzed in 62 juvenile patients diagnosed with gastroduodenitis using the Bio-Plex multiplex assay. infection was confirmed in 32 patients, while 30 patients were -free. Cytokines CXCL5 and CXCL6, potent neutrophil chemoattractants, were upregulated in all patients diagnosed with gastroduodenitis. Serum levels of IL8, a prototype neutrophil attractant, remained unchanged in subjects with gastroduodenitis relative to controls. Therefore, our data suggest that CXCL5 and CXCL6 play a role in directing neutrophil trafficking into inflamed gastroduodenal tissue. In addition, the CCL25/GM-CSF ratio differed significantly between -positive and -negative juveniles. Further, study is needed to evaluate the role of CCL25 and GM-CSF in the pathogenesis of the different etiologies of gastroduodenitis.
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http://dx.doi.org/10.3389/fmicb.2016.01916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5156714PMC
December 2016

Humoral Immunity Profiling of Subjects with Myalgic Encephalomyelitis Using a Random Peptide Microarray Differentiates Cases from Controls with High Specificity and Sensitivity.

Mol Neurobiol 2018 01 15;55(1):633-641. Epub 2016 Dec 15.

Nevada Center for Biomedical Research, 1664 N Virginia St. MS 0552, Reno, NV, 89557-0552, USA.

Myalgic encephalomyelitis (ME) is a complex, heterogeneous illness of unknown etiology. The search for biomarkers that can delineate cases from controls is one of the most active areas of ME research; however, little progress has been made in achieving this goal. In contrast to identifying biomarkers that are directly involved in the pathological process, an immunosignature identifies antibodies raised to proteins expressed during, and potentially involved in, the pathological process. Although these proteins might be unknown, it is possible to detect antibodies that react to these proteins using random peptide arrays. In the present study, we probe a custom 125,000 random 12-mer peptide microarray with sera from 21 ME cases and 21 controls from the USA and Europe and used these data to develop a diagnostic signature. We further used these peptide sequences to potentially uncover the naturally occurring candidate antigens to which these antibodies may specifically react with in vivo. Our analysis revealed a subset of 25 peptides that distinguished cases and controls with high specificity and sensitivity. Additionally, Basic Local Alignment Search Tool (BLAST) searches suggest that these peptides primarily represent human self-antigens and endogenous retroviral sequences and, to a minor extent, viral and bacterial pathogens.
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http://dx.doi.org/10.1007/s12035-016-0334-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472503PMC
January 2018

Transcriptional Analysis of Blood Lymphocytes and Skin Fibroblasts, Keratinocytes, and Endothelial Cells as a Potential Biomarker for Alzheimer's Disease.

J Alzheimers Dis 2016 10;54(4):1373-1383

Kazan Federal University, Kazan, Russia.

Alzheimer's disease (AD) is a devastating and progressive form of dementia that is typically associated with a build-up of amyloid-β plaques and hyperphosphorylated and misfolded tau protein in the brain. Presently, there is no single test that confirms AD; therefore, a definitive diagnosis is only made after a comprehensive medical evaluation, which includes medical history, cognitive tests, and a neurological examination and/or brain imaging. Additionally, the protracted prodromal phase of the disease makes selection of control subjects for clinical trials challenging. In this study we have utilized a gene-expression array to screen blood and skin punch biopsy (fibroblasts, keratinocytes, and endothelial cells) for transcriptional differences that may lead to a greater understanding of AD as well as identify potential biomarkers. Our analysis identified 129 differentially expressed genes from blood of dementia cases when compared to healthy individuals, and four differentially expressed punch biopsy genes between AD subjects and controls. Additionally, we identified a set of genes in both tissue compartments that showed transcriptional variation in AD but were largely stable in controls. The translational products of these variable genes are involved in the maintenance of the Golgi structure, regulation of lipid metabolism, DNA repair, and chromatin remodeling. Our analysis potentially identifies specific genes in both tissue compartments that may ultimately lead to useful biomarkers and may provide new insight into the pathophysiology of AD.
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http://dx.doi.org/10.3233/JAD-160457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5260811PMC
October 2016

Hantavirus Infection Suppresses Thrombospondin-1 Expression in Cultured Endothelial Cells in a Strain-Specific Manner.

Front Microbiol 2016 19;7:1077. Epub 2016 Jul 19.

Nevada Center for Biomedical ResearchReno, NV, USA; Department of Biochemistry and Molecular Biology, University of NevadaReno, NV, USA.

Hantavirus infection is associated with two frequently fatal diseases in humans: Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). The pathogenesis of hantavirus infection is complex and not fully understood; however, it is believed to involve virus-induced hyperinflammatory immune responses. Thrombospondin-1 (THBS1) is a large homotrimeric protein that plays a putative role in regulating blood homeostasis. Hyperresponsiveness to inflammatory stimuli has also been associated with defects in the THBS1 gene. Our data suggest that hantavirus infection of human umbilical cord vein endothelial cells (HUVEC) suppress the accumulation of THBS1 in the extracellular matrix. Additionally, this suppression is dependent on virus replication, implying a direct mechanism of action. Our data also imply that the pathogenic Andes and Hantaan strains inhibit THBS1 expression while the non-pathogenic Prospect Hill strain showed little inhibition. These observations suggest that a dysregulation of THBS1 may contribute to the pathogenesis of hantavirus infection.
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http://dx.doi.org/10.3389/fmicb.2016.01077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4950404PMC
August 2016

Decreased Numbers of CD57+CD3- Cells Identify Potential Innate Immune Differences in Patients with Autism Spectrum Disorder.

In Vivo 2016 Mar-Apr;30(2):83-9

Biomedical Centre for Autism Research and Treatment, Bari, Italy.

Background/aim: Autism spectrum disorders (ASD) are complex, and severe heterogeneous neurodevelopmental pathologies with accepted but complex immune system abnormalities. Additional knowledge regarding potential immune dysfunctions may provide a greater understanding of this malady. The aim of this study was to evaluate the CD57(+)CD3(-) mature lymphocyte subpopulation of natural killer cells as a marker of immune dysfunction in ASD.

Materials And Methods: Three-color flow cytometry-based analysis of fresh peripheral blood samples from children with autism was utilized to measure CD57(+)CD3(-) lymphocytes.

Results: A reduction of CD57(+)CD3(-) lymphocyte count was recorded in a significant number of patients with autism.

Discussion And Conclusion: We demonstrated that the number of peripheral CD57(+)CD3(-) cells in children with autism often falls below the clinically accepted normal range. This implies that a defect in the counter-regulatory functions necessary for balancing pro-inflammatory cytokines exists, thus opening the way to chronic inflammatory conditions associated with ASD.
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December 2016

Gut-Associated Plasmacytoid Dendritic Cells Display an Immature Phenotype and Upregulated Granzyme B in Subjects with HIV/AIDS.

Front Immunol 2015 24;6:485. Epub 2015 Sep 24.

Institute of Fundamental Medicine and Biology, Kazan Federal University , Kazan , Russia ; Nevada Center for Biomedical Research , Reno, NV , USA ; Department of Biochemistry and Molecular Biology, School of Medicine, University of Nevada , Reno, NV , USA.

Plasmacytoid dendritic cells (pDCs) in the periphery of subjects with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) decrease over time, and the fate of these cells has been the subject of ongoing investigation. Previous studies using animal models as well as studies with humans suggest that these cells may redistribute to the gut. Other studies using animal models propose that the periphery pDCs are depleted and gut is repopulated with naive pDCs from the bone marrow. In the present study, we utilized immunohistochemistry to survey duodenum biopsies of subjects with HIV/AIDS and controls. We observed that subjects with HIV/AIDS had increased infiltration of Ki-67(+)/CD303(+) pDCs, a phenotype consistent with bone marrow-derived pre-pDCs. In contrast, Ki-67(+)/CD303(+) pDCs were not observed in control biopsies. We additionally observed that gut-associated pDCs in HIV/AIDS cases upregulate the proapoptotic enzyme granzyme B; however, no granzyme B was observed in the pDCs of control biopsies. Our data are consistent with reports in animal models that suggest periphery pDCs are depleted by exhaustion and that naive pDCs egress from the bone marrow and ultimately infiltrate the gut mucosa. Additionally, our observation of granzyme B upregulation in naive pDCs may identify a contributing factor to the gut pathology associated with HIV infection.
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http://dx.doi.org/10.3389/fimmu.2015.00485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4585323PMC
October 2015

Multiplex Analysis of Serum Cytokines in Humans with Hantavirus Pulmonary Syndrome.

Front Immunol 2015 31;6:432. Epub 2015 Aug 31.

Whittemore Peterson Institute , Reno, NV , USA ; Department of Biochemistry, School of Medicine, University of Nevada , Reno, NV , USA.

Hantavirus pulmonary syndrome (HPS) is an acute zoonotic disease transmitted primarily through inhalation of virus-contaminated aerosols. Hantavirus infection of endothelial cells leads to increased vascular permeability without a visible cytopathic effect. For this reason, it has been suggested that the pathogenesis of HPS is indirect with immune responses, such as cytokine production, playing a dominant role. In order to investigate their potential contribution to HPS pathogenesis, we analyzed the serum of hantavirus-infected subjects and healthy controls for 68 different cytokines, chemokines, angiogenic, and growth factors. Our analysis identified differential expression of cytokines that promote tissue migration of mononuclear cells including T lymphocytes, natural killer cells, and dendritic cells. Additionally, we observed a significant upregulation of cytokines known to regulate leukocyte migration and subsequent repair of lung tissue, as well as cytokines known to increase endothelial monolayer permeability and facilitate leukocyte transendothelial migration. Conversely, we observed a downregulation of cytokines associated with platelet numbers and function, consistent with the thrombocytopenia observed in subjects with HPS. This study corroborates clinical findings and extends our current knowledge regarding immunological and laboratory findings in subjects with HPS.
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http://dx.doi.org/10.3389/fimmu.2015.00432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4553709PMC
September 2015

CCL27: Novel Cytokine with Potential Role in Pathogenesis of Multiple Sclerosis.

Biomed Res Int 2015 29;2015:189638. Epub 2015 Jul 29.

Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Tatarstan 420008, Russia.

Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease of unknown etiology. Leukocyte infiltration of brain tissue and the subsequent inflammation, demyelination, axonal damage, and formation of sclerotic plaques is a hallmark of MS. Upregulation of proinflammatory cytokines has been suggested to play an essential role in regulating lymphocyte migration in MS. Here we present data on serum cytokine expression in MS cases. Increased serum levels of IL-17 and IL-23 were observed, suggesting activation of the Th17 population of immune effector cells. Additionally, increased levels of IL-22 were observed in the serum of those with acute phase MS. Unexpectedly, we observed an upregulation of the serum chemokine CCL27 in newly diagnosed and acute MS cases. CCL27 is an inflammatory chemokine associated with homing of memory T cells to sites of inflammation. Therefore, its upregulation in association with MS suggests a potential role in disease pathogenesis. Our data supports previous reports showing IL-17 and -23 upregulation in association with MS and potentially identify a previously unknown involvement for CCL27.
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http://dx.doi.org/10.1155/2015/189638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532821PMC
April 2016

Differential immuno-reactivity to genomic DNA, RNA and mitochondrial DNA is associated with auto-immunity.

Cell Physiol Biochem 2014 4;34(6):2200-8. Epub 2014 Dec 4.

Kazan Federal University, Kazan, Russia.

Background: Circulating auto-reactive antibodies are hallmark features of auto-immune diseases, however little is known with respect to the specificity of such bio-markers. In the present study, we investigated the specificity of anti-nucleic acid antibodies in the blood of subjects with systemic lupus erythematosus (SLE) and healthy controls.

Methods: Sera from 12 SLE cases and 8 controls were evaluated for immuno-reactivity to purified RNA, DNA and mitochondrial DNA (mtDNA) by enzyme-linked immuno-sorbent assay (ELISA).

Results: As expected, immuno-reactivity to total nucleic acids was significantly higher in subjects with SLE when compared to healthy controls, however a clear distinction was observed among the various nucleic acid sub-types, with sera from SLE subjects displaying the greatest immuno-reactivity to RNA followed by mtDNA and then total DNA.

Conclusion: The identification of auto-reactive antibodies can serve as highly sensitive biomarkers, although their specificity may not always allow diagnostic certainty. The knowledge that auto-antibodies in subjects with SLE display differential immuno-reactivity may help to improve existing diagnostics and may lead to a better understanding of the pathogenesis of auto-immune disorders.
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http://dx.doi.org/10.1159/000369663DOI Listing
September 2015

Plasmacytoid dendritic cells, a role in neoplastic prevention and progression.

Eur J Clin Invest 2015 Jan;45 Suppl 1:1-8

Department of Biochemistry and Molecular Biology, University of Nevada School of Medicine, University of Nevada, Reno, NV, USA; Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Republic of Tatarstan, Russian Federation.

Background: Plasmacytoid dendritic cells (pDCs) are multifunctional bone-marrow-derived immune cells that are key players in bridging the innate and adaptive immune systems. Activation of pDCs through toll-like receptor agonists has proven to be an effective treatment for some neoplastic disorders.

Materials And Methods: In this mini-review, we will explore the fascinating contribution of pDCs to neoplastic pathology and discuss their potential utilization in cancer immunotherapy.

Results: Current research suggests that pDCs have cytotoxic potential and can effectively induce apoptosis of tumour-derived cells lines. They are also reported to display tolerogenic function with the ability to suppress T-cell proliferation, analogous to regulatory T cells. In this capacity, they are critical in the suppression of autoimmunity but can be exploited by tumour cells to circumvent the expansion of tumour-specific T cells, thereby allowing tumours to persist.

Conclusion: Several forms of skin cancer are successfully treated with the topical drug Imiquimod, which activates pDCs through toll-like receptor 7 engagement. Additionally, pDC-based anticancer vaccines have shown encouraging results for the treatment of melanoma in early trials. Future studies regarding the contributions of pDCs to malignancy will likely afford many opportunities for immunotherapy strategies.
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http://dx.doi.org/10.1111/eci.12363DOI Listing
January 2015

Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis.

Cytokine 2015 Mar 13;72(1):1-8. Epub 2014 Dec 13.

Department of Biochemistry and Molecular Biology, University of Nevada School of Medicine, Reno, NV, USA; WPI, Reno, NV, USA; Sierra Veterans Research and Education Foundation, VA Sierra Nevada Health Care System, Reno, NV, USA. Electronic address:

Gulf War illness (GWI) is a chronic disease of unknown etiology characterized by persistent symptoms such as cognitive impairment, unexplained fatigue, pervasive pain, headaches, and gastrointestinal abnormalities. Current reports suggest that as many as 200,000 veterans who served in the 1990-1991 Persian Gulf War were afflicted. Several potential triggers of GWI have been proposed including chemical exposure, toxins, vaccines, and unknown infectious agents. However, a definitive cause of GWI has not been identified and a specific biological marker that can consistently delineate the disease has not been defined. Myalgic encephalomyelitis (ME) is a disease with similar and overlapping symptomology, and subjects diagnosed with GWI typically fit the diagnostic criteria for ME. For these reasons, GWI is often considered a subgroup of ME. To explore this possibility and identify immune parameters that may help to understand GWI pathophysiology, we measured 77 serum cytokines in subjects with GWI and compared these data to that of subjects with ME as well as healthy controls. Our analysis identified a group of cytokines that identified ME and GWI cases with sensitivities of 92.5% and 64.9%, respectively. The five most significant cytokines in decreasing order of importance were IL-7, IL-4, TNF-α, IL-13, and IL-17F. When delineating GWI and ME cases from healthy controls, the observed specificity was only 33.3%, suggesting that with respect to cytokine expression, GWI cases resemble control subjects to a greater extent than ME cases across a number of parameters. These results imply that serum cytokines are representative of ME pathology to a greater extent than GWI and further suggest that the two diseases have distinct immune profiles despite their overlapping symptomology.
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http://dx.doi.org/10.1016/j.cyto.2014.11.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4410698PMC
March 2015

Inflammatory cytokines kinetics define the severity and phase of nephropathia epidemica.

Biomark Med 2015 14;9(2):99-107. Epub 2014 Oct 14.

Bashkir State Medical University, Ufa, Republic of Bashkortostan, Russian Federation.

Aims: Nephropathia epidemica (NE) is a form of hemorrhagic fever with renal syndrome associated with the Puumala virus species of Hantavirus. The pathogenesis of NE is not well understood; therefore, investigating the inflammatory cytokine response to infection may provide useful knowledge in deciphering the pathophysiology of NE.

Materials & Methods: Using Luminex and ELISA, we analyzed the serum of 137 NE cases and 44 controls to investigate if serum cytokines associate with different clinical presentations.

Results: Serum levels of TNF-α and IL-1β are associated with disease severity while upregulation of IL-6, CXCL10, CCL2 and CCL3 are associated with clinical presentation.

Conclusion: Inflammatory cytokine kinetics associate with the severity and phase of NE. Our data support a role for inflammatory cytokines in the pathophysiology of NE.
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http://dx.doi.org/10.2217/bmm.14.88DOI Listing
December 2015

Plasmacytoid dendritic cells of the gut: relevance to immunity and pathology.

Clin Immunol 2014 Jul 24;153(1):165-77. Epub 2014 Apr 24.

Department of Biochemistry and Molecular Biology, University of Nevada School of Medicine, WPI, University of Nevada, Reno, 1664 N Virginia St. MS 0552, Reno, NV 89557, USA; Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia. Electronic address:

Plasmacytoid dendritic cells (pDCs) are bone marrow-derived immune cells with the ability to express copious amounts of type I and III interferon (IFN) and can differentiate into antigen-presenting dendritic cells as a result of stimulation by pathogen-derived nucleic acid. These powerful combined functionalities allow pDCs to bridge the innate and adaptive immune systems resulting in a concerted pathogen response. The contribution of pDCs to gastrointestinal immunity is only now being elucidated and is proving to be a critical component in systemic immunity. This review will explore the immunology of pDCs and will discuss their involvement in human disease and tolerance with an emphasis on those in the gastrointestinal lymphoid tissue.
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http://dx.doi.org/10.1016/j.clim.2014.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063559PMC
July 2014

Human dendritic cells transfected with a human papilloma virus-18 construct display decreased mobility and upregulated cytokine production.

Int J Oncol 2013 Nov 21;43(5):1701-9. Epub 2013 Aug 21.

Department of Biochemistry and Molecular Biology, University of Nevada, Reno, NV 89557, USA.

The marked depletion of dendritic cells (DCs) in skin cancers, as well as preneoplastic and neoplastic cervical epithelium, suggests a central role for DCs in productive human papillomavirus (HPV) infection and cancer promotion. It has been suggested that HPV may facilitate tumor development by reducing DC density, contributing to a decrease in local immune surveillance. In this study, we have examined the response of human DCs transfected with a construct containing the HPV18 genome and their subsequent expression of papilloma virus proteins. Transfected cells expressed the L1 major capsid protein and upregulated E6 and E7 oncoprotein transcripts as detected by RT-PCR. Transfection of DCs also resulted in a significant increase in cytokine production. Finally, we observed that HPV18 transfection decreased the migratory activity of DCs. Our data indicate that HPV transfection of DCs leads to changes in migratory activity and cytokine production, which potentially can suppress or delay immune responses to viral antigens. Additionally, changes in cytokine production by HPV-transformed human fibroblasts and human cervical epithelial cells revealed that the migratory and antigen-presenting functions of DCs may be impaired by the suppressive effects of cytokines produced by HPV-infected epithelial and stromal cells.
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http://dx.doi.org/10.3892/ijo.2013.2074DOI Listing
November 2013

Death-domain associated protein-6 (DAXX) mediated apoptosis in hantavirus infection is counter-balanced by activation of interferon-stimulated nuclear transcription factors.

Virology 2013 Sep 3;443(2):338-48. Epub 2013 Jul 3.

Whittemore Peterson Institute, University of Nevada-Reno, Reno, USA.

Hantaviruses are negative strand RNA species that replicate predominantly in the cytoplasm. They also activate numerous cellular responses, but their involvement in nuclear processes is yet to be established. Using human umbilical vein endothelial cells (HUVECs), this study investigates the molecular finger-print of nuclear transcription factors during hantavirus infection. The viral-replication-dependent activation of pro-myelocytic leukemia protein (PML) was followed by subsequent localization in nuclear bodies (NBs). PML was also found in close proximity to activated Sp100 nuclear antigen and interferon-stimulated gene 20 kDa protein (ISG-20), but co-localization with death-domain associated protein-6 (DAXX) was not observed. These data demonstrate that hantavirus triggers PML activation and localization in NBs in the absence of DAXX-PLM-NB co-localization. The results suggest that viral infection interferes with DAXX-mediated apoptosis, and expression of interferon-activated Sp100 and ISG-20 proteins may indicate intracellular intrinsic antiviral attempts.
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http://dx.doi.org/10.1016/j.virol.2013.05.024DOI Listing
September 2013

Plasmacytoid dendritic cells in the duodenum of individuals diagnosed with myalgic encephalomyelitis are uniquely immunoreactive to antibodies to human endogenous retroviral proteins.

In Vivo 2013 Mar-Apr;27(2):177-87

Whittemore Peterson Institute for Neuro-Immune Disease, University of Nevada, Reno 1664 N Virginia Street MS 0552, Reno, NV 89557 USA.

Myalgic encephalomyelitis (ME) is a debilitating illness of unknown etiology characterized by neurocognitive dysfunction, inflammation, immune abnormalities and gastrointestinal distress. An increasing body of evidence suggests that disruptions in the gut may contribute to the induction of neuroinflammation. Therefore, reports of human endogenous retroviral (HERV) expression in association with neuroinflammatory diseases prompted us to investigate the gut of individuals with ME for the presence of HERV proteins. In eight out of 12 individuals with ME, immunoreactivity to HERV proteins was observed in duodenal biopsies. In contrast, no immunoreactivity was detected in any of the eight controls. Immunoreactivity to HERV Gag and Env proteins was uniquely co-localized in hematopoietic cells expressing the C-type lectin receptor CLEC4C (CD303/BDCA2), the co-stimulatory marker CD86 and the class II major histocompatibility complex HLA-DR, consistent with plasmacytoid dendritic cells (pDCs). Although the significance of HERVs present in the pDCs of individuals with ME has yet to be determined, these data raise the possibility of an involvment of pDCs and HERVs in ME pathology. To our knowledge, this report describes the first direct association between pDCs and HERVs in human disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776582PMC
August 2013

Andes-virus-induced cytokine storm is partially suppressed by ribavirin.

Antivir Ther 2013 8;18(4):575-84. Epub 2013 Jan 8.

Whittemor Peterson Institute, University of Nevada-Reno, Reno, NV, USA.

Background: Microbe-induced over-activation of cytokines, especially tumour necrosis factor (TNF)-α, is key to the pathogenesis of hantavirus infection leading to severe inflammation with high mortality rate. Although ribavirin showed promise in inhibiting viral replication in vitro, its clinical efficacy remains controversial.

Methods: Various concentrations of ribavirin were used to determine its effect on cytokine activation in our infectious model system.

Results: Ribavirin decreased the virus load and dose-dependently inhibited the accumulation of RANTES messenger RNA in Andes-virus (ANDV)-infected human endothelial cells, but failed to suppress TNF-α-induced activation of RANTES and interleukin-6 in ANDV-inoculated cultures. This report also shows, for the first time, that the deleterious over-stimulation by TNF-α is mediated by nuclear factor-κB, and describes the effect of ribavirin on cytokine production following ANDV infection.

Conclusions: Although highly effective in preventing ANDV replication and suppressing activation of select inflammatory mediators, the therapeutic efficacy of ribavirin is limited due to its inability to fully inhibit cytokine outburst triggered by hantavirus infection.
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http://dx.doi.org/10.3851/IMP2524DOI Listing
April 2014

Xenotropic murine leukemia virus-related virus-associated chronic fatigue syndrome reveals a distinct inflammatory signature.

In Vivo 2011 May-Jun;25(3):307-14

Whittemore Peterson Institute, University of Nevada, Reno MS 0552, 1664 N. Virginia St. Reno, NV 89557-0552, USA.

Background: The recent identification of xenotropic murine leukemia virus-related virus (XMRV) in the blood of patients with chronic fatigue syndrome (CFS) establishes that a retrovirus may play a role in the pathology in this disease. Knowledge of the immune response might lead to a better understanding of the role XMRV plays in this syndrome. Our objective was to investigate the cytokine and chemokine response in XMRV-associated CFS.

Materials And Methods: Using Luminex multi-analyte profiling technology, we measured cytokine and chemokine values in the plasma of XMRV-infected CFS patients and compared these data to those of healthy controls. Analysis was performed using the Gene Expression Pattern Analysis Suite and the Random Forest tree classification algorithm.

Results: This study identifies a signature of 10 cytokines and chemokines which correctly identifies XMRV/CFS patients with 93% specificity and 96% sensitivity.

Conclusion: These data show, for the first time, an immunological pattern associated with XMRV/CFS.
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August 2011

Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome.

Virulence 2010 Sep-Oct;1(5):386-90

Whittemore Peterson Institute, Reno, Nevada, USA.

In October 2009, we reported the first direct isolation of infectious xenotropic murine leukemia virus-related virus (XMRV). In that study, we used a combination of biological amplification and molecular enhancement techniques to detect XMRV in more than 75% of 101 patients with chronic fatigue syndrome (CFS). Since our report, controversy arose after the publication of several studies that failed to detect XMRV infection in their CFS patient populations. In this addenda, we further detail the multiple detection methods we used in order to observe XMRV infection in our CFS cohort. Our results indicate that PCR from DNA of unstimulated peripheral blood mononuclear cells is the least sensitive method for detection of XMRV in subjects' blood. We advocate the use of more than one type of assay in order to determine the frequency of XMRV infection in patient cohorts in future studies of the relevance of XMRV to human disease.
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http://dx.doi.org/10.4161/viru.1.5.12486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073172PMC
April 2011

Distribution of xenotropic murine leukemia virus-related virus (XMRV) infection in chronic fatigue syndrome and prostate cancer.

AIDS Rev 2010 Jul-Sep;12(3):149-52

Whittemore-Peterson Institute for Neuroimmune Diseases, University of Nevada, Reno, NV 89557, USA.

In 2006, sequences described as xenotropic murine leukemia virus-related virus (XMRV) were discovered in prostate cancer patients. In October 2009, we published the first direct isolation of infectious XMRV from humans and the detection of infectious XMRV in patients with chronic fatigue syndrome. In that study, a combination of classic retroviral methods were used including: DNA polymerase chain reaction and reverse transcriptase polymerase chain reaction for gag and env, full length genomic sequencing, immunoblotting for viral protein expression in activated peripheral blood mononuclear cells, passage of infectious virus in both plasma and peripheral blood mononuclear cells to indicator cell lines, and detection of antibodies to XMRV in plasma. A combination of these methods has since allowed us to confirm infection by XMRV in 85% of the 101 patients that were originally studied. Since 2009, seven studies, predominantly using DNA polymerase chain reaction of blood products or tumor tissue, have reported failures to detect XMRV infection in patients with either prostate cancer or chronic fatigue syndrome. A review of the current literature on XMRV supports the importance of applying multiple independent techniques in order to determine the presence of this virus. Detection methods based upon the biological and molecular amplification of XMRV, which is usually present at low levels in unstimulated blood cells and plasma, are more sensitive than assays for the virus by DNA polymerase chain reaction of unstimulated peripheral blood mononuclear cells. When we examined patient blood samples that had originally tested negative by DNA polymerase chain reaction by more sensitive methods, we observed that they were infected with XMRV; thus, the DNA polymerase chain reaction tests provided false negative results. Therefore, we conclude that molecular analyses using DNA from unstimulated peripheral blood mononuclear cells or from whole blood are not yet sufficient as stand-alone assays for the identification of XMRV-infected individuals. Complementary methods are reviewed, that if rigorously followed, will likely show a more accurate snapshot of the actual distribution of XMRV infection in humans.
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November 2010