SARS-CoV-2 Virus and Human Leukocyte Antigen Class II: Investigation in silico of Binding Affinities for COVID-19 Protection and Vaccine Development
Human Leukocyte AntigenClass II molecule, not the antigen alone: in the absence of such a match, even a highly antigenic epitope in vitro will not elicit antibody formation in vivo. Here we assessed systematically in silico the binding affinity of epitopes of the spike-glycoprotein to 66 common
HLA-Class-II alleles (frequency ≥ 0.01). We used a sliding epitope window of 22-amino-acid-width to scan the entire protein and determined the binding affinity of each subsequence to each
HLAallele. DPB1 had highest binding affinities, followed by DRB1 and DQB1. Higher binding affinities were concentrated in the...
Nanomedicine: Photo-activated nanostructured titanium dioxide, as a promising anticancer agent
permalinkPharmacology & Therapeutics - 2021-06-01Lagopati N, Evangelou K, Falaras P, Tsilibary EC, Vasileiou PVS, Havaki S, Angelopoulou A, Pavlatour, Gorgoulis VG10.1016/j.pharmthera.2020.107795The multivariate condition of cancer disease has been approached in various ways, by the scientific community. Recent studies focus on individualized treatments, minimizing the undesirable consequences of the conventional methods, but the development of an alternative effective therapeutic scheme remains to be held. Nanomedicine could provide a solution, filling this gap, exploiting the unique properties of innovative nanostructured materials.
Nanostructured titanium dioxide (TiO2) has a variety of applications of daily routine and of advanced technology. Due to its biocompatibility, it has also a great number of biomedical applications. It is now clear that photo-excited TiO2 nanoparticles, induce generation of pairs of electrons and holes which react with water and oxygen to yield reactive oxygen species (ROS) that have been proven to damage cancer cells, triggering controlled cellular processes.
The aim of this review is to provide insights into the field of nanomedicine and particularly into the wide context of TiO2-NP-mediated anticancer effect, shedding...
Association of Lupus Anticoagulant with Brain Atrophy in Gulf War Illness
permalinkJournal of Immunological Sciences - 2021-05-27James L, Christova P, Johnson R, Engdahl B, Lewis S, Carpenter A, Georgopoulos APSeparate lines of research have documented brain atrophy and evidence of autoimmune mechanisms in
Gulf War Illness, including the presence of lupus anticoagulant (LAC), in veterans with
GWI. Here we evaluated the possible association of LAC and brain volume in veterans with
GWI. The presence of LAC was determined using Silica Clotting Time and dilute Russell's Viper Venom Time assays. MRI data was acquired using a Philips 3T MR scanner from which total gray matter, total cortical gray matter, total subcortical gray matter, and total cerebral white matter were derived. The results demonstrated a statistically significant reduction of brain volume in all regions tested in
GWIveterans with positive LAC, as compared to those without LAC. These findings add to the literature implicating autoimmune mechanisms in
GWIand point to the presence of prothrombotic antiphospholipid antibodies as contributing to brain atrophy in
Immunogenetic Epidemiology of Multiple Sclerosis in 14 Continental Western European Countries
HLADRB1*15:01 exerts the strongest susceptibility effect, although other
HLAalleles have been implicated in both susceptibility to, and protection against, MS. Here we utilized an immunogenetic epidemiological approach to evaluate correlations between the population frequencies of 127
HLAClass I and II alleles and the population prevalence of MS in 14 Continental Western European countries to identify an
HLAprofile for MS. The results of these analyses, which largely corroborated prior findings and revealed several novel and highly robust
HLAassociations with MS, revealed a larger number of protective
HLAalleles than susceptibility alleles, particularly for
HLAClass I. Given the role of
HLAin pathogen elimination and autoimmunity, these findings point to a contributory role of exposure to pathogens in the...
Biological Effect of Silver-modified Nanostructured Titanium Dioxide in Cancer
permalinkCancer Genomics & Proteomics - 2021-05-01Lagopati N, Kotsinas A, Veroutis D, Evangelou K, Papaspyropoulos A, Arfanis M, Falaras P, Kitsiou PV, Tsoukleris DS, Tsilibary EC, Gazouli M, Pavlatou EA, Gorgoulis VG10.21873/cgp.20269Nanomedicine is a promising scientific field that exploits the unique properties of innovative nanomaterials, providing alternative solutions in diagnostics, prevention and therapeutics. Titanium dioxide nanoparticles (TiO2 NPs) have a great spectrum of photocatalytic antibacterial and anticancer applications. The chemical modification of TiO2 optimizes its bioactive performance. The aim of this study was the development of silver modified NPs (Ag/TiO2 NPs) with anticancer potential. Materials and Methods: Ag/TiO2 NPs were prepared through the sol-gel method, were fully characterized and were tested on cultured breast cancer epithelial cells (MCF-7 and MDA-MB-231). The MTT colorimetric assay was used to estimate cellular viability. Western blot analysis of protein expression along with a
Deoxyribonucleic Acid-laddering assay were employed for apoptosis detection. Results and Conclusion: We show that photo-activated Ag/TiO2 NPs exhibited significant cytotoxicity on the highly malignant MDA-MB-231 cancer cells, inducing apoptosis, while MCF-7 cells that are characterized by low invasive properties were unaffected under the same...
Immunogenetic Epidemiology of Dementia and Parkinson's Disease in 14 Continental European Countries: Shared Human Leukocyte Antigen Profiles
HLAClass I and II alleles and the population prevalence of dementia and Parkinson's disease in 14 Continental Western European countries, extending previous work1,2. We used these correlations to construct and compare
HLAprofiles for each disease3. We found that (a) the
HLAprofiles of the two diseases were significantly correlated across both
HLAClass I and Class II alleles, (b) negative ("protective")
HLA-disease correlations did not differ significantly for either
HLAclass, but (c) positive ("susceptibility")
HLA-disease correlations were significantly higher in dementia than in Parkinson's disease for both
HLAclasses of alleles. These findings indicate that (a) dementia and Parkinson's disease share immunogenetic
HLA-related mechanisms, (b)
HLA-related protective mechanisms (presumably against pathogens) do...
Lupus Anticoagulant in Gulf War Illness and Autoimmune Disorders: A Common Pathway Toward Autoimmunity
permalinkJournal of Immunological Sciences - 2021-02-25James L, Johnson R, Lewis S, Carpenter A, Engdahl B, Krug HE, Georgopoulos APMounting evidence suggests that autoimmune mechanisms may underlie the chronic symptoms characteristic of
GWI. The presence of antiphospholipid antibodies including Lupus Anticoagulant (LA) are often associated with autoimmune disorders. Here we evaluated and compared blood samples from veterans with
GWIand veterans with other autoimmune conditions including relapsing remitting multiple sclerosis, rheumatoid arthritis, Sj"ogren's syndrome, and lupus for the presence of LA using Silica Clotting Time and dilute Russell's Viper Venom Time assays. Positive LA was identified in one-quarter of veterans with
GWI; this proportion was not statistically different from the proportion of positive LA identified in patients diagnosed with the other autoimmune conditions. The present findings add to the literature implicating autoimmune mechanisms in
GWIand point to the presence of prothrombotic antiphospholipid antibodies as a common contributing factor in
GWIand other autoimmune disorders. Furthermore, activation of the coagulation system suggests new potential avenues for treatment for...
Human Connectome Project: heritability of brain volumes in young healthy adults
permalinkExperimental Brain Research - 2021-02-21Christova P, Joseph J, Georgopoulos AP10.1007/s00221-021-06057-0Here we report on the heritability and Intraclass Correlation Coefficients (ICCs) of brain volumes in 1,103 young healthy adults with mean age 29.2 years. Among them are: 153 monozygotic (MZ) twin pairs and 86 dizygotic (DZ) twin pairs, 133 non-twin siblings of MZ twins, 76 non-twin siblings of DZ twins, 335 siblings, and 81 unrelated individuals. ICCs were calculated between pairs of the following genetic groups: (1) MZ twins; (2) DZ twins; (3) MZ twins—their singleton siblings; (4) DZ twins—their singleton siblings; (5) siblings (SB); and (6) unrelated individuals (NR). We studied 4 brain groups: global, lobar, subcortical, and cortical brain regions. For each of 4 brain groups we found the same order of ICCs ranging from the highest values for MZ twins, statistically significantly smaller for the DZ twins and 3 sibling groups, and practically zero for NR. The DZ twins and 3 sibling groups were not different. No hemispheric...
Human Leukocyte Antigens
The missing link in Alzheimer's disease etiology
Vaccines for Influenza
Synchronous neuronal interactions in rat hypothalamic culture: a novel model for the study of network dynamics in metabolic disorders
permalinkExperimental Brain Research - 2021-01-03Mavanji V, Georgopoulos AP, Kotz CM10.1007/s00221-020-05977-7Synchronous neural activity is a feature of normal brain function, and altered synchronization is observed in several neurological diseases. Dysfunction in hypothalamic pathways leads to obesity, suggesting that hypothalamic neural synchrony is critical for energy homeostasis. The lateral hypothalamic orexin neurons are extensively interconnected with other brain structures and are important for energy balance. Earlier studies show that rats with higher orexin sensitivity are obesity resistant. Similarly, topiramate, an anti-epileptic drug, has been shown to reduce weight in humans. Since orexin enhances neuronal excitation, we hypothesized that obesity-resistant rats with higher orexin sensitivity may exhibit enhanced hypothalamic synchronization. We further hypothesized that anti-obesity agents such as orexin and topiramate will enhance hypothalamic synchronization. To test this, we examined neural synchronicity in primary embryonic hypothalamic cell cultures, obtained from embryonic day 18 (E18) obesity-susceptible Sprague-Dawley (SD) and obesity-resistant rats. Hypothalamic tissue was cultured in multielectrode array (MEA), and recordings were performed twice...
Commentary: COVID-19 and the Path to Immunity
permalinkJournal of Immunological Sciences - 2020-11-23James L, Tsilibary EC, Charonis S, Georgopoulos APA recently published Viewpoint1 underscored the importance of T- and B- cell-mediated immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) but omitted to mention the very first step necessary to trigger those responses, namely the formation of a complex between the virus antigen and a suitably matching
HLAmolecule. Here, we discuss the role of
HLAin individual variability in immune response to SARS-CoV-2, emphasizing the implications of
HLAas potentially underlying sustained symptoms seen in "long-COVID", as distinguished from the severe, acute COVID-19, which is associated with "stormy" immune response.
Human Leukocyte Antigen Alleles Prevent Metabolically-Induced Inflammation and Cerebrocortical Thinning in Gulf War Illness
permalinkJournal of Neurology & Neuromedicine - 2020-10-20Christova P, James L, Carpenter A, Lewis S, Engdahl B, Georgopoulos APIndependent lines of research have demonstrated that
GWIis associated with elevated inflammatory markers, metabolic disruptions, and alterations in brain morphometry. Possessing specific Class II
HLAalleles, on the other hand, has been shown to protect against
GWIand to be inversely associated with symptom severity in a dose-dependent manner. The aim of the present study was to evaluate the association between C-reactive protein (CRP), a marker of inflammation, body mass index (BMI), and brain morphometry in
GWIveterans with and without a protective
HLAallele. Sixty-three veterans with
GWIprovided blood samples for evaluation of CRP and
HLA, height and weight for calculating BMI, and underwent a 3T magnetic resonance imaging scan from which the volume, surface area, and cortical thickness of 68 cortical regions of interest (ROI) were determined. Results demonstrated that the CRP was highly significantly associated with BMI and cortical thinning in veterans lacking...
C-Reactive Protein is Associated with Brain White Matter Anomalies in Gulf War Illness
permalinkJournal of Neurology & Neuromedicine - 2020-10-01Christova P, James L, Carpenter A, Lewis S, Johnson R, Engdahl B, Georgopoulos APIndependent lines of research have documented elevated peripheral inflammation and brain white matter alterations in
GWI. We recently documented an association of C-reactive protein (CRP), a marker of inflammation, and decreased fornix white matter integrity in
GWI. The aim of the present study was to extend those findings to evaluate the association between CRP and white matter anisotropy and diffusion throughout the brain in
GWI. Sixty-three veterans with
GWIprovided blood samples for evaluation of CRP and underwent a 3T magnetic resonance imaging scan from which fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) were obtained. An additional index characterizing the shape of the diffusion ellipsoid, Ca, which reflects deviation from sphericity (or isotropy) was obtained. Results demonstrated that CRP was significantly associated with decreased FA and Ca and with increased RD and MD, but not AD. These findings documenting a highly significant...
Shared Human Leukocyte Antigen Coverage in dementia and Parkinson's disease
HLAClass II DRB1 alleles that are protective or neutral with respect to dementia. Here we extend those findings to evaluate the association of the population frequency of
HLADRB1 alleles with the prevalence of dementia and Parkinson's disease in14 Continental Western European countries. Nine
HLADRB1 alleles were identified including four that are protective against dementia (DRB1*01:01, DRB1*04:01, DRB1*13:02, DRB1*15:01), three that are neutral (DRB1*03:01, DRB1*07:01, DRB1*08:01), and two susceptibility alleles (DRB1*11:01, DRB1*04:05). Results demonstrated that the population prevalence's of dementia and Parkinson's disease are highly correlated and that the association between the nine DRB1 alleles above and the population prevalence of dementia is highly overlapping with that of Parkinson's disease. These findings suggest a common
HLAClass II DRB1 profile. Given the diverse role of
HLAClass II alleles in...
Assessing Recovery from Mild Traumatic Brain Injury (Mtbi) using Magnetoencephalography : An Application of the Synchronous Neural Interactions Test
permalinkJournal of Neurology & Neuromedicine - 2020-09-03Thorpe D, Engdahl B, Leuthold A, Georgopoulos APMild traumatic brain injury (mTBI) affects 22% of U.S. service members returning from Afghanistan and Iraq. Its diagnosis is challenging due to the heterogeneous structural and functional alterations inflicted by diverse injury mechanisms. mTBI is diagnosed mainly based on history (trauma) and clinical evaluation, since conventional neuroimaging methods, such as magnetic resonance imaging (MRI) and computerized tomography (CT) of the brain, typically do not reveal clear abnormalities. Similarly, the assessment of recovery following mTBI relies exclusively on clinical evaluation, based on several criteria. With respect to brain function, we hypothesized that mTBI reflects disturbed dynamic interactions among neuronal populations, a disturbance not detectable by the aforementioned techniques. In a quest for an objective tool to detect the presence of mTBI and assess recovery from it, here we used
Magnetoencephalography, a modality highly suited to assess the dynamic functional status of the brain. Specifically, we used the
Gulf War Illness: C-Reactive Protein is Associated with Reduction of the Volume of Hippocampus and Decreased Fractional Anisotropy of the Fornix
permalinkJournal of Neurology & Neuromedicine - 2020-08-11Christova P, James L, Carpenter A, Lewis S, Johnson R, Engdahl B, Georgopoulos APMemory and mood impairments are among the most commonly reported symptoms in veterans with
GWI, suggesting hippocampal involvement. Several studies have also documented evidence of inflammation in
GWI. The aim of the present study was to evaluate the association between C-reactive protein (CRP), a marker of inflammation, and hippocampal volume and microstructural alterations of its major output, the fornix. Sixty-three veterans with
GWIprovided blood samples for evaluation of CRP and underwent a 3T magnetic resonance imaging scan from which hippocampal volume and fornix fractional anisotropy (FA) were obtained. Results demonstrated that CRP was significantly and negatively associated with hippocampal volume and fornix FA in
GWI. Given the known closely interwoven associations between inflammation and neurodegeneration, it is possible that the effects we observed could be due to neurodegeneration, secondary to chronic neuroinflammation. Finally, given the known association of hippocampus to memory and mood disorders, our findings provide...
Behavioral-genetic associations in the Human Connectome Project
permalinkExperimental Brain Research - 2020-08-10Christova P, Joseph J, Georgopoulos AP10.1007/s00221-020-05893-wThe Human Connectome Project (HCP) provides a rich dataset of quantitative and domain-specific behavioral measures from twins and extensive family structures. This makes the dataset a unique and a valuable resource to investigate heritability and determine individual differences. Using a set of measures of behavioral domains (motor, emotion, personality, sensory, and cognition), we estimated the intraclass correlations (ICCs) and heritability of 56 behavioral measures for 4 genetically identified groups of participants: monozygotic (MZ) twins, dizygotic (DZ) twins, non-twin siblings (SB), and unrelated individuals (NR). The ICCs range varied among behavioral domains but systematically so among the four genetic groups. We found the same rank order of ICCs, from the highest values for MZ twins, statistically significantly smaller for the DZ twins and sibling group (compared to MZ), and close to zero for NR. The mean heritability values of the five behavioral domains were: cognition h2 = 0.405, emotion h2 = 0.316, motor h2 = 0.138, personality h2 = 0.444,...
In silico assessment of binding affinities of three dementia-protective 2 Human Leukocyte Antigen alleles to nine human herpes virus 3 antigens
permalinkCurrent Research in Translational Medicine - 2020-07-02Charonis S, James L, Georgopoulos AP10.1016/j.retram.2020.06.002BackgroundHuman herpes viruses (HHV) have been implicated in dementia. Class II Human Leukocyte Antigens (
HLA) play a critical role in host protection from foreign antigens including herpes viruses through stimulating antibody production against them. In the present study we investigated the in silico binding affinity of 9 H HV to three Class II
HLAalleles that have been found to protect against dementia: DRB1*01:01, DRB1*13:02, and DRB1*15:01.
MethodsA sliding window approach was used to partition the amino acid sequences of surface glycoproteins from HHV 1-8 into subsequences. The binding affinity of the HHV subsequences to Class II
HLAsurface receptor proteins was predicted using the Sturniolo method in the Immune Epitope Database and reported as a percentile rank. The binding affinity of HHV subsequences to protective alleles was compared to that of three dementia-neutral Class II
HLAalleles: DRB1*03:01, DRB1*07:01, and DRB1*08:01.
FindingsBinding affinity varied widely for each
HLAallele, HHV type, and HHV subsequence....
Anthrax Protective Antigen 63 (PA63): Toxic Effects in Neural Cultures and Role in Gulf War Illness
permalinkNeuroscience Insights - 2020-06-30Tsilibary EC, Souto EP, Kratzke M, James L, Engdahl B, Georgopoulos AP10.1177/2633105520931966Protective antigen (PA) 63 (PA63) is a protein derived from the PA83 component contained in the anthrax vaccine. The anthrax vaccine ("Biothrax") was administered together with other vaccines to Gulf War veterans, about 35% of whom later developed a multisymptom disease (
GWI]), with prominent neurological/cognitive/mood symptoms, among others. The disease has been traditionally attributed to exposures to toxic chemicals during the war but other factors could be involved, including vaccines received. Of these, the anthrax vaccine is the most toxic. Here, we assessed directly the PA63 toxin's harmful effects on cultured neuroblastoma 2A (N2A) cells with respect to cell spreading, process formation, apoptosis, and integrity of cell membrane, cytoskeleton, and mitochondria. We found that, when added in N2A cultures, PA63 toxin led to decreased cell spreading and cell aggregation, leading to apoptosis. The mechanisms of PA63-induced cell damage included compromised cell membrane permeability indicated by enhanced access of...
Vaccine-Induced Adverse Effects in Cultured Neuroblastoma 2A (N2A) Cells Duplicate Toxicity of Serum from Patients with Gulf War Illness and Are Prevented in the Presence of Specific Anti-Vaccine Antibodies
permalinkVaccines - 2020-05-18Tsilibary EC, Souto EP, Kratzke M, James L, Engdahl B, Georgopoulos AP10.3390/vaccines8020232GWI is a chronic disease of unknown etiology affecting over 200,000 veterans with symptoms including neurocognitive problems. We previously demonstrated
GWIserum toxicity on neural cell cultures manifested by compromised neural network function, decreased cell spreading, and enhanced cell apoptosis. These patients lacked six
HLAclass II alleles, resulting in an inability to form antibodies. Therefore, we hypothesized that
GWIpatients have vaccine-derived, persistent pathogens, which contribute to the development of the disease. Here, we examined whether individual vaccines were toxic in cultured N2A cells. Moreover, we used antibodies against each of the 20 vaccines administered to Gulf War (GW) veterans, to examine the effects of these antibodies on cell spreading and apoptosis in N2A cells. Antibodies against cholera toxin, hepatitis B, hemagglutinin H1N1, H3N2, and B from influenza A and B strains, measles, and Salmonella Typhi polysaccharide Vi had a remarkable protective effect on...