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.
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.
SARS-CoV-2 Virus and Human Leukocyte Antigen Class II: Investigation in silico of Binding Affinities for COVID-19 Protection and Vaccine Development
HLAClass 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 initial part of the glycoprotein (S1-S460), with a peak at S223-S238. This region would be well suited for effective vaccine development by ensuring high probability for successful matching of the vaccine antigen from that region to a
HLAClass II molecule for CD4+ T cell activation by the antigen-
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
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 protective
HLAalleles but not in those possessing a protective
HLAallele. Given the role of
HLAin antibody production against foreign antigens, the findings suggest that persistent foreign antigens stemming from lack of immunogenetic protection against them contribute to inflammation, metabolic disruption, and cortical thinning in
GWI. The findings are discussed in terms of GW-related exposures that are known to result in inflammation.
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 protection from foreign antigens, autoimmunity, and, possibly, neuroprotection, the shared
HLAprofile between dementia and Parkinson's disease indicates that common immunogenetic mechanisms underlie the pathogenesis and manifestation of these diseases
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. The protective alleles had significantly higher binding affinity that than the neutral alleles. The largest differences in binding affinity between the protective and neutral alleles was shown for HHV-6A and HHV-6B, which had the best overall binding affinity with the protective alleles.
The dementia protection conferred by the three protective
HLAalleles investigated here is related to their superior ability to bind and successfully eliminate HHV epitopes - in particular, HHV6 - that could otherwise cause dementia if they persisted.
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.
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 present in those vaccines should have a high affinity for matching with the 6
HLAclass II protective alleles above. Here we tested this prediction by using the Immune Epitope DataBase (IEDB7) to determine the ranked affinity of each one of the 6
GWIprotective alleles to the 10 most frequently assayed epitopes of each pathogen for which a vaccine was administered. We found that our 6
GWIprotective alleles above collectively covered all vaccine antigens except for rubella for which all alleles above showed low binding affinity. Affinity strength varied among antigen-allele pairs, with DRB1*01:01 and DRB1*13:02 showing overall higher affinities. These two alleles also had the highest binding affinities for the anthrax antigen contained in the anthrax vaccine administered to GW veterans. These findings document a good match between the 6
HLAprotective alleles above and the antigens contained in the GW vaccines, and support the fundamental assumption that the
GWIis mediated through the successful elimination of potentially harmful persistent antigens contained in those vaccines.
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
ApoE4 allele, a known risk factor for Alzheimer's disease. This finding documents the protective effect of DRB1*13:02 on dementia prevalence in CWE. Since the function of
HLAclass II genes is to aid in the elimination of pathogens by enabling the production of antibodies against their antigens in specific immunity, the protective effect of DRB1*13:02 points to the presence of persistent harmful antigens as causal factors in development of dementia, antigens specific to DRB1*13:02 that could not be eliminated in its absence.
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 review.
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.
Human Leukocyte Antigen in Gulf War Veterans: Association with Symptoms and Inflammatory Markers
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.