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 (
Gulf War Illness[
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
Human Leukocyte Antigenclass 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, Christova PThis 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...
Gulf War Illness and Inflammation: Association of symptom severity with C-reactive protein
GWIetiology remains unclear, mounting evidence points to immune system involvement and inflammation, in particular, as underlying the host of symptoms associated with the condition. Here we investigated the association between
GWIsymptoms and C-reactive protein (CRP), a marker of inflammation, in 76 veterans with
GWI. Results indicated a highly significant positive association between CRP and mean
GWIsymptom severity. At the symptom domain level, CRP was significantly and positively associated with Pain, Neurocognitive/Mood, Fatigue, and Respiratory symptom severity but not with Skin or Gastrointestinal symptom severity. These results support the premise that
GWIsymptoms, particularly those implicating brain involvement, are a result of neuroinflammation. The cause for inflammation is not known. We have hypothesized that at the root of
GWIare harmful persistent antigens stemming from environmental...
The Degree of Modulation of Beta Band Activity During Motor Planning Is Related to Trait Impulsivity
permalinkFrontiers in Integrative Neuroscience - 2019-01-17Tzagarakis C, Thompson A, Rogers RD, Pellizzer G10.3389/fnint.2019.00001Impulsivity is a prominent personality trait, and a key modulating component of neurologic and psychiatric disorders. How impulsivity is related to the brain mechanisms associated with action planning is poorly understood. Here, we investigated the relation between impulsivity and the modulation of beta band oscillatory activity associated with action planning and execution. Given that beta power decreases during action planning and decreases further during action execution, we hypothesized that during planning the level of beta band power of more impulsive individuals would be closer to the level reached during execution than that of less impulsive individuals. This could explain the tendency to "jump the gun" (commission errors) in high impulsivity. To test this hypothesis, we recruited healthy volunteers (50 participants analyzed) and used the Barratt Impulsiveness Scale questionnaire to evaluate their impulsivity as high or low. We then recorded their brain neuromagnetic signals while they performed an instructed-delay task that induced...
Persistent Antigens Hypothesis: The Human Leukocyte Antigen Connection
HLAgenes code for glycoproteins that exist on the surface of most cells in order to facilitate immune surveillance and initiate an immune response to eliminate foreign antigens. There are two main classes of
HLA(Class I and Class II) that support the elimination of cytosolic or extracellular foreign antigens through cell destruction and antibody production, respectively.
HLAgenes have evolved to be the most highly polymorphic in the human genome, thereby maximizing species resistance to foreign antigens and promoting survival. Nonetheless, successful elimination of foreign antigens is predicated on a match between one's
HLAand epitopes derived from foreign antigen proteins. Each person has a limited repertoire of
HLAproteins inherited in a Mendelian fashion for each class. Fortunately, each
Stories about the Brain Sciences Center
- The origins: A million dollar baby
- The leadership: The doctor from Athens
- What it's done: Posttraumatic Stress Disorderto Gulf Illness
Decades of Posttraumatic Stress Disorder and Gulf War Illnes Research: Driven to Discover Causes and New Therapies
Human Immunoglobulin G (IgG) Neutralizes Adverse Effects of Gulf War Illness Serum in Neural Cultures: Paving the Way to Immunotherapy for GWI
permalinkJ Neurol Neuromedicine - 2018-10-12Tsilibary EC, Souto EP, James L, Engdahl B, Georgopoulos APGWI is a chronic debilitating disease of unknown etiology that affects the brain and has afflicted many veterans of the 1990-91 Gulf War (GW). We showed recently1 that blood serum from patients suffering from
GWIexerts detrimental effects on neural cultures, including reduced growth, increased apoptosis, and disruption of neural network function. Remarkably, these adverse effects were prevented by the concomitant addition to the culture of serum from healthy Gulf War (GW) era veterans. We interpreted those findings1 in the context of our hypothesis that
GWIis, at least partly, due to circulating pathogenic persistent antigens2, probably coming from vaccines administered to GW veterans who lacked crucial
HLAclass 2 alleles3 and, therefore, could not make antibodies against those antigens; by contrast, healthy GW veterans who received the same vaccines and possessed
HLAprotection3 made antibodies that neutralized the various antigens. Thus, we hypothesized that...
Human Leukocyte Antigen in Gulf War Veterans: Association with Symptoms and Inflammatory Markers
A Two-Hit Model of the Biological Origin of Posttraumatic Stress Disorder
permalinkJournal of Mental Health and Clinical Psychology - 2018-10-01Georgopoulos AP, James L, Christova P, Engdahl BWe focus on the origin of
PTSD, on the meural mechanisms underlying its development. Specifically, we propose a two-hit model for
PTSDdevelopment, with the following components:
- the 1st hit is a neuroimmune challenge, as a preexisting condition
- the 2nd hit is intense glutamatergic neurotrasmission, induced by the traumatic event.
PTSDand maintains associated symptomatology, such as fear and avoidance
American Legion recognizes Brian Engdahl for "unwavering commitment to our nation's veterans"
Brain Sciences Centerfaculty, holder of the Anderson Chair for
PTSDResearch, and adjunct professor in Neuroscience, Psychology and Cognitive Science, U of MN, was recognized on August 24th during the national convention of the American Legion by their TBI /
PTSDCommittee for "unwavering commitment to our nation's veterans, and for inspiring us with your motivating words during our 100th national convention". Brian began his 40th year at the VA in September.The award was presented by Chairman and past National Commander, William Detweiler