Autoimmune Study News
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
Human Leukocyte AntigenDRB1*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 absence of protective
HLAin underlying the inflammation and autoimmunity associated with MS.
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 not differ between the two diseases, but (c)
HLA-related susceptibility mechanisms (presumably underlying autoimmunity) are significantly stronger in dementia than in Parkinson's disease.
Vaccines for Influenza
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 propidium iodide in cells. In addition, signaling pathways leading to organization of N2A cytoskeleton were negatively affected, as both actin and microtubular networks were compromised. Finally, the mitochondrial membrane potential was impaired in specific assays. Altogether, these alterations led to apoptosis as a collective toxic effect of PA63 which was substantially reduced by the concomitant addition of specific antibodies against PA63.
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 both cell spreading and apoptosis, whereas none of the other antibodies administered to GW veterans had an effect. The in vitro observed adverse effects of
GWIserum may be due in part to vaccine-derived pathogens, antibodies against which had a protective effect in N2A cell cultures.
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.
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 exposures associated with service during the Gulf War that could not be successfully eliminated due to lack of specific immunity1,2. Work is underway in our laboratory to identify and eliminate persistent antigens in veterans with
GWIwhich we anticipate will result in reduced inflammation and reduced
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
HLAprotein can match with various epitopes and, since everyone has one or two alleles at each of the classical loci (Class I
HLA-A, B, and C and Class II
HLA-DP, DQ, and DR), a large number of antigens can be effectively eliminated.
Decades of Posttraumatic Stress Disorder and Gulf War Illnes Research: Driven to Discover Causes and New Therapies
Posttraumatic Stress Disorderand
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 the beneficial effect of the healthy serum on preventing the adverse
GWIserum effects was due to the presence of antibodies against the persistent antigens. Here we tested this hypothesis by assessing the effect of pooled human immunoglobulin G (IgG) on ameliorating the
GWIadverse effects on neural growth and apoptosis in neuroblastoma N2A cultures. We tested this effect in 14
GWIpatients and found that IgG exerted a potent ameliorating effect by inhibiting the reduction in growth and increased apoptosis of
GWIserum. These results lend support to our persistent antigen hypothesis1,2 and suggest an immunotherapy approach for treating
GWI. This approach is further strengthened by our finding that the severity of
GWIneurocognitive/mood (NCM) symptoms was positively correlated with the degree of apoptosis caused by
GWIserum on the neural culture, thus validating the relevance of the apoptotic effect to NCM symptomatology. Finally, we used this relation to predict NCM scores based on the reduced apoptosis effected by IgG addition and found a predicted reduction in NCM symptom severity by ~60%. Altogether, these findings point to the possible beneficial use of IgG in treating
Kare 11 explores Posttraumatic Stress Disorder and PTSD research involving the Brain Sciences Center
permalinkKare 11 - 2018-05-18Join Kare 11 as they explore Former Army infantryman Brian Zimmerman's experience with
PTSD, its treatment, and potential
PTSDresearch at the
Brain Sciences Center.
Watch the trailer video, part 1, and part 2
Adverse effects of Gulf War Illness serum on neural cultures and their prevention by healthy serum
permalinkJ Neurol Neuromedicine - 2018-04-27Georgopoulos AP, Tsilibary EC, Souto EP, James L, Engdahl B, Georgopoulos AGWI is a chronic debilitating disease of unknown etiology that affects the brain and has afflicted many veterans of the 1990-91 Gulf War (GW). Here we tested the hypothesis that brain damage may be caused by circulating harmful substances to which GW veterans were exposed but which could not be eliminated due to lack of specific immunity. We assessed the effects of serum from
GWIpatients on function and morphology of brain cultures in vitro, including cultures of embryonic mouse brain and neuroblastoma N2A line. Blood serum from
GWIand healthy GW veterans was added, alone and in combination, to the culture and its effects on the function and morphology of the culture assessed. Neural network function was assessed using electrophysiological recordings from multielectrode arrays in mouse brain cultures, whereas morphological assessments (neural growth and cell apoptosis) were done in neuroblastoma cultures. In contrast to healthy serum, the addition of
GWIserum disrupted neural network communication and caused reduced cell growth and increased apoptosis. All of these detrimental effects were prevented or ameliorated by the concomitant addition of serum from healthy GW veterans. These findings indicate that
GWIserum contains neuropathogenic factors that can be neutralized by healthy serum. We hypothesize that these factors are persistent antigens circulating in
GWIblood that can be neutralized, possibly by specific antibodies present in the healthy serum, as proposed earlier.
Human Leukocyte Antigen and Gulf War Illness: HLA-DRB1*13:02 Spares Subcortical Atrophy in Gulf War Veterans
permalinkEBioMedicine - 2017-12-01James L, Christova P, Engdahl B, Lewis S, Carpenter A, Georgopoulos AP10.1016/j.ebiom.2017.11.005Background
GWI is a multisystem disorder that has affected a substantial number of veterans who served in the 1990-91 Gulf War. The brain is prominently affected, as manifested by the presence of neurological, cognitive and mood symptoms. We reported previously on the protective role of six
GWI(Georgopoulos et al., 2016) and their association with regional brain function (James et al., 2016). More recently, we reported on the presence of subcortical brain atrophy in
GWI(Christova et al., 2017) and discussed its possible relation to immune mechanisms. Here we focused on one of the six
HLAalleles, DRB1*13:02, which has been found to have a protective role in a broad range of autoimmune diseases (Furukawa et al., 2017), and tested its effects on brain volumes.
Seventy-six Gulf War veterans (55 with
GWIand 21 healthy controls) underwent a
Structural Magnetic Resonance Imagingscan to measure the volumes of 9 subcortical brain regions to assess differences between participants with (N = 11) and without (N = 65)
HLAclass II allele DRB1*13:02.
We found that DRB1*13:02 spared subcortical brain atrophy in Gulf War veterans; overall subcortical volume was 6.6% higher in carriers of DRB1*13:02 (P = 0.007). The strongest effect was observed in the volume of cerebellar gray matter which was 9.6% higher (P = 0.007) in carriers of DRB1*13:02 than in non-carriers. By contrast, DRB1*13:01 had no effect.
These findings document the protective effect of DRB1*13:02 on brain atrophy in Gulf War veterans and are in keeping with recent results documenting sharing of brain mechanisms between
GWIand other immune-related diseases (Georgopoulos et al., 2017). We hypothesize that the protective role of DRB1*13:02 is due to its successful elimination of external antigens to which Gulf War veterans were exposed, antigens that otherwise would persist causing low-grade inflammation and possibly leading to autoimmunity.
U.S. Department of Defense (W81XWH-15-1-0520), Department of Veterans Affairs, American Legion Brain Sciences Chair, and University of Minnesota.
Brain function in Gulf War Illness and associated mental health comorbidities
Gulf War Illness as a neuroimmune disease
permalinkExperimental Brain Research - 2017-10-01Georgopoulos AP, James L, Carpenter A, Engdahl B, Leuthold A, Lewis S10.1007/s00221-017-5050-0GWI is a chronic disease characterized by the involvement of several organs, including the brain (Christova et al., Exp Brain Res doi: 10.1007/s00221-017-5010-8, 2017). In a previous study (Georgopoulos et al., J Neural Eng 4:349-355, 2015), we identified six protective alleles from Class II
HLAgenes, and more recently, we investigated the brain correlates of this protection (James et al., EBioMedicine 13:72-79, 2016). Those and other studies (Israeli, Lupus, 21:190-194, 2012) suggested an involvement of the immune system in
GWI. In a recent study (Engdahl et al., EBioMedicine doi: 10.1016/j.ebiom.2016.08.030, 2016), we showed that the brain pattern of
Synchronous Neural Interactions(
SNI; Georgopoulos et al., J Neural Eng 4:349-355, 2007) in
GWIis distinctly different from that in healthy controls. Here we focused on the
SNIitself, as a basic measure of neural communication (irrespective of specific connections) and compared it between
GWIand seven other diseases that cover a broad spectrum of etiology and pathophysiology. Specifically, we sought to determine which, if any, of those diseases might resemble
SNI, overall and within the
HLAprotective domain, and thus gain further knowledge regarding the nature of
GWIbrain abnormality. We studied a total of 962 participants from a healthy control population (N = 583) and eight different diseases, including
GWI(N = 40), schizophrenia (SZ; N = 21), Alzheimer's disease (AD; N = 66),
PTSD; N = 159), major depressive disorder (MDD; N = 10), relapsing-remitting multiple sclerosis (RRMS; N = 43), Sj"ogren's syndrome (SS; N = 32), and rheumatoid arthritis (RA; N = 8). They all underwent a resting-state magnetoencephalographic (
Magnetoencephalography) scan to calculate SNIs. Data were analyzed using analysis of covariance (ANCOVA) with disease as fixed factor, and sex and age as covariates. We found that
GWISNIs differed significantly from control SZ, AD,
PTSDand MDD but not from RRMS, SS and RA. In addition, we compared
GWIto RRMS, SS and RA with respect to SNIs of
MEGsensor pairs that were related to the
HLAalleles protective for
GWI(James et al., EBioMedicine 13:72-79, 2016). We found that
GWISNIs did not differ significantly from any of these three diseases but they did so from control SZ, AD,
PTSDand MDD. These findings indicate that (a)
GWIbrain synchronicity does not differ significantly from that of known immune-related diseases (RRMS, SS, RA), and (b) that this
SNIsimilarity is present within the
HLA-related SNIs. In contrast,
GWISNIs differed significantly from those of the other diseases. We conclude that altered brain communication in
GWIlikely reflects immune-related processes, as postulated previously (James et al., EBioMedicine 13:72-79, 2016). By extension, these findings also indicate that functional brain abnormalities in RRMS, SS and RA might be, in part, due to lack of protective
HLAalleles as documented for
GWI(Georgopoulos et al., EBioMedicine 3:79-85, 2015).
Subcortical brain atrophy in Gulf War Illness
permalinkExperimental Brain Research - 2017-09-01Christova P, James L, Engdahl B, Lewis S, Carpenter A, Georgopoulos AP10.1007/s00221-017-5010-8GWI is a multisystem disorder that has affected a substantial number of veterans who served in the 1990-1991 Gulf War. The brain is prominently affected, as manifested by the presence of neurological, cognitive and mood symptoms. Although brain dysfunction in
GWIhas been well documented (EBioMedicine 12:127-32, 2016), abnormalities in brain structure have been debated. Here we report a substantial (~10%) subcortical brain atrophy in
GWIcomprising mainly the brainstem, cerebellum and thalamus, and, to a lesser extent, basal ganglia, amygdala and diencephalon. The highest atrophy was observed in the brainstem, followed by left cerebellum and right thalamus, then by right cerebellum and left thalamus. These findings indicate graded atrophy of regions anatomically connected through the brainstem via the crossed superior cerebellar peduncle (left cerebellum → right thalamus, right cerebellum → left thalamus). This distribution of atrophy, together with the observed systematic reduction in volume of other subcortical areas (basal ganglia, amygdala and diencephalon), resemble the distribution of atrophy seen in toxic encephalopathy (Am J Neuroradiol 13:747-760, 1992) caused by a variety of substances, including organic solvents. Given the potential exposure of Gulf War veterans to "a wide range of biological and chemical agents including sand, smoke from oil-well fires, paints, solvents, insecticides, petroleum fuels and their combustion products, organophosphate nerve agents, pyridostigmine bromide, …" (Institute of Medicine National Research Council. Gulf War and Health: Volume 1. Depleted uranium, pyridostigmine bromide, sarin, and vaccines. National Academies Press, Washington DC, 2000), it is reasonable to suppose that such exposures, alone or in combination, could underlie the subcortical atrophy observed.
Researchers pinpoint reductions in brain volume of ill Gulf War Vets
permalinkMike Richman, VA Research Communications - 2017-07-20The
BSCat the Minneapolis VA Health Care System has evolved into one of the leading facilities in the country for researching
GWI, a condition that is of major concern to the Veteran community.
Researchers at the center have made what they believe to be key breakthroughs with
In Minnesota, the promise of a test for Gulf War Illness
GWIand new developments in ways to test for
GWI. "In Minnesota, the promise of a test for
Reduced Human Leukocyte Antigen Protection in Gulf War Illness
permalinkEBioMedicine - 2016-01-01Georgopoulos AP, James L, Mahan M, Joseph J, Georgopoulos A, Engdahl B10.1016/j.ebiom.2015.11.037Background
GWI is a disease of unknown etiology with symptoms suggesting the involvement of an immune process. Here we tested the hypothesis that
HLAcomposition might differ between veterans with and without
We identified 144 unique alleles of Class I and II
HLAgenes in 82 veterans (66 with and 16 without
GWI). We tested the hypothesis that a subset of
HLAalleles may classify veterans in their respective group using a stepwise linear discriminant analysis. In addition, each participant rated symptom severity in 6 domains according to established
GWIcriteria, and an overall symptom severity was calculated.
We found 6 Class II alleles that classified participants 84.1% correctly (13/16 control and 56/66
GWI). The number of copies of the 6 alleles was significantly higher in the control group, suggesting a protective role. This was supported by a significant negative dependence of overall symptom severity on the number of allele copies, such that symptom severity was lower in participants with larger numbers of allele copies.
These results indicate a reduced
HLAprotection (i.e. genetic susceptibility) in veterans with
University of Minnesota and U.S. Department of Veterans Affairs.