Immunogenetic profiles of 9 human herpes virus envelope glycoproteins.

Human herpes viruses (HHV) are ubiquitous and have been implicated in numerous long-term health conditions. Since the association between viral exposure and long-term health impacts is partially influenced by variation in human leukocyte antigen (HLA) genes, we evaluated in silico the binding affinities of 9 HHV envelope glycoproteins with 127 common HLA Class I and Class II molecules. The findings show substantial variability in HHV binding affinity across viruses, HLA Class, HLA genes, and HLA alleles. Specific findings were as follows: (1) the predicted binding affinities of HHVs were characterized by four distinct groupings-[HHV1, HHV2], [HHV3, HHV4, HHV5], [HHV6A], [HHV6B, HHV7, HHV8]-with relatively lower binding affinities for HHV1, HHV2, and HHV6a compared to other HHVs; (2) significantly higher binding affinity was found for HLA Class I relative to Class II; (3) analyses within each class demonstrated that alleles of the C gene (for Class I) and DRB1 gene (for Class II) had the highest binding affinities; and (4) for each virus, predicted binding affinity to specific alleles varied, with HHV6a having the lowest affinity for HHV-HLA complexes, and HHV3, HHV4, and HHV5 having the highest. Since HLA-antigen binding is the first step in initiating an immune response to foreign antigens, these relative differences in HHV binding affinities are likely to influence long-term health impacts such that the cells infected with viruses associated with higher binding affinities across common HLA alleles may be more reduced in numbers, thereby lowering the potential for long-term sequelae of their infections.

Association between resting-state neurovascular coupling and neural signals as revealed by a combined fMRI and magnetoencephalography (MEG) study in humans.

The Blood Oxygenation Level-Dependent (BOLD) activation reflects hemodynamic events mediated by neurovascular coupling. During task performance, the BOLD hemodynamic response in a relevant area is mainly driven by the high levels of synaptic activity (reflected in local field potentials, LFP) but, in contrast, during a task-free, resting state, the contribution to BOLD of such neural events is small, as expected by the comparatively (to the task state) low level of neural events. Concomitant recording of BOLD and LFP at rest in animal experiments has estimated the neural contribution to BOLD to ~10%. Such experiments have not been performed in humans. As an approximation, we recorded (in the same subject, N = 57 healthy participants) at a task-free, resting state the BOLD signal and, in a different session, the magnetoencephalographic (MEG) signal, which reflects purely neural (synaptic) events. We then calculated the turnover of these signals by computing the successive moment-to-moment difference in the BOLD and MEG time series and retaining the median of the absolute value of the differenced series (TBOLD and TMEG, respectively). A linear regression of normalized TBOLD vs. TMEG revealed that ~30% of TMEG contributes to TBOLD, accounting for 11.3% of the latter's variance. This percentage estimate is close to the ~10% estimate above obtained by direct recordings in animal experiments.

Nine Human Leukocyte Antigen (HLA) Class I Alleles are Omnipotent Against 11 Antigens Expressed in Melanoma Tumors.

Objective: Host immunogenetics (Human Leukocyte Antigen, HLA) play a critical role in the human immune response to melanoma, influencing both melanoma prevalence and immunotherapy outcomes. Beneficial outcomes hinge on the successful binding of epitopes of melanoma antigens to HLA Class I molecules for an effective engagement of cytotoxic CD8+ lymphocytes and subsequent elimination of the cancerous cell. This study evaluated the binding affinity and immunogenicity of HLA Class I to melanoma tumor antigens to identify alleles best suited to facilitate elimination of melanoma antigens. Methods: In this study, we used freely available software tools to determine in silico the binding affinity and immunogenicity of 2462 reported HLA Class I alleles to all linear nonamer epitopes of 11 known antigens expressed in melanoma tumors (TRP2, S100, Tyrosinase, TRP1, PMEL(17), MAGE1, MAGE4, CTA, BAGE, GAGE/SSX2, Melan). Results: We identified the following 9 HLA Class I alleles with very high immunogenicity and binding affinity against all 11 melanoma antigens: A*02:14, B*07:10, B*35:10, B*40:10, B*40:12, B*44:10, C*07:11, and C*07:13, and C*07:14. Conclusion: These 9 HLA alleles possess the potential to aid in the elimination of melanoma both by themselves and by enhancing the beneficial effect of immune checkpoint inhibitors.

Breast cancer, viruses, and human leukocyte antigen (HLA).

Several viruses have been implicated in breast cancer, including human herpes virus 4 (HHV4), human herpes virus 5 (HHV5), human papilloma virus (HPV), human JC polyoma virus (JCV), human endogenous retrovirus group K (HERVK), bovine leukemia virus (BLV) and mouse mammary tumor virus (MMTV). Human leukocyte antigen (HLA) is involved in virus elimination and has been shown to influence breast cancer protection/susceptibility. Here we investigated the hypothesis that the contribution of a virus to development of breast cancer would depend on the presence of the virus, which, in turn, would be inversely related to the success of its elimination. For that purpose, we estimated in silico predicted binding affinities (PBA) of proteins of the 7 viruses above to 127 common HLA alleles (69 Class I [HLA-I] and 58 Class II HLA-II]) and investigated the association of these binding affinities to the breast cancer-HLA (BC-HLA) immunogenetic profile of the same alleles. Using hierarchical tree clustering, we found that, for HLA-I, viruses BLV, JCV and MMTV were grouped with the BC-HLA, whereas, for HLA-II, viruses BLV, HERVK, HPV, JCV, and MMTV were grouped with BC-HLA. Finally, for both HLA classes, the average PBAs of the viruses grouped with the BC-HLA profile were significantly lower than those of the other, non BC-HLA associated viruses. Assuming that low PBAs are likely associated with slower viral elimination, these findings support the hypothesis that a defective/slower elimination and, hence, longer persistence and inefficient/delayed production of antibodies against them underlies the observed association of the low-PBA group with breast cancer.

Anthrax Vaccination, Gulf War Illness, and Human Leukocyte Antigen (HLA).

We report on a highly significant, positive association between anthrax vaccination and occurrence of Gulf War Illness (GWI) in 111 Gulf War veterans (42 with GWI and 69 controls). GWI was diagnosed in 47.1% of vaccinated veterans but only in 17.2% of non-vaccinated veterans (Pearson χ2 = 7.08, p = 0.008; odds ratio = 3.947; relative risk = 2.617), with 1.6x higher GWI symptom severity in vaccinated veterans (p = 0.007, F-test in analysis of covariance). Next, we tested the hypothesis that the susceptibility to GWI following anthrax vaccination could be due to inability to make antibodies against the anthrax protective antigen (PA), the key protein contained in the vaccine. Since the first step in initiating antibody production would be the binding of PA peptide fragments (typically 15-amino acid long [15-mer]) to peptide-binding motifs of human leukocyte antigen (HLA) Class II molecules, we assessed the binding-motif affinities of such HLA specific molecules to all linear 15-mer peptide fragments of the anthrax PA. We identified a total of 58 HLA Class II alleles carried by the veterans in our sample and found that, of those, 18 (31%) were present in the vaccinated group that did not develop GWI but were absent from the vaccinated group who developed GWI. Remarkably, in silico analyses revealed very high binding affinities of peptide-binding motifs of those 18 HLA alleles with fragments of anthrax vaccine PA, leading to the successful production of anti-PA antibodies. Conversely, the absence of these protective HLA alleles points to a reduced ability to develop antibodies against PA, thus resulting in harmful PA persistence and development of GWI.

Negative Association of Cognitive Performance With Blood Serum Neurotoxicity and Its Modulation by Human Herpes Virus 5 (HHV5) Seropositivity in Healthy Women.

Identification of early influences on cognitive decline is of paramount importance in order to stem the impacts of decrements in cognitive functioning and to potentially intervene. Thus, here we focused on 132 healthy adult women (age range 26-98 years) to (a) determine whether factors circulating in serum may exert neurotoxic effects in vitro, (b) evaluate associations between serum neurotoxicity and cognitive performance, and (c) assess the influence of human herpes virus (HHV) seroprevalence and other factors on apoptosis and cognitive performance. The results documented that the addition of serum from healthy adult women to neural cell cultures resulted in apoptosis, indicating the presence of circulating neurotoxic factors in the serum. Furthermore, apoptosis increased with age, and was associated with decreased cognitive performance. Stepwise regression evaluating the influence of 6 HHVs on apoptosis and cognitive function revealed that only HHV5 (cytomegalovirus; CMV) seropositivity was significantly associated with apoptosis and cognitive decline, controlling for age. These findings document neurotoxic effects of serum from healthy women across the adult lifespan and suggest a unique detrimental influence associated with CMV seropositivity.

Negative association between neurovascular coupling and cortical gray matter volume during the lifespan.

Recent studies have established the moment-to-moment turnover of the blood-oxygen-level-dependent signal (TBOLD) at resting state as a key measure of local cortical brain function. Here, we sought to extend that line of research by evaluating TBOLD in 70 cortical areas with respect to corresponding brain volume, age, and sex across the lifespan in 1,344 healthy participants including 633 from the Human Connectome Project (HCP)-Development cohort (294 males and 339 females, age range 8-21 yr) and 711 healthy participants from HCP-Aging cohort (316 males and 395 females, 36-90 yr old). In both groups, we found that 1) TBOLD increased with age, 2) volume decreased with age, and 3) TBOLD and volume were highly significantly negatively correlated, independent of age. The inverse association between TBOLD and volume was documented in nearly all 70 brain areas and for both sexes, with slightly stronger associations documented for males. The strong correspondence between TBOLD and volume across age and sex suggests a common influence such as chronic neuroinflammation contributing to reduced cortical volume and increased TBOLD across the lifespan.NEW & NOTEWORTHY We report a significant negative association between resting functional magnetic resonance imaging (fMRI) blood-oxygen-level-dependent (BOLD) signal turnover (TBOLD) and cortical gray matter volume across the lifespan, such that TBOLD increased whereas volume decreased. We attribute this association to a hypothesized chronic, low-grade neuroinflammation, probably induced by various neurotropic pathogens, including human herpes viruses known to be dormant in the brain in a latent state and reactivated by stress, fever, and various environmental exposures, such as ultraviolet light.

Anthrax Vaccines in the 21st Century.

Vaccination against Bacillus anthracis is the best preventive measure against the development of deadly anthrax disease in the event of exposure to anthrax either as a bioweapon or in its naturally occurring form. Anthrax vaccines, however, have historically been plagued with controversy, particularly related to their safety. Fortunately, recent improvements in anthrax vaccines have been shown to confer protection with reduced short-term safety concerns, although questions about long-term safety remain. Here, we (a) review recent and ongoing advances in anthrax vaccine development, (b) emphasize the need for thorough characterization of current (and future) vaccines, (c) bring to focus the importance of host immunogenetics as the ultimate determinant of successful antibody production and protection, and (d) discuss the need for the systematic, active, and targeted monitoring of vaccine recipients for possible Chronic Multisymptom Illness (CMI).

Positive Association Between the Immunogenetic Human Leukocyte Antigen (HLA) Profiles of Multiple Sclerosis and Brain Cancer.

Previous research has documented elevated risk of brain cancer in patients with multiple sclerosis (MS). Separately, human leukocyte antigen (HLA) has been implicated in protection or susceptibility for both conditions. The aim of the current study was to assess a possible role of shared immunogenetic influence on risk of MS and brain cancer. We first identified an immunogenetic profile for each condition based on the covariance between the population frequency of 127 high-resolution HLA alleles and the population prevalence of each condition in 14 Continental Western European countries and then evaluated the correspondence between MS and brain cancer immunogenetic profiles. Also, since each individual carries 12 HLA alleles (2 × 6 genes), we estimated HLA protection and susceptibility for MS and brain cancer at the individual level. We found that the immunogenetic profiles of MS and brain cancer were highly correlated overall (P < .001) and across all 6 HLA genes with the strongest association observed for DRB1, followed by DQB1 and HLA-A. These findings of immunogenetic overlap between MS and brain cancer are discussed in light of the role of HLA in the immune system response to viruses and other foreign antigens.

Association between brain cancer immunogenetic profile and in silico immunogenicities of 11 viruses.

Several viruses including human herpes viruses (HHVs), human polyomavirus JCV, and human papilloma virus (HPV) have been implicated in brain cancer, albeit inconsistently. Since human leukocyte antigen (HLA) is centrally involved in the human immune response to viruses and has been implicated in brain cancer, we evaluated in silico the immunogenicity between 69 Class I HLA alleles with epitopes of proteins of 9 HHVs, JCV, and HPV with respect to a population-based HLA-brain cancer profile. We found that immunogenicity varied widely across HLA alleles with HLA-C alleles exhibiting the highest immunogenicity, and that immunogenicity scores were negatively associated with the population-based HLA-brain cancer profile, particularly for JCV, HHV6A, HHV5, HHV3, HHV8, and HHV7. Consistent with the role of HLA in foreign antigen elimination, the findings suggest that viruses with proteins of high HLA immunogenicity are eliminated more effectively and, consequently, less likely to cause brain cancer; conversely, the absence of highly immunogenic HLA may allow the viral antigens to persist, contributing to cancer.

Negative association between multiple sclerosis immunogenetic profile and in silico immunogenicities of 12 viruses.

Human Leukocyte Antigen (HLA) is involved in both multiple sclerosis (MS) and immune response to viruses. Here we investigated the virus-HLA immunogenicity (V-HLA) of 12 viruses implicated in MS with respect to 17 HLA Class I alleles positively associated to MS prevalence in 14 European countries. Overall, higher V-HLA immunogenicity was associated with smaller MS-HLA effect, with human herpes virus 3 (HHV3), JC human polyoma virus (JCV), HHV1, HHV4, HHV7, HHV5 showing the strongest association, followed by HHV8, HHV6A, and HHV6B (moderate association), and human endogenous retrovirus (HERV-W), HHV2, and human papilloma virus (HPV) (weakest association). These findings suggest that viruses with proteins of high HLA immunogenicity are eliminated more effectively and, consequently, less likely to be involved in MS.

Melanoma and Human Leukocyte Antigen (HLA): Immunogenicity of 69 HLA Class I Alleles With 11 Antigens Expressed in Melanoma Tumors.

Host immunogenetics play a critical role in the human immune response to melanoma, influencing both melanoma prevalence and immunotherapy outcomes. Beneficial outcomes that stimulate T cell response hinge on binding affinity and immunogenicity of human leukocyte antigen (HLA) with melanoma antigen epitopes. Here, we use an in silico approach to characterize binding affinity and immunogenicity of 69 HLA Class I human leukocyte antigen alleles to epitopes of 11 known melanoma antigens. The findings document a significant proportion of positively immunogenic epitope-allele combinations, with the highest proportions of positive immunogenicity found for the Q13072/BAGE1 melanoma antigen and alleles of the HLA B and C genes. The findings are discussed in terms of a personalized precision HLA-mediated adjunct to immune checkpoint blockade immunotherapy to maximize tumor elimination.

Risk assessment of substance use disorders based on the human leukocyte antigen (HLA).

Substance use disorders (SUDs) are common and costly conditions that are partially attributable to genetic factors. In light of immune system influences on neural and behavioral aspects of addiction, the present study evaluated the influence of genes involved in the human immune response, human leukocyte antigen (HLA), on SUDs. We used an immunogenetic epidemiological approach to evaluate associations between the population frequencies of 127 HLA alleles and the population prevalences of six SUDs (alcohol, amphetamine, cannabis, cocaine, opioid, and "other" dependence) in 14 countries of Continental Western Europe to identify immunogenetic profiles of each SUD and evaluate their associations. The findings revealed two primary groupings of SUDs based on their immunogenetic profiles: one group comprised cannabis and cocaine, whereas the other group comprised alcohol, amphetamines, opioids, and "other" dependence. Since each individual possesses 12 HLA alleles, the population HLA-SUD scores were subsequently used to estimate individual risk for each SUD. Overall, the findings highlight similarities and differences in immunogenetic profiles of SUDs that may influence the prevalence and co-occurrence of problematic SUDs and may contribute to assessment of SUD risk of an individual on the basis of their HLA genetic makeup.

Schizophrenia, Human Leukocyte Antigen (HLA), and Herpes Viruses: Immunogenetic Associations at the Population Level.

Several factors have been implicated in schizophrenia (SZ), including human herpes viruses (HHV) and the adaptive immunity Human Leukocyte Antigen (HLA) genes. Here we investigated these issues in 2 complementary ways. In one analysis, we evaluated SZ-HLA and HHV-HLA associations at the level of a single allele by computing (a) a SZ-HLA protection/susceptibility (P/S) score based on the covariance between SZ and 127 HLA allele prevalences in 14 European countries, (b) estimating in silico HHV-HLA best binding affinities for the 9 HHV strains, and (c) evaluating the dependence of P/S score on HHV-HLA binding affinities. These analyses yielded (a) a set of 127 SZ-HLA P/S scores, varying by >200× (maximum/minimum), which could not be accounted for by chance, (b) a set of 127 alleles × 9 HHV best-estimated affinities, varying by >600×, and (c) a set of correlations between SZ-HLA P/S scores and HHV-HLA binding which indicated a prominent role of HHV1. In a subsequent analysis, we extended these findings to the individual person by taking into account the fact that every individual carries 12 HLA alleles and computed (a) the average SZ-HLA P/S scores of 12 randomly chosen alleles (2 per gene), an indicator of HLA-based SZ P/S for an individual, and (b) the average of the corresponding HHV estimated affinities for those alleles, an indicator of overall effectiveness of HHV-HLA binding. We found (a) that HLA protection for SZ was significantly more prominent than susceptibility, and (b) that protective SZ-HLA scores were associated with higher HHV-HLA binding affinities, indicating that HLA binding and subsequent elimination of several HHV strains may confer protection against schizophrenia.

Dependence of cognitive ability on synchronous neural interactions determined by magnetoencephalography.

Previous studies have shown that synchronous neural interactions (SNIs) underlying healthy brain function can be readily distinguished from neural anomalies associated with diseases including dementia; however, it is imperative to identify biomarkers that facilitate early identification of individuals at risk for cognitive decline before the onset of clinical symptoms. Here, we evaluated whether variation in brain function, controlling for age, corresponds with subtle decrements in cognitive performance in cognitively healthy women. A total of 251 women (age range 24-102 yr) who performed above established cutoffs on the Montreal cognitive assessment (MoCA) also underwent a task-free magnetoencephalography scan from which SNIs were computed. The results demonstrated that increased SNI was significantly associated with decreased cognitive performance (r2 = 0.923, P = 0.009), controlling for age. Compared with the lowest performers with normal cognition (MoCA = 26), SNI of the highest performers (MoCA = 30) was associated with decorrelation primarily in the right anterior temporal cortex region, with additional (weaker) foci in left anterior temporal cortex, right posterior temporal cortex, and cerebellum. The findings highlight the relevance of neural network decorrelation on cognitive functioning and suggest that subtle increases in SNI may presage future cognitive impairment.NEW & NOTEWORTHY This study in cognitively healthy women showed that decreased cognitive performance is associated with increased neural network correlations, particularly involving the temporal cortices. As healthy brain function relies on dynamic neural network communication, these findings suggest that subtle increases in correlated neural network activity may be a useful early indicator of decrements in cognitive function.

Human Leukocyte Antigen (HLA) Modulates the Dependence on Age of the Variability of Synchronous Neural Interactions.

Recent evidence documented a protective effect of Class II human leukocyte antigen (HLA) DRB1*13 on brain health across the lifespan including evidence of reduced neural network variability relative to non-carriers. Here, in an extension of those findings, we evaluated the influence of a large number of Class I and Class II HLA alleles on aging-related changes in neural network variability. Cognitively healthy women (N = 178) ranging in age from 28 to 99 years old underwent a magnetoencephalography scan from which neural network variability was calculated and provided a blood sample from which HLA and apolipoprotein E (ApoE) genotype were determined. The primary analyses assessed the dependence of network variability on age in carriers of a specific HLA allele compared to non-carriers. Effects were considered protective if there was a significant increase of network variability with age in the absence of a given HLA allele but not in its presence, and were considered to confer susceptibility if the converse was documented; HLA alleles that did not influence the dependence of network variability on age in their presence or absence were considered neutral. Of 50 alleles investigated, 22 were found to be protective, 7 were found to confer susceptibility, and 21 were neutral. The frequencies of those 50 alleles were not associated significantly with ApoE genotype. The findings, which document the influence of HLA on age-related brain changes and highlight the role of HLA in healthy brain function, are discussed in terms of the role of HLA in the human immune response to foreign antigens.

Immunogenetic Profiles and Associations of Breast, Cervical, Ovarian, and Uterine Cancers.

It is increasingly recognized that the human immune response influences cancer risk, progression, and survival; consequently, there is growing interest in the role of human leukocyte antigen (HLA), genes that play a critical role in initiating the immune response, on cancer. Recent evidence documented clustering of cancers based on immunogenetic profiles such that breast and ovarian cancers clustered together as did uterine and cervical cancers. Here we extend that line of research to evaluate the HLA profile of those 4 cancers and their associations. Specifically, we evaluated the associations between the frequencies of 127 HLA alleles and the population prevalences of breast, ovarian, cervical, and uterine cancer in 14 countries in Continental Western Europe. Factor analysis and hierarchical clustering were used to evaluate groupings of cancers based on their immunogenetic profiles. The results documented highly similar immunogenetic profiles for breast and ovarian cancers that were characterized predominantly by protective HLA effects. In addition, highly similar immunogenetic profiles for cervical and uterine cancers were observed that were, conversely, characterized by susceptibility effects. In light of the role of HLA in host immune system protection against non-self antigens, these findings suggest that certain cancers may be associated with similar contributory factors such as viral oncoproteins or neoantigens.

Immunogenetics of posttraumatic stress disorder (PTSD) in women veterans.

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric condition that is associated with concomitant immune system dysfunction. Here we evaluated the influence of genes involved in the human immune response, Human Leukocyte Antigen (HLA), on lifetime PTSD in primarily Caucasian women veterans. High-resolution HLA genotyping was completed for 372 participants. We assessed differences in HLA makeup between Control (n = 277) and lifetime PTSD (n = 95) groups. HLA was found to have a significant overall effect on lifetime PTSD occurrence (P < 0.00001). Of the 192 alleles identified in this sample, the frequencies of 15 alleles significantly differed between groups. Two alleles - HLA-A*02:01 and DPB1*04:01 -occurred more frequently in controls, presumably indicating protective effects. Thirteen alleles (6 Class I, 7 Class II) occurred more frequently in the lifetime PTSD group, presumably indicating susceptibility effects. In analysis evaluating the effect of the combined presence in individual participants of a protective allele and a susceptibility allele, the presence of a protective allele neutralized the effect of the susceptibility alleles. These findings, which add to the nascent literature on immunogenetics of PTSD, are discussed in terms of the evolutionary role of HLA in host protection against foreign antigens.

Reply to the Letter to the Editor by Sipila, Jussi.

This a Reply to the Letter to the Editor by Sipila, Jussi regarding our article titled: James LM, Georgopoulos AP. High Correlations Among Worldwide Prevalences of Dementias, Parkinson's Disease, Multiple Sclerosis, and Motor Neuron Diseases Indicate Common Causative Factors. Neurosci Insights. 2022 Aug 8;17:26331055221117598. doi: 10.1177/26331055221117598.

The brain landscape of the two-hit model of posttraumatic stress disorder.

The neurophysiological mechanisms underlying the development of posttraumatic stress disorder (PTSD) are poorly understood. Here we test a proposal that PTSD symptoms reflect fixed, highly correlated neural networks resulting from massive engagement of sensory inputs and the sequential involvement of those projections to limbic areas. Three-tesla functional magnetic resonance imaging (fMRI) data were acquired at rest in 15 veterans diagnosed with PTSD and 21 healthy control veterans from which zero-lag cross correlations between 50 brain areas (N = 1,225 pairs) were computed and analyzed. The brain areas were assigned to tiers based on the neurocircuitry of successively converging sensory pathways proposed by Jones and Powell (Jones EG, Powell TP. Brain 93: 793-820, 1970). The primary analyses assessed normalized proportional differences in cross correlation strength within and across tiers in veterans with PTSD and control veterans. Compared with control veterans, cross correlation strength was higher in veterans with PTSD, within and across tiers of areas involved in processing sensory inputs, and systematically increased from sensory processing areas to limbic areas. The functional relevance of this hypercorrelation was further documented by the finding that the severity of self-reported PTSD symptomatology was positively associated with higher neural correlations.NEW & NOTEWORTHY The neurophysiological mechanisms underlying the development of PTSD are poorly understood. Here we document that massive engagement of sensory modalities during trauma exposure leads to fixed, hypercorrelated frontal, parietal, temporal, and limbic networks, reflecting the successive integration of salient sensory inputs along the framework of Jones and Powell.