Immunogenetic Factors Research Articles

ПРОГНОСТИЧЕСКАЯ ВОЗМОЖНОСТЬ ИММУНОГЕНЕТИЧЕСКИХ ИССЛЕДОВАНИЙ В ИЗУЧЕНИИ ЗАБОЛЕВАЕМОСТИ МОЧЕКАМЕННОЙ БОЛЕЗНЬЮ У ДЕТЕЙ

Objective: To determine the genetic polymorphism associated with the development of urolithiasis (UL) in children of the Uzbek population. Methods: The study was conducted in the Specialized Children's Surgical Hospital of the Samarkand State Medical University between 2012 and 2019. In the first stage, a retrospective analysis of the case histories of 652 admitted patients was undertaken. In the second stage, 200 children aged 1 to 17 years were enrolled in the study, of which 100 were diagnosed with UL (main group), and 100 comprised the control group without UL (hospitalized for minor planned surgical interventions, such as circumcision or hernia repair). Immunogenetic studies of the vitamin D receptor (VDR), IL-1β, and IL-18 genes were carried out. Results: The obtained results indicate that polymorphism of the VDR and IL-1β genes plays an important role in susceptibility to UL. In the study groups, a statistically significant association of F/f+f/f genotypes of the VDR gene (Fok-1) with UL was found, which was 1.3 times more frequent in the main group than in the control one (p=0.033; χ2 =4.56). The C/C allele of the IL-1β gene was significantly more frequently detected in the main vs. control group (p=0.027; χ2 =7.23; df=2). The distribution of frequency of IL-18 (+105A/C) gene polymorphism for all models of inheritance was not statistically significantly different in the main and control groups (p>0.05; χ2 =3.93; df=2). Conclusion: : The role of the immunogenetic method in the detection of susceptibility to UL development was determined in the study of the distribution of polymorphic markers of the VDR and IL-1β genes, indicating the significance of the immunogenetic factors for the predisposition to UL in children of the Uzbek population which may predict the disease at its preclinical stage. Therefore, in the interests of the early diagnosis of UL in children of the Uzbek population, it is reasonable to include testing for FokI genotype and polymorphism of VDR and IL-1β genes in the complex program of examination.

Determinants of natural HIV-1 control.

HIV-1 infection usually progresses to AIDS within 10 years in antiretroviral therapy untreated individuals, but there is a group of infected individuals, known as controllers, who maintain low plasma HIV-1 RNA levels and normal CD4+ T-cell counts for many years. Evidence suggests that the mechanisms of viral control in these individuals are heterogeneous. In this review, we highlight the viral and host factors, particularly host immunological and immunogenetic factors that are associated with controller status. Despite the broad heterogeneity within controllers, there is compelling evidence that cytotoxic CD8+ T lymphocyte responses act as the main driver of control in the majority of these individuals, especially in those with protective HLA-I alleles. Further investigation of controllers without protective HLA-I alleles is required as it seems that this subset exhibits more durable control of HIV-1 disease progression. Understanding the immune defense mechanisms in controllers provides hope for harnessing these responses in the general population, either for protective or therapeutic vaccines or to achieve a functional cure in infected individuals.

Genetic characterization of biopsy-proven myocarditis: a pilot study

Abstract Background Myocarditis is characterized by the presence of an inflammatory infiltrate in the myocardium with degenerative/necrotic changes of cardiomyocytes, not-related to ischemic damage. Its clinical presentation is extremely heterogenous1. Endomyocardial Biopsy (EMB) is the diagnostic gold standard and provides etiopathogenetic diagnosis. Biopsy-proven myocarditis may be infectious, mainly viral, toxic o non-infectious immune-mediated/autoimmune. A complex interplay between genetic factors, environmental triggers (i.e. viral infection) and the immune response of the host is postulated at the basis of different disease evolution2. Purpose To determine the prevalence of pathogenic/likely pathogenic (P/LP) variants in cardiomyopathy-related genes in a well-characterized cohort of biopsy-proven myocarditis. Methods Sixty-six biopsy-proven myocarditis-affected patients (mean age 51±9, 41 males) underwent screening of 200 genes related to inherited cardiomyopathies. Definite/moderate gene association with Dilated Cardiomyopathy (DCM)3 and Arrhythmogenic Cardiomyopathy4 was based on the ClinGen framework. Variant prioritization was carried out using American College of Medical Genetics and Genomics rules5. Correlation with presence of virus on endomyocardial biopsy by polymerase chain reaction, family history and serum anti-heart autoantibodies (AHA) and/or aintiintercalated-disk autoantibodies (AIDA) was appraised. Results Nineteen of the 66 biopsy-proven myocarditis patients (28%) carried a P/LP variant in cardiac-related genes. Titin (TTN) was the most overrepresented gene accounting for 11% of cases (7/66), followed by Myosin Heavy Chain 7 (MYH7) and Myosin Binding Protein C3 (MYBPC3) each accounting for 3% of cases (2/66), respectively. Of note, 29 of the 66 of index cases (44%) referred family history for cardiomyopathy and/or sudden cardiac death. However only 13/29 patients with family history were genotype-positive (45%), indicating that other immunogenetic factors might contribute to triggering myocarditis. Circulating AHA and/or AIDA were detected in 31% of our genotype-positive cohort (6 of 19); a virus positive diagnosis was obtained in 15% of cases. Conclusion The prevalence of clinically actionable P/LP variants in cardiomyopathy-related genes is nearly one third of biopsy-proven viral or autoimmune myocarditis patients, most of them associated with DCM. On the other hand, positive family history (44%) in the absence of known cardiomyopathy-related genes indicates that additional immunogenetic factors might contribute to disease pathogenesis. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministero della Salute - Italy - Ricerca Sanitaria Finalizzata

P297 Takayasu arteritis presents at an older age in a northern European population

Abstract Background/Aims The definition of Takayasu arteritis includes the age of onset of disease as being <50 years. It has been reported most frequently in young females from Asian populations. We investigated whether the epidemiological features are the same in Norfolk, where the population is predominantly of northern European ancestry. Methods n our centre, cases are classified using validated international criteria. The electronic records of our vasculitis clinic were reviewed to identify all individuals with a new diagnosis of large vessel vasculitis from 2011-2020 who met a modified ACR 1990 criteria for Takayasu arteritis. The original criteria include decreased brachial artery pulse, bruit over subclavian arteries or aorta, and arteriogram abnormality. The respective modifications of these three criteria were to accept decreased radial pulse as well as the brachial pulse, bruit over the axillary artery as well as the subclavian artery, and abnormality of positron emission tomography and/or ultrasonography instead of arteriograms. Results 14 individuals met the modified ACR 1990 criteria for Takayasu arteritis. 13 were female. The mean (standard deviation) age at diagnosis was 68.2 (7.7) years. None of the individuals were <40 years old. On presentation, 8 had upper limb claudication, 8 had pulse discrepancy, 4 had a blood pressure difference >10 mm Hg systolic, and 8 had an audible bruit over either subclavian or axillary artery. The diagnosis was confirmed on positron emission tomography in 7, ultrasonography of extracranial arteries in 5, and 2 by both modalities. The mean (standard deviation) ESR was 66.7 (48.1) and CRP was 49.2 (33.8). 2/14 also met the ACR 1990 criteria for GCA. Conclusion Takayasu arteritis can present at an older age in Norfolk where the population predominantly has northern European ancestry. Some of these individuals also fulfil the criteria for GCA. This has implications for treatment, identification of immunogenetic factors and disease classification. Disclosure T. Ecclestone: None. F. Coath: None. G. Ducker: None. S. Fordham: None. C. Mukhtyar: None.

A Protective HLA Extended Haplotype Outweighs the Major COVID-19 Risk Factor Inherited From Neanderthals in the Sardinian Population.

Sardinia has one of the lowest incidences of hospitalization and related mortality in Europe and yet a very high frequency of the Neanderthal risk locus variant on chromosome 3 (rs35044562), considered to be a major risk factor for a severe SARS-CoV-2 disease course. We evaluated 358 SARS-CoV-2 patients and 314 healthy Sardinian controls. One hundred and twenty patients were asymptomatic, 90 were pauci-symptomatic, 108 presented a moderate disease course and 40 were severely ill. All patients were analyzed for the Neanderthal-derived genetic variants reported as being protective (rs1156361) or causative (rs35044562) for severe illness. The β°39 C>T Thalassemia variant (rs11549407), HLA haplotypes, KIR genes, KIRs and their HLA class I ligand combinations were also investigated. Our findings revealed an increased risk for severe disease in Sardinian patients carrying the rs35044562 high risk variant [OR 5.32 (95% CI 2.53 - 12.01), p = 0.000]. Conversely, the protective effect of the HLA-A*02:01, B*18:01, DRB*03:01 three-loci extended haplotype in the Sardinian population was shown to efficiently contrast the high risk of a severe and devastating outcome of the infection predicted for carriers of the Neanderthal locus [OR 15.47 (95% CI 5.8 – 41.0), p < 0.0001]. This result suggests that the balance between risk and protective immunogenetic factors plays an important role in the evolution of COVID-19. A better understanding of these mechanisms may well turn out to be the biggest advantage in the race for the development of more efficient drugs and vaccines.

Allelic variation in HLA-DRB1 is associated with development of antidrug antibodies in cancer patients treated with atezolizumab that are neutralizing in vitro.

The treatment of diseases with biologic agents can result in the formation of antidrug antibodies (ADA). Although drivers for ADA formation are unknown, a role for antigen presentation is likely, and variation in human leukocyte antigen (HLA) genes has been shown to be associated with occurrence of ADA for several biologics. Here, we performed an HLA‐wide association study in 1982 patients treated with the anti‐PD‐L1 antibody atezolizumab across eight clinical trials. On average, 29.8% of patients were ADA‐positive (N = 591, range of 13.5%–38.4% per study) and 14.6% of patients were positive for ADA that were neutralizing in vitro (neutralizing antibodies [NAb], N = 278, range of 6.4%–21.9% per study). In a meta‐analysis of logistic regression coefficients, we found statistically significant associations between HLA class II alleles and ADA status. The top‐associated alleles were HLA‐DRB1*01:01 in a comparison of ADA‐positive versus ADA‐negative patients (p = 3.4 × 10−5, odds ratio [OR] 1.96, 95% confidence interval [95% CI] 1.64–2.28) and HLA‐DQA1*01:01 when comparing NAb‐positive with ADA‐negative patients (p = 2.8 × 10−7, OR 2.31, 95% CI 1.98–2.66). Both alleles occur together on a common HLA haplotype, and analyses considering only NAb‐negative, ADA‐positive patients did not yield significant results, suggesting that the genetic association is mainly driven by NAb status. In conclusion, our study showed that HLA class II genotype is associated with the risk of developing ADA, and specifically NAb, in patients treated with atezolizumab, but the effect estimates suggest that immunogenetic factors are not sufficient as clinically meaningful predictors.

Seroprevalence of diphtheria and measles antibodies and their association with demographics, self-reported immunity, and immunogenetic factors in healthcare workers in Latvia

Latvia is among European countries with outbreaks of diphtheria and measles. Healthcare workers (HCW) are exposed to infections and can transmit them to unvaccinated patients. We assessed the seroprevalence of antibodies against diphtheria and measles and their association with demographics, self-reported immunity, the presence of the HLA-B27 allele, and level of interferon regulatory factor 5 (IRF5) in Latvian HCW. Anti-diphtheria and anti-measles IgG antibodies and the level of IRF5 in serum were tested by enzyme immunoassay. The presence of the HLA-B27 allele was detected by a real-time polymerase chain reaction. The study involved 176 HCW, including 29% doctors and 44% nurses. Among HCW, 95.5% were seropositive for diphtheria. However, only 65.9% had full seroprotection against it. The seronegativity for measles (21.6%) was higher than for diphtheria (4.5%) without differences in gender and medical staff groups. Older age was associated with waning immunity against diphtheria and a higher rate of seropositivity for measles. Considered immunogenetic factors did not affect the level of antibodies, and variability of the level of IRF5 in serum can reflect ageing processes. Self-reported vaccination status had a low informative value regarding full seroprotection against diphtheria and seropositivity for measles indicating the need for pre-vaccination IgG screening in planning the booster vaccination.

The elimination of circulating Epstein-Barr virus infected B cells underlies anti-CD20 monoclonal antibody activity in multiple sclerosis: A hypothesis

Multiple sclerosis is a chronic immune-mediated disease of the central nervous system that has aspects of repetitive inflammatory activity as well as a slow neurodegenerative process. The immune assault on the nervous system is triggered by a complex interaction between immunogenetic and environmental factors. Among the different environmental factors, a compelling case, buttressed by strong epidemiological, serological and other data, has been made for the role of Epstein-Barr virus (EBV) in the pathogenesis of MS. However, the ubiquity of EBV, lack of a well understood role in MS pathogenesis, and controversies regarding its presence in brains of people with MS has caused debate as to how exactly it contributes to MS. Recent years have seen the remarkable effect of anti-CD20 therapies on the inflammatory component of MS. How B cell depletion results in a salutary effect in MS remains incompletely understood. It has been proposed that depletion of CD20+ B-cells disrupts other pro-inflammatory pathways in the immune system, especially T-cells. In this paper, we make the case that the robust effect of anti-CD20 therapies on MS activity could actually be from removal of circulating EBV-infected memory B-cells that drive CNS inflammation and not through other immune pathways - in essence that this is from an anti-viral effect, and not necessarily an immuno-modulatory effect.

Genotypic and allelic distribution of IFN-γ +874T/A and TGF-β1 -509C/T single-nucleotide polymorphisms in human immunodeficiency virus-infected Thais.

Advances in antiretroviral therapy (ART) have led to a decrease of acquired immunodeficiency syndrome (AIDS)-related mortality, and an increase of non-AIDS illnesses in people living with HIV (PLWH). Risks for HIV-related chronic inflammation leading to non-AIDS illnesses in PLWH have been increasingly clarified including immunogenetic factors. This study aimed to examine distribution of genotypic and allelic frequencies of the well-characterized interferon-γ (IFN-γ) +874T/A and transforming growth factor-β1 (TGF-β1) -509C/T single nucleotide polymorphisms (SNPs) in Thai PLWH. The cross-sectional study was conducted in 191 Thai HIV patients. Most patients were under ART (74.3%) and maintained a relatively high median of CD4+ cell count (364.5 [5-1601] cells/μl). The frequencies of IFN-γ +874T/A SNPgenotypes were 9.0% AA, 38.3% AT, and 52.7% TT and those of the SNPalleles were 28.1% A and 71.9% T. The rates of TGF-β1-509C/T SNP genotypes were 15.7% CC, 44.0% CT, and 40.3% TT and those of the SNP alleles were 37.7% C and 62.3% T. The more frequent TT genotypes and T allele of the IFN-γ +874T/A SNP, and relatively more prevalent TT and CT genotypes and T allele of TGF-β1 -509C/T SNP were potentially associated with disease progression to non-AIDS complication in Thai PLWH and required further investigation. This study provides the immunogenetic data potentially supporting mechanisms for chronic immune activation in PLWH under long-term suppressive ART.

COMPLEX ANALYSIS OF THE ROLE OF CYTOKINE GENE POLYMORPHISMS AS PROGNOSTIC FACTOR OF THE RISK OF PLASMA CELL MYELOMA IN PERSONS SUFFERED AFTER THE CHORNOBYL NPP ACCIDENT.

to provide a comparative characterization of the prevalence of polymorphic variants of cytokine genes in plasma cell myeloma (PCM) patients suffered after the Chornobyl disaster and patients who were in contact with ionizing radiation within the natural radiation background, based on comparison with population controls to determine their contribution as genetic markers of disease risk. Molecular genetic studies of polymorphism of cytokine genes (TNF-α, TGF-β1, IL-6, IL-10, IFN-γ) and complex frequency analysis of occurrence in three-, four-, and five-locus combinations of their allelic variants as prognostic markers of the risks of plasma cell myeloma was carried out in 102 patients - 56 victims of the Chornobyl nuclear power plant accident and 46 patients irradiated within the limits of the natural radiation background, in comparison with the control group (364 practically healthy people, residents of the Central geno-geographical region of Ukraine). The same probable increase in the prevalence of the TGF-β genotype codon10 T/T of the TGF-β1 gene was established in the groups of patients irradiated after the Chornobyl NPP accident and non-irradiated patients. In patients with plasma cell myeloma a protective effect for IL-10 -1082 A/G and an association with the risk of disease occurrence for IL-10 -1082 G/G were determined. Probable difference in the frequency of the TGF-β1 genotype codon10 T/T of the TGF-β1 gene in the observed groups relative to the control group provides grounds for considering this single-nucleotide polymorphism of the TGF-β1 gene as an immunogenetic factor of predisposition to the development of PCM independent of exogenous factors. The study of the contribution of multigene combinations of «gene-gene» interaction indicates their role in the mechanisms of plasma cell myeloma occurrence and confirms the presence of an additive interaction.

Enhancement of the Reliability of Animal Genotyping Regarding the Betterment of Wool Productivity in South-Kazakh Merino Sheep in Kazakhstan.

Enhancement of the production and productivity in animals is possible by improving the environment and changing the genetic structure of the herd which is done through selection. The present study aimed to investigate the efficiency of using genetic resources in the population of South-Kazakh merino sheep breed to improve and enhance the quality of wool productivity by determining a combination of phenotypic traits, morphobic and chemical parameters, as well as immunogenetic factors. Wool productivity was studied and accounted for by cutting each animal's wool during the period of shearing with an accuracy of 0.1 kg. At the age of 14 months, samples of wool were taken from 10 ewes of each group to study the yield of pure wool using physical and technological indicators. The value of reproducibility coefficients was determined by conducting correlation analysis. The value was estimated from 0.439 to 0.871 and 0.331 to 0.776 for the live weight and wool cutting, respectively. The number of woolens per 1 mm2 of skin positively correlated with pure wool cutting (0.276±0.135) and woolliness factor (0.293±0.134), while it negatively correlated with the live weight of sheep (-0.055±0.140), staple length (-0.146±0.139), and toner wool (-0.180±0.138). This negative correlation implies that the most densely woolly sheep will not necessarily have a breeding advantage for the herd improvement on a combination of signs. However, the outstanding wool density as a separate indicator of sheep woolen productivity has a great breeding advantage; therefore, in the merino population, it is necessary to create a small factory line of sheep with a very large wool density. A variety of sheep productivity indices in each age had a high correlation with a variety of maximum productivity levels of animals bred in the conditions of "Batay-Shu" LLP.

Structural dissimilarity of partners' immune genes increases sperm viability in women's reproductive tract.

Human leucocyte antigen (HLA) genes appear to mediate pre- and post-copulatory mate choice towards HLA-dissimilar ('compatible') partners. However, since genetically distinct alleles often have similar immunogenic properties, genetic dissimilarity is not necessarily an accurate predictor of the functional compatibility of HLA alleles and, hence, may not reflect partners' true compatibility. Furthermore, it has remained unclear whether other genes of the immune system could also play a role in male-female compatibility. We studied whether the immunoglobulin binding regions (eplets) of HLA molecules and the immunoglobulin structural dissimilarity of the partners affect their gamete-level compatibility. We exposed sperm of multiple men to follicular fluid or cervical mucus of multiple women and tested whether sperm viability in these reproductive secretions was influenced by HLA eplet and immunoglobulin structural dissimilarity between partners. We found that eplet dissimilarity positively affects sperm viability in follicular fluid, whereas immunoglobulin dissimilarity enhanced sperm viability in cervical mucus. Together, these findings indicate that structural characteristics of both HLA alleles and immunoglobulins may facilitate cryptic female choice towards immunologically compatible partners. Our results, thus, indicate that partners' genetic compatibility may have wider immunological basis than traditionally has been assumed. Relative contribution of different immunogenetic factors to overall compatibility of the reproductive partners needs to be clarified in future studies.

Immunogenetic determinants of heterosexual HIV-1 transmission: key findings and lessons from two distinct African cohorts.

Immunogenetic studies in the past three decades have uncovered a broad range of human genetic factors that seem to influence heterosexual HIV-1 transmission in one way or another. In our own work that jointly evaluated both genetic and non-genetic factors in two African cohorts of cohabiting, HIV-1-discordant couples (donor and recipient pairs) at risk of transmission during quarterly follow-up intervals, relatively consistent findings have been seen with three loci (IL19, HLA-A and HLA-B), although the effect size (i.e., odds ratio or hazards ratio) of each specific variant was quite modest. These studies offered two critical lessons that should benefit future research on sexually transmitted infections. First, in donor partners, immunogenetic factors (e.g., HLA-B*57 and HLA-A*36:01) that operate directly through HIV-1 viral load or indirectly through genital co-infections are equally important. Second, thousands of single nucleotide polymorphisms previously recognized as “causal” factors for human autoimmune disorders did not appear to make much difference, which is somewhat puzzling as these variants are predicted or known to influence the expression of many immune response genes. Replicating these observations in additional cohorts is no longer feasible as the field has shifted its focus to early diagnosis, universal treatment and active management of comorbidities.

Elevated expression of complement C4 in the mouse prefrontal cortex causes schizophrenia-associated phenotypes.

Accumulating evidence supports immune involvement in the pathogenesis of schizophrenia, a severe psychiatric disorder. In particular, high expression variants of C4, a gene of the innate immune complement system, were shown to confer susceptibility to schizophrenia. However, how elevated C4 expression may impact brain circuits remains largely unknown. We used in utero electroporation to overexpress C4 in the mouse prefrontal cortex. We found reduced glutamatergic input to pyramidal cells of juvenile and adult, but not of newborn C4-overexpressing (C4-OE) mice, together with decreased spine density, which mirrors spine loss observed in the schizophrenic cortex. Using time-lapse two-photon imaging in vivo, we observed that these deficits were associated with decreased dendritic spine gain and elimination in juvenile C4-OE mice, which may reflect poor formation and/or stabilization of immature spines. In juvenile and adult C4-OE mice, we found evidence for NMDA receptor hypofunction, another schizophrenia-associated phenotype, and synaptic accumulation of calcium-permeable AMPA receptors. Alterations in cortical GABAergic networks have been repeatedly associated with schizophrenia. We found that functional GABAergic transmission was reduced in C4-OE mice, in line with diminished GABA release probability from parvalbumin interneurons, lower GAD67 expression, and decreased intrinsic excitability in parvalbumin interneurons. These cellular abnormalities were associated with working memory impairment. Our results substantiate the causal relationship between an immunogenetic risk factor and several distinct cortical endophenotypes of schizophrenia and shed light on the underlying cellular mechanisms.

Killer-Cell Immunoglobulin-Like Receptors (KIR) in HIV-Exposed Infants in Cameroon.

The biological reason(s) behind persistent mother-to-child transmission (MTCT) of HIV (albeit at reduced rate compared to the preantiretroviral therapy era) in spite of the successful implementation of advanced control measures in many African countries remains a priority concern to many HIV/AIDS control programs. This may be partly due to differences in host immunogenetic factors in highly polymorphic regions of the human genome such as those encoding the killer-cell immunoglobulin-like receptor (KIR) molecules which modulate the activities of natural killer cells. The primary aim of this study was to determine the variants of KIR genes that may have a role to play in MTCT in a cohort of infants born to HIV-infected mothers in Yaoundé, Cameroon. We designed a cross-sectional study to molecularly determine the frequencies of 15 KIR genes in 14 HIV-exposed infected (HEI), 39 HIV-exposed/uninfected (HEU), and 27 HIV-unexposed/uninfected (HUU) infants using the sequence specific primer polymerase chain reaction (PCR-SSP) method. We found that all 15 KIR genes were present in our cohort. The frequency of KIR2DL1 was significantly higher in the unexposed (control) group than in the HIV-exposed group (OR = 0.22, P = 0.006). Stratifying analysis by infection status but focusing only on exposed infants revealed that KIR2DL5, KIR2DS1, and KIR2DS5 were significantly overrepresented among the HIV-exposed/uninfected compared to infected infants (OR = 0.20, P = 0.006). Similarly, the frequencies of KIR2DS1, KIR2DS5, and KIR2DL5 were significantly different between infants perinatally infected with HIV (HIV+ by 6 months of age) and HIV-negative infants. Our study demonstrates that KIR genes may have differential effects with regard to MTCT of HIV-1.

Polymorphism of interleukin-6 -174 G/C (rs1800795) & the corresponding interleukin-6 level as a prognostic marker of cervical cancer.

Background & objectives:Aetiology of cervical cancer (CaCx) is multifactorial. Besides human papillomavirus (HPV) infection, many immunogenetic factors are involved in this complex process. The present study was carried out to investigate one such factor, interleukin-6 (IL-6), a central pro-inflammatory cytokine and a polymorphism at its promoter region -174 G/C (rs1800795) with CaCx.Methods:HPV-infected women with or without CaCx were enrolled in group I and II, respectively. Another group of uninfected healthy women was also included as group III for comparison. Polymorphism in IL-6-174 G/C and IL-6 levels were analyzed by sequence-specific primer PCR (PCR-SSP) and ELISA, respectively.Results:Groups I (n=111) and II (n=87) had significantly higher frequency of IL-6-174 GG genotype [odds ratios (OR)=3.9; P<0.001 and OR=3.2; P<0.001, respectively] as compared to group III (n=163). Furthermore, individuals with GG or GC genotypes had high IL-6 levels than those with CC genotypes. IL-6 levels were significantly (P<0.001) elevated in group I. This was also significantly high in untreated cases as compared to treated (P<0.05) ones. IL-6 levels of treated group were comparable with groups II and III.Interpretation & conclusions:Our results suggested a possible association of IL-6-174 GG with CaCx, which was also associated with high IL-6 levels. Decreased levels of IL-6 following treatment indicate its possible prognostic use in CaCx cases.

Geriatrics and COVID-19.

Since December 2019, a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has begun to infect people. The virus first occurred in Wuhan, China, but the whole world is now struggling with the pandemic. Over 13million confirmed cases and 571,000 deaths have been reported so far, and this number is growing. Older people, who constitute a notable proportion of the world population, are at an increased risk of infection because of altered immunity and chronic comorbidities. Thus, appropriate health care is necessary to control fatalities and spread of the disease in this specific population. The chapter provides an overview of diagnostic methods, laboratory and imaging findings, clinical features, and management of COVID-19 in aged people. Possible mechanisms behind the behavior of SARS-CoV-2 in the elderly include immunosenescence and related impaired antiviral immunity, mature immunity and related hyper-inflammatory responses, comorbidities and their effects on the functioning of critical organs/systems, and the altered expression of angiotensin-converting enzyme 2 (ACE2) that acts as an entry receptor for SARS-CoV-2. This evidence defines the herding behavior of COVID-19 in relation to ACE2 under the influence of immune dysregulation. Then, identifying the immunogenetic factors that affect the disease susceptibility and severity and as well as key inflammatory pathways that have the potential to serve as therapeutic targets needs to remain an active area of research.

Human Leukocyte Antigen Complex and Other Immunogenetic and Clinical Factors Influence Susceptibility or Protection to SARS-CoV-2 Infection and Severity of the Disease Course. The Sardinian Experience.

AimSARS-CoV-2 infection is a world-wide public health problem. Several aspects of its pathogenesis and the related clinical consequences still need elucidation. In Italy, Sardinia has had very low numbers of infections. Taking advantage of the low genetic polymorphism in the Sardinian population, we analyzed clinical, genetic and immunogenetic factors, with particular attention to HLA class I and II molecules, to evaluate their influence on susceptibility to SARS-CoV-2 infection and the clinical outcome.Method and MaterialsWe recruited 619 healthy Sardinian controls and 182 SARS-CoV-2 patients. Thirty-nine patients required hospital care and 143 were without symptoms, pauci-symptomatic or with mild disease. For all participants, we collected demographic and clinical data and analyzed the HLA allele and haplotype frequencies.ResultsMale sex and older age were more frequent in hospitalized patients, none of whom had been vaccinated during the previous seasonal flu vaccination campaignes. Compared to the group of asymptomatic or pauci-symptomatic patients, hospitalized patients also had a higher frequency of autoimmune diseases and glucose-6-phosphate-dehydrogenase (G6PDH) deficiency. None of these patients carried the beta-thalassemia trait, a relatively common finding in the Sardinian population. The extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 [OR 0.1 (95% CI 0–0.6), Pc = 0.015] was absent in all 182 patients, while the HLA-C*04:01 allele and the three-loci haplotype HLA-A*30:02, B*14:02, C*08:02 [OR 3.8 (95% CI 1.8–8.1), Pc = 0.025] were more frequently represented in patients than controls. In a comparison between in-patients and home care patients, the HLA-DRB1*08:01 allele was exclusively present in the hospitalized patients [OR > 2.5 (95% CI 2.7–220.6), Pc = 0.024].ConclusionThe data emerging from our study suggest that the extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 has a protective effect against SARS-CoV-2 infection in the Sardinian population. Genetic factors that resulted to have a negative influence on the disease course were presence of the HLA-DRB1*08:01 allele and G6PDH deficiency, but not the beta-thalassemic trait. Absence of influenza vaccination could be a predisposing factor for more severe disease.

Unraveling the susceptibility of paracoccidioidomycosis: Insights towards the pathogen-immune interplay and immunogenetics

Paracoccidioidomycosis (PCM) is a life-threatening systemic mycosis caused by Paracoccidioides spp. This disease comprises three clinical forms: symptomatic acute and chronic forms (PCM disease) and PCM infection, a latent form without clinical symptoms. PCM disease differs markedly according to severity, clinical manifestations, and host immune response. Fungal virulence factors and adhesion molecules are determinants for entry, latency, immune escape and invasion, and dissemination in the host. Neutrophils and macrophages play a paramount role in first-line defense against the fungus through the recognition of antigens by pattern recognition receptors (PRRs), activating their microbicidal machinery. Furthermore, the clinical outcome of the PCM is strongly associated with the variability of cytokines and immunoglobulins produced by T and B cells. While the mechanisms that mediate susceptibility or resistance to infection are dictated by the immune system, some genetic factors may alter gene expression and its final products and, hence, modulate how the organism responds to infection and injury. This review outlines the main findings relative to this topic, addressing the complexity of the immune response triggered by Paracoccidioides spp. infection from preclinical investigations to studies in humans. Here, we focus on mechanisms of fungal pathogenesis, the patterns of innate and adaptive immunity, and the genetic and molecular basis related to immune response and susceptibility to the development of the PCM and its clinical forms. Immunogenetic features such as HLA system, cytokines/cytokines receptors genes and other immune-related genes, and miRNAs are likewise discussed. Finally, we point out the occurrence of PCM in patients with primary immunodeficiencies and call attention to the research gaps and challenges faced by the PCM field.

Integrate structural analysis, isoform diversity, and interferon-inductive propensity of ACE2 to predict SARS-CoV2 susceptibility in vertebrates

The current new coronavirus disease (COVID-19) has caused globally over 0.4/6 million confirmed deaths/infected cases across more than 200 countries. As the etiological coronavirus (a.k.a. SARS-CoV2) may putatively have a bat origin, our understanding about its intermediate reservoir between bats and humans, especially its tropism in wild and domestic animals are mostly unknown. This constitutes major concerns in public health for the current pandemics and potential zoonosis. Previous reports using structural analysis of the viral spike protein (S) binding its cell receptor of angiotensin-converting enzyme 2 (ACE2), indicate a broad potential of SARS-CoV2 susceptibility in wild and particularly domestic animals. Through integration of key immunogenetic factors, including the existence of S-binding-void ACE2 isoforms and the disparity of ACE2 expression upon early innate immune response, we further refine the SARS-CoV2 susceptibility prediction to fit recent experimental validation. In addition to showing a broad susceptibility potential across mammalian species based on structural analysis, our results also reveal that domestic animals including dogs, pigs, cattle and goats may evolve ACE2-related immunogenetic diversity to restrict SARS-CoV2 infections. Thus, we propose that domestic animals may be unlikely to play a role as amplifying hosts unless the virus has further species-specific adaptation. Findings may relieve relevant public concerns regarding COVID-19-like risk in domestic animals, highlight virus-host coevolution, and evoke disease intervention through targeting ACE2 molecular diversity and interferon optimization.