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...
Human Leukocyte Antigens
The missing link in Alzheimer's disease etiology
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 - 2020-10-20Savayan PC, James L, Carpenter A, Lewis S, Engdahl B, Georgopoulos APIndependent lines of research have demonstrated that
Gulf War Illnessis 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 - 2020-10-01Savayan PC, 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 - 2020-08-11Savayan PC, 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 - 2020-08-10Savayan PC, 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.2020.06.002Background
Human 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.
A 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.
Binding 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...
permalinkJustin Harris (University of Minnesota Legacy) - 2020-05-01
It was 2010, and Kunin and her friends and fellow philanthropists Barbara Forster and Sally Kling were meeting with Apostolos Georgopoulos, a Regents Professor and McKnight Presidential Chair in Cognitive Neuroscience at the University of Minnesota Medical School. Georgopoulos was asking for their support in launching a first-of-its-kind study of women's brain health across the lifespan. He wanted to know: Why do some women show signs of cognitive decline as they age while others do not? Kunin, Forster, and Kling were interested in helping him find answers. They shared the idea with other like-minded women, hosting small fundraising gatherings and meet-and-greets with Georgopoulos, and sent letters to more than 170 people asking for gifts of any size...
Dementia Prevention Linked to Disposal of Pathogenic Debris
permalinkUMN Inquiry - Deane Morrison - 2020-02-21
What if surviving an infection like herpes, pneumonia, or Lyme desease set you up for dementia later in life?For some people that is, sadly, the case, studies by two University of Minnesota researchers indicate. Evidence is mounting that proteins in fragments of bacteria, viruses, or other pathogens left over from battles with our immune system can harm the brain and raise the chance of dementia. These proteins are all termed "antigenic" - i.e., able to provoke an immune response, especially one involving antibody production.But Lisa James, PhD, and Apostolos Georgopoulos, MD, PhD, have also found that many people have genes that shield against such an outcome. And now they have demonstrated their beneficial effects across the populations of entire countries.Article Continued at Publisher's Site.
Tri-Allelic Human Leukocyte Antigen Protection Against Dementia
HLAalleles - DRB1*01:01 and DRB1*15:01 - alone and in combination with DRB1*13:02, on dementia prevalence in Continental Western Europe. Results indicated that the prevalence of dementia in 14 Continental Western European (CWE) countries significantly decreased exponentially with increasing frequency of any of the three alleles alone and in combination (P's < 0.001). When combined, the population frequency of the three alleles accounted for 67% of the variance in dementia prevalence. The combined frequency of DRB1*01:01, DRB1*13:02, and DRB1*15:01 was also significantly associated with dementia prevalence in those aged 65 years and older (P = 0.004) and with a change in dementia prevalence between 1990 and 2016 (P = 0.006). These findings, which document the protective effects of three common Class II HLA alleles on dementia prevalence in CWE, are discussed in terms of the role of HLA class II genes in pathogen elimination. More specifically, we hypothesize that dementia prevalence is higher for countries in which the population frequency of these protective alleles is low, prohibiting the successful elimination of pathogens that may play a causal role in dementia.>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
Dementias Caused by Persistent Pathogens and the Protective Role of Human Leukocyte Antigen Against them
HLA) in maintaining brain health by facilitating the elimination of pathogens and highlight evidence suggesting that the inability to eliminate pathogens contributes to dementia. Finally, we briefly review common forms of dementia including Alzheimer's disease, vascular dementia, frontotemporal dementia, Lewy body dementia, and prion dementia in an effort to contextualize the role of persistent pathogens across the various dementia phenotypes.
Heritability of Behavioral and Brain Measures in a Large Cohort of Healthy Twin and non-Twin Subjects
permalinkBioinformatics and Computational Biology, University of Minnesota - 2019-12-05Joseph J, Georgopoulos AP, Savayan PCThis research investigated comprehensively the effects of genetics on behavioral traits, brain structure and function, and their associations in a large cohort of monozygotic (MZ) twins, dizygotic (DZ) twins, non-twin siblings (SIB) and non related (NR) individuals (N = 1206, total) provided by the Human Connectome Project (HCP). All primary measures available are of the highest quality and quantitatively assessed. They include the following for each individual: (a) Measures of behavioral traits in 5 domains (motor, sensory, cognitive, emotion, and personality); (b) volumes of 70 cortical brain areas extracted from high-resolution (0.7 mm isotropic)
Structural Magnetic Resonance Imagingdata; (c) resting-state blood oxygenation level dependent (BOLD) activity of the same areas extracted from long-duration (1200 volumes), fast-acquisition (every 0.72 s), high-resolution (2 mm isotropic) functional MRI (
Functional Magnetic Resonance Imaging) data; and (d) white matter integrity measures (fractional anisotropy [FA] and mean diffusivity [MD] for 7 brain regions regions) derived from high angular...
Anthrax and Gulf War Illness: Evidence for the Presence of Harmful Anthrax Antigen PA63 In the Serum of Veterans with GWI
permalinkJournal of Neurology & Neuromedicine - 2019-11-25Tsilibary EC, Souto EP, Kratzke M, James L, Engdahl B, Georgopoulos APGWI is a multisystem disorder of unknown etiology that has afflicted many veterans of the 1990-91 Gulf War who have sustained progressively worsening health since the war. Recent studies have demonstrated the presence of active inflammation in
GWIand, in addition, a positive association of the levels of C-reactive protein (CRP), an inflammatory marker, with
GWIsymptom severity. Moreover, we have shown that
GWIserum contains substances that are harmful to neural cultures`, a detrimental effect that can be prevented by serum of healthy GW veterans and partially so by pooled human immunoglobulin G (IgG). Although possible exposure to environmental toxins in war theater has been traditionally blamed for
GWI6, the evidence above and the fact that the disease also afflicted nondeployed veterans, point to other causes, including the vaccines administered to GW veterans, such as the vaccine against anthrax. Here we present, for the first time, evidence...
In Silico Analysis of the Binding Affinities of Antigenic Epitopes of Vaccines Administered to Gulf War Veterans to Specific HLA Class II Alleles Protective for GWI
HLAclass II alleles that are protective for
GWI, namely DPB1*01:01, DPB1*06:01, DQB1*02:02, DRB1*01:01, DRB1*08:11, and DRB1*13:02. Since the function of
HLAclass II molecules is to connect with matching extracellular antigens of various pathogens (mostly viruses), as an initial step in the sequence of events leading to the development of antibodies against the matched antigen and its subsequent elimination, we hypothesized that
GWImay be due, in part, to the persistence of offending antigens which could not be eliminated. We further hypothesized that such antigens were contained in the 16 vaccines administered to GW veterans against adenovirus, anthrax, botulinum, cholera, diphtheria, hepatitis B, influenza A, Japanese encephalitis, measles, meningococcus, poliomyelitis, rabies, smallpox, tetanus, typhoid, yellow fever. This hypothesis predicts that antigens...
The Human Leukocyte Antigen DRB1*13:02 Allele Protects against Dementia in Continental Western Europe
Apolipoprotein E4 (
ApoE4), suggesting a possible protection against dementia. Here we evaluated the association between the population frequency of common DRB1*13 alleles and the prevalence of dementia in Continental Western Europe. Prevalence of dementia in Continental Western Europe was derived from published reports on dementia frequency from the Global Burden of Disease Study 2016 and population totals obtained from the Population Reference Bureau. DRB1*13:01 and DRB1*13:02 allele frequencies were obtained from a publicly available database (allelefrequency.net) and
ApoEwas obtained from published reports on the world distribution of
ApoE4. The prevalence of dementia in 14 Continental Western European (CWE) countries, where life expectancy is practically identical, significantly decreases exponentially with increasing frequency of DRB1*13:02 (R2 = 0.452, P = 0.008), even when adjusted for the prevalence of...
Human Leukocyte Antigen as a Key Factor in Preventing Dementia and Associated Apolipoprotein E4 Risk
permalinkFrontiers in Aging Neuroscience - 2019-04-12James L, Georgopoulos AP10.3389/fnagi.2019.00082Itzhaki's (2018) recent review discusses the evidence for a role of herpes virus (mainly herpes virus 1) in the development of Alzheimer's disease (AD), particularly among genetically vulnerable individuals. Specifically, the viral concept proposes that latent herpes virus in the brain of
ApoE4) carriers is intermittently reactivated causing cumulative damage that ultimately results in AD. The viral concept and collective findings are particularly intriguing given the potential for intervention for AD aimed at neutralizing or eliminating herpes virus. Here we discuss
HLAas an additional genetic link in the viral concept of AD that not only accounts for the role of herpes virus in AD, but also extends to other viruses that may contribute to AD and to other diseases, and is consistent with beneficial brain effects of treatments aimed at eliminating the damaging effects of herpes virus via antivirals or IVIG as discussed in the...