Association of neutrophil extracellular trap levels with Raynaud's phenomenon, glomerulonephritis and disease index score in SLE patients from Brazil.

Neutrophil extracellular traps (NETs) are cell-extruded DNA strands coated with neutrophils' nuclear proteins and enzymes from cytotoxic granules, produced by NETosis, a cell death pathway. They perform an important defensive role in innate immunity, but their increased production and/or inefficient degradation expose new antigens, such as DNA or citrullinated histone peptides, triggering autoimmunity. This study aimed to access possible associations between serum NETs levels with epidemiological, clinical, and serological data from a well-characterized SLE Brazilian patients' cohort. NET levels were evaluated in one hundred seventy serum samples of patients with Systemic Lupus Erythematosus (SLE) using an Immunoassay. Univariate and multivariate binary logistic regression used clinical patients' data as independent variables. Parametric and non-parametric tests compared log10 base serum NET levels transformed between patients' groups. SLE patients were also dichotomized into "High serum NET levels" and "Low serum NET levels" groups. All analyses were performed in R language 4.1.2, and p < 0.05 were considered significant. Increased susceptibility for high serum NET levels was observed in SLE patients with Raynaud's phenomenon (OR = 2.30, 95 % CI = 1.06-5.21 and p = 0.039), independently of any other risk factor. Also, SLE patients with Raynaud's phenomenon presented higher mean NET serum levels (mean = -0.13 vs. -0.51, p = 0.01). In addition, higher mean NET serum levels were associated with glomerulonephritis (mean = -0.45 vs. -0.12, p = 0.03). Ultimately, the SLEDAI index scored higher in the high NETs serum levels group (median = 2.0 vs. 0.0, p = 6 × 10-3). The formation of NETs might be implicated in Raynaud's phenomenon, glomerulonephritis, and disease index score in SLE patients. Our results highlight the importance of serum NET levels as a possible therapeutical target to modulate the clinical course of SLE.

Clinical characteristics of headaches in an urban Mennonite group in South Brazil.

BACKGROUND: Genetic variants play a pathophysiological role in headaches, especially in migraine. The Mennonite group (MG) has been geographically and genetically isolated throughout its history, harboring a distinctive distribution of diseases. OBJECTIVE: To determine the characteristics of headaches in a group with direct Mennonite ancestry contrasting with other urban community members (control group [CG]). METHODS: Subjects with headaches were asked to complete a questionnaire covering: the type of headache, presence of aura, frequency and duration of attacks, pain location and severity, analgesic consumption, premonitory and postdromic manifestations, Depressive Thoughts Scale, Epworth Sleepiness Scale (ESS), General Anxiety Disorder-7, Patient Health Questionnaire-9 (PHQ-9), Migraine Disability Assessment, and Composite Autonomic System Score. RESULTS: We included 103 participants (CG: 45, Mennonite group [MG]: 58). Migraine was the most common headache (CG: 91.1%; MG: 81.0%; p = 0.172), followed by tension-type headache (CG: 8.9%; MG: 15.5%; p = 0.381). Aura was identified by 44.4% and 39.7% in the CG and MG, respectively (p = 0.689). The groups differed only concerning the frequency of retro-orbital pain (CG: 55.6%; MG: 32.8%; p = 0.027), PHQ-9 (CG: median 7, range 0 to 22; MG: median 5, range 0 to 19; p = 0.031) and ESS (CG: median 0, range 0 to 270; MG: median 0, range 0 to 108; p = 0.048) scores. CONCLUSION: There were no major differences in the prevalence and clinical characterization of headaches between the MG and the CG. However, the latter showed more diffuse pain, sleepiness, and depressive symptoms. Specific genetic or epigenetic variants in Mennonite descendants might account for these differences.

ANTECEDENTES: Variantes genéticas desempenham um papel fisiopatológico nas cefaleias, especialmente na migrânea. O grupo menonita (GM) tem estado geográfica e geneticamente isolado ao longo de sua história, abrigando uma distribuição distinta de doenças. OBJETIVO: Determinar as características das cefaleias em um grupo com ascendência menonita direta, comparando-as com as de outros membros da comunidade urbana (grupo controle [GC]). MéTODOS: Participantes com cefaleia foram convidados a preencher um questionário abrangendo: tipo de cefaleia; presença de aura; frequência e duração dos ataques; localização e gravidade da dor; consumo de analgésicos; manifestações premonitórias e posdrômicas; Escala de Pensamentos Depressivos; Escala de Sonolência de Epworth (ESS); Transtorno de Ansiedade Geral-7 (GAD-7); Questionário de Saúde do Paciente-9 (PHQ-9); Avaliação de Incapacidade da Migrânea (MIDAS) e Escore do Sistema Autônomo Composto (COMPASS-31). RESULTADOS: Incluímos 103 participantes (GC: 45, GM: 58). A migrânea foi a cefaleia mais frequente (GC: 91,1%; GM: 81,0%; p = 0,172), seguida pela cefaleia tensional (GC: 8,9%; GM: 15,5%; p = 0,381). Aura foi identificada por 44,4% e 39,7% nos GC e GM, respectivamente (p = 0,689). Os grupos diferiram apenas com relação à frequência de dor retro-orbitária (GC: 55,6%; GM: 32,8%; p = 0,027), PHQ-9 (GC: mediana 7, amplitude 0 a 22; GM: mediana 5, amplitude 0 a 19; p = 0,031) e ESS (GC: mediana 0, amplitude 0 a 270; GM: mediana 0, amplitude 0 a 108; p = 0,048). CONCLUSãO: Não houve diferenças significativas na prevalência e caracterização clínica das cefaleias nos GM e GC. Entretanto, o último grupo mostrou mais dor difusa, sonolência e sintomas depressivos. Variantes genéticas ou epigenéticas específicas em descendentes de menonitas podem justificar tais diferenças.

Glucocorticoid Receptor Gene (NR3C1) Polymorphisms and Metabolic Syndrome: Insights from the Mennonite Population.

The regulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with polymorphisms and the methylation degree of the glucocorticoid receptor gene (NR3C1) and is potentially involved in the development of metabolic syndrome (MetS). In order to evaluate the association between MetS with the polymorphisms, methylation, and gene expression of the NR3C1 in the genetically isolated Brazilian Mennonite population, we genotyped 20 NR3C1 polymorphisms in 74 affected (MetS) and 138 unaffected individuals without affected first-degree relatives (Co), using exome sequencing, as well as five variants from non-exonic regions, in 70 MetS and 166 Co, using mass spectrometry. The methylation levels of 11 1F CpG sites were quantified using pyrosequencing (66 MetS and 141 Co), and the NR3C1 expression was evaluated via RT-qPCR (14 MetS and 25 Co). Age, physical activity, and family environment during childhood were associated with MetS. Susceptibility to MetS, independent of these factors, was associated with homozygosity for rs10482605*C (OR = 4.74, pcorr = 0.024) and the haplotype containing TTCGTTGATT (rs3806855*T_ rs3806854*T_rs10482605*C_rs10482614*G_rs6188*T_rs258813*T_rs33944801*G_rs34176759*A_rs17209258*T_rs6196*T, OR = 4.74, pcorr = 0.048), as well as for the CCT haplotype (rs41423247*C_ rs6877893*C_rs258763*T), OR = 6.02, pcorr = 0.030), but not to the differences in methylation or gene expression. Thus, NR3C1 polymorphisms seem to modulate the susceptibility to MetS in Mennonites, independently of lifestyle and early childhood events, and their role seems to be unrelated to DNA methylation and gene expression.

Clinical characteristics of headaches in an urban Mennonite group in South Brazil / Características clínicas das cefaleias em um grupo menonita urbano do sul do Brasil

Abstract Background Genetic variants play a pathophysiological role in headaches, especially in migraine. The Mennonite group (MG) has been geographically and genetically isolated throughout its history, harboring a distinctive distribution of diseases. Objective To determine the characteristics of headaches in a group with direct Mennonite ancestry contrasting with other urban community members (control group [CG]). Methods Subjects with headaches were asked to complete a questionnaire covering: the type of headache, presence of aura, frequency and duration of attacks, pain location and severity, analgesic consumption, premonitory and postdromic manifestations, Depressive Thoughts Scale, Epworth Sleepiness Scale (ESS), General Anxiety Disorder-7, Patient Health Questionnaire-9 (PHQ-9), Migraine Disability Assessment, and Composite Autonomic System Score. Results We included 103 participants (CG: 45, Mennonite group [MG]: 58). Migraine was the most common headache (CG: 91.1%; MG: 81.0%; p = 0.172), followed by tension-type headache (CG: 8.9%; MG: 15.5%; p = 0.381). Aura was identified by 44.4% and 39.7% in the CG and MG, respectively (p = 0.689). The groups differed only concerning the frequency of retro-orbital pain (CG: 55.6%; MG: 32.8%; p = 0.027), PHQ-9 (CG: median 7, range 0 to 22; MG: median 5, range 0 to 19; p = 0.031) and ESS (CG: median 0, range 0 to 270; MG: median 0, range 0 to 108; p = 0.048) scores. Conclusion There were no major differences in the prevalence and clinical characterization of headaches between the MG and the CG. However, the latter showed more diffuse pain, sleepiness, and depressive symptoms. Specific genetic or epigenetic variants in Mennonite descendants might account for these differences.

Resumo Antecedentes Variantes genéticas desempenham um papel fisiopatológico nas cefaleias, especialmente na migrânea. O grupo menonita (GM) tem estado geográfica e geneticamente isolado ao longo de sua história, abrigando uma distribuição distinta de doenças. Objetivo Determinar as características das cefaleias em um grupo com ascendência menonita direta, comparando-as com as de outros membros da comunidade urbana (grupo controle [GC]). Métodos Participantes com cefaleia foram convidados a preencher um questionário abrangendo: tipo de cefaleia; presença de aura; frequência e duração dos ataques; localização e gravidade da dor; consumo de analgésicos; manifestações premonitórias e posdrômicas; Escala de Pensamentos Depressivos; Escala de Sonolência de Epworth (ESS); Transtorno de Ansiedade Geral-7 (GAD-7); Questionário de Saúde do Paciente-9 (PHQ-9); Avaliação de Incapacidade da Migrânea (MIDAS) e Escore do Sistema Autônomo Composto (COMPASS-31). Resultados Incluímos 103 participantes (GC: 45, GM: 58). A migrânea foi a cefaleia mais frequente (GC: 91,1%; GM: 81,0%; p = 0,172), seguida pela cefaleia tensional (GC: 8,9%; GM: 15,5%; p = 0,381). Aura foi identificada por 44,4% e 39,7% nos GC e GM, respectivamente (p = 0,689). Os grupos diferiram apenas com relação à frequência de dor retro-orbitária (GC: 55,6%; GM: 32,8%; p = 0,027), PHQ-9 (GC: mediana 7, amplitude 0 a 22; GM: mediana 5, amplitude 0 a 19; p = 0,031) e ESS (GC: mediana 0, amplitude 0 a 270; GM: mediana 0, amplitude 0 a 108; p = 0,048). Conclusão Não houve diferenças significativas na prevalência e caracterização clínica das cefaleias nos GM e GC. Entretanto, o último grupo mostrou mais dor difusa, sonolência e sintomas depressivos. Variantes genéticas ou epigenéticas específicas em descendentes de menonitas podem justificar tais diferenças.

The Second Highest Prevalence of Celiac Disease Worldwide: Genetic and Metabolic Insights in Southern Brazilian Mennonites.

Celiac disease (CD), despite its high morbidity, is an often-underdiagnosed autoimmune enteropathy. Using a modified version of the Brazilian questionnaire of the 2013 National Health Survey, we interviewed 604 Mennonites of Frisian/Flemish origin that have been isolated for 25 generations. A subgroup of 576 participants were screened for IgA autoantibodies in serum, and 391 participants were screened for HLA-DQ2.5/DQ8 subtypes. CD seroprevalence was 1:29 (3.48%, 95% CI = 2.16-5.27%) and biopsy-confirmed CD was 1:75 (1.32%, 95% CI = 0.57-2.59%), which is superior to the highest reported global prevalence (1:100). Half (10/21) of the patients did not suspect the disease. HLA-DQ2.5/DQ8 increased CD susceptibility (OR = 12.13 [95% CI = 1.56-94.20], p = 0.003). The HLA-DQ2.5 carrier frequency was higher in Mennonites than in Brazilians (p = 7 × 10-6). HLA-DQ8 but not HLA-DQ2.5 carrier frequency differed among settlements (p = 0.007) and was higher than in Belgians, a Mennonite ancestral population (p = 1.8 × 10-6), and higher than in Euro-Brazilians (p = 6.5 × 10-6). The glutathione pathway, which prevents reactive oxygen species-causing bowel damage, was altered within the metabolic profiles of untreated CD patients. Those with lower serological positivity clustered with controls presenting close relatives with CD or rheumatoid arthritis. In conclusion, Mennonites have a high CD prevalence with a strong genetic component and altered glutathione metabolism that calls for urgent action to alleviate the burden of comorbidities due to late diagnosis.

HLA alleles and antiseizure medication-induced cutaneous reactions in Brazil: A case-control study.

In this observational case-control study, 107 cutaneous adverse reaction (CAR) cases (CAR+) manifesting up to 12 weeks after the start of treatment with antiseizure medication (ASM) were identified. Control groups consisted of 98 epilepsy patients without a history of CAR (CAR-) and 3965 healthy individuals in the Brazilian National Registry of Bone Marrow Donors. All participants were HLA typed by high-resolution Next Generation Sequencing for HLA-A, B, C, DQB1 and DRB1; HLA-DPA1, DPB1, DQA1, DRB3, DRB4 and DRB5 were also sequenced in samples from CAR+ and CAR- individuals. The relationship between the carrier frequency of each allele, CAR type and ASM for all participants was investigated. The ASMs most frequently associated with CAR were carbamazepine (48% of CAR+ subjects), lamotrigine (23%), phenytoin (18%), phenobarbital (13%) and oxcarbazepine (5%). The main alleles associated with a risk of CAR were HLA-A*02:05 (OR = 6.28; p = 0.019, carbamazepine or oxcarbazepine); HLA-DPA1*02:02 (OR = 4.16, p = 0.003, carbamazepine); HLA-B*53:01 (OR = 47.9, p = 0.014, oxcarbazepine), HLA-DPA1*03:01/DPB1*105:01 (OR = 25.7, p = 0.005, phenobarbital); HLA-C*02:10 (OR = 25.7, p = 0.005, phenobarbital) and HLA-DRB1*04:02 (OR = 17.22, p = 0.007, phenytoin). HLA-A*03:01 increased the risk for phenytoin-induced maculopapular exanthema 4.71-fold (p = 0.009), and HLA-B*35:02 was associated with a 25.6-fold increase in the risk of carbamazepine-induced Stevens-Johnson syndrome (p = 0.005). None of the 4170 subjects carried the HLA-B*15:02 allele, and HLA-A*31:01 was not associated with CAR. Hence, HLA-A*31:01 and HLA-B*15:02 were not associated with CAR in this population. Although other HLA class I and II alleles tested were associated with a risk of CAR, none of these associations were strong enough to warrant HLA testing before prescribing ASM.

Folic Acid and Vitamin B12 Prevent Deleterious Effects of Rotenone on Object Novelty Recognition Memory and Kynu Expression in an Animal Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by a range of motor signs, but cognitive dysfunction is also observed. Supplementation with folic acid and vitamin B12 is expected to prevent cognitive impairment. To test this in PD, we promoted a lesion within the substantia nigra pars compacta of rats using the neurotoxin rotenone. In the sequence, the animals were supplemented with folic acid and vitamin B12 for 14 consecutive days and subjected to the object recognition test. We observed an impairment in object recognition memory after rotenone administration, which was prevented by supplementation (p < 0.01). Supplementation may adjust gene expression through efficient DNA methylation. To verify this, we measured the expression and methylation of the kynureninase gene (Kynu), whose product metabolizes neurotoxic metabolites often accumulated in PD as kynurenine. Supplementation prevented the decrease in Kynu expression induced by rotenone in the substantia nigra (p < 0.05), corroborating the behavioral data. No differences were observed concerning the methylation analysis of two CpG sites in the Kynu promoter. Instead, we suggest that folic acid and vitamin B12 increased global DNA methylation, reduced the expression of Kynu inhibitors, maintained Kynu-dependent pathway homeostasis, and prevented the memory impairment induced by rotenone. Our study raises the possibility of adjuvant therapy for PD with folic acid and vitamin B12.

Non-coding RNA network associated with obesity and rheumatoid arthritis.

Obesity causes epigenetic alterations mediated by non-coding RNAs (ncRNAs) that increase susceptibility to autoimmune and inflammatory pathways. Obese individuals with rheumatoid arthritis (RA) are particularly affected, with worse clinical outcomes and treatment responses. In order to identify micro RNAs (miRNAs) and long ncRNAs (lncRNAs) that may influence RA development, progression, treatment efficacy, and clinical outcomes in obese individuals, we systematically screened PubMed, Web of Science, and Scopus databases for articles on these topics, published in the last decade. We ended up with 38 of initially 1110 documents and found that both obesity and RA share dysregulated expression of miR-21, miR-143, miR-146a, miR-155 miRNAs, H19, and HOTAIR lncRNAs (all but H19, up-regulated). With one exception (H19 and BMI in brown fat tissue), they correlated positively with clinical measures and disease activity. H19 and HOTAIR regulate 24 miRNAs, some differentially expressed in the investigated diseases. Both regulate miR-143-3p. We also investigated eleven GWAS-identified SNVs found in exonic lncRNA regions (there were none in exonic miRNA genes). Eight were associated with RA and three with obesity-related traits, seven change binding sites for miRNAs, especially on LINC01184 and GATA3-AS1, four were associated with gene expression in adipocytes (including LINC01184) and two may also change the secondary structure of ENSG00000284825 and LINC02656. These ncRNAs compose a unique regulatory network in obese RA patients, compiled for the first time in this review, which we suggest as future therapeutic targets in these simultaneous conditions.

Genetic Associations and Differential mRNA Expression Levels of Host Genes Suggest a Viral Trigger for Endemic Pemphigus Foliaceus.

The long search for the environmental trigger of the endemic pemphigus foliaceus (EPF, fogo selvagem) has not yet resulted in any tangible findings. Here, we searched for genetic associations and the differential expression of host genes involved in early viral infections and innate antiviral defense. Genetic variants could alter the structure, expression sites, or levels of the gene products, impacting their functions. By analyzing 3063 variants of 166 candidate genes in 227 EPF patients and 194 controls, we found 12 variants within 11 genes associated with differential susceptibility (p < 0.005) to EPF. The products of genes TRIM5, TPCN2, EIF4E, EIF4E3, NUP37, NUP50, NUP88, TPR, USP15, IRF8, and JAK1 are involved in different mechanisms of viral control, for example, the regulation of viral entry into the host cell or recognition of viral nucleic acids and proteins. Only two of nine variants were also associated in an independent German cohort of sporadic PF (75 patients, 150 controls), aligning with our hypothesis that antiviral host genes play a major role in EPF due to a specific virus−human interaction in the endemic region. Moreover, CCL5, P4HB, and APOBEC3G mRNA levels were increased (p < 0.001) in CD4+ T lymphocytes of EPF patients. Because there is limited or no evidence that these genes are involved in autoimmunity, their crucial role in antiviral responses and the associations that we observed support the hypothesis of a viral trigger for EPF, presumably a still unnoticed flavivirus. This work opens new frontiers in searching for the trigger of EPF, with the potential to advance translational research that aims for disease prevention and treatment.

Marked to Die-Cell Death Mechanisms for Keratinocyte Acantholysis in Pemphigus Diseases.

Pemphigus is a group of blistering autoimmune diseases causing painful skin lesions, characterized by acantholysis and by the production of autoantibodies against, mainly, adhesion proteins. We reviewed the literature for molecules and/ or features involved in the 12 cell death pathways described by Nomenclature Committee on Cell Death, taking place in pemphigus patients, cell lines, or human skin organ cultures treated with sera or IgG from pemphigus patients or in pemphigus mouse models, and found 61 studies mentioning 97 molecules involved in cell death pathways. Among the molecules, most investigated were pleiotropic molecules such as TNF and CASP3, followed by FASL and CASP8, and then by FAS, BAX, BCL2, and TP53, all involved in more than one pathway but interpreted to function only within apoptosis. Most of these previous investigations focused only on apoptosis, but four recent studies, using TUNEL assays and/or electron microscopy, disqualified this pathway as a previous event of acantholysis. For PV, apoptolysis was suggested as a cell death mechanism based on pathogenic autoantibodies diversity, mitochondrial dysfunction, and p38 MAPK signaling. To answer those many questions that remain on cell death and pemphigus, we propose well-controlled, statistically relevant investigations on pemphigus and cell death pathways besides apoptosis, to overcome the challenges of understanding the etiopathology of pemphigus diseases.

Inside the pocket: Critical elements of HLA-mediated susceptibility to cervical precancerous lesions.

Human papillomavirus (HPV) infection is a necessary cause for cervical cancer (CC), but it also depends on genetic factors, such as HLA polymorphism. However, few reports addressed the role of amino acids residues at the HLA peptide-binding cleft in HPV-related cervical disease. Therefore, we aimed to investigate the association between HLA-B, HLA-C, and HLA-DRB1 polymorphism and amino acid residues composing the pockets of the peptide-binding cleft of the respective polypeptide chains with cervical intraepithelial neoplasia (CIN II/III). HLA typing was performed by PCR-SSOP in 184 women with CIN II/III and 174 controls from South Brazil. Associations were estimated by multivariate logistic regression. FDR test was performed to correct the p-value for multiple comparisons. HLA-DRB1*13:01 was associated with protection against CIN II/III, while HLA-C*03:04 was associated with susceptibility. The amino acid residues isoleucine, tyrosine, and leucine at positions 95, 116, and 163 of HLA-C, respectively, were associated with CIN II/III susceptibility. In contrast, serine at positions 11 and 13 of HLA-DRB1 was associated with protection against the disease. Our results confirm previously reported associations between HLA and cervical diseases caused by HPV and suggest a role for amino acid residues at different positions of HLA-C and HLA-DRB1 in CIN II/III. This finding may be further explored to better understand the genetic risk and the influence of immune response to CC development.

GWAS-Top Polymorphisms Associated With Late-Onset Alzheimer Disease in Brazil: Pointing Out Possible New Culprits Among Non-Coding RNAs.

Several genome-wide association studies (GWAS) have been carried out with late-onset Alzheimer's disease (LOAD), mainly in European and Asian populations. Different polymorphisms were associated, but several of them without a functional explanation. GWAS are fundamental for identifying loci associated with diseases, although they often do not point to causal polymorphisms. In this sense, functional investigations are a fundamental tool for discovering causality, although the failure of this validation does not necessarily indicate a non-causality. Furthermore, the allele frequency of associated genetic variants may vary widely between populations, requiring replication of these associations in other ethnicities. In this sense, our study sought to replicate in 150 AD patients and 114 elderly controls from the South Brazilian population 18 single-nucleotide polymorphisms (SNPs) associated with AD in European GWAS, with further functional investigation using bioinformatic tools for the associated SNPs. Of the 18 SNPs investigated, only four were associated in our population: rs769449 (APOE), rs10838725 (CELF1), rs6733839, and rs744373 (BIN1-CYP27C1). We identified 54 variants in linkage disequilibrium (LD) with the associated SNPs, most of which act as expression or splicing quantitative trait loci (eQTLs/sQTLs) in genes previously associated with AD or with a possible functional role in the disease, such as CELF1, MADD, MYBPC3, NR1H3, NUP160, SPI1, and TOMM40. Interestingly, eight of these variants are located within long non-coding RNA (lncRNA) genes that have not been previously investigated regarding AD. Some of these polymorphisms can result in changes in these lncRNAs' secondary structures, leading to either loss or gain of microRNA (miRNA)-binding sites, deregulating downstream pathways. Our pioneering work not only replicated LOAD association with polymorphisms not yet associated in the Brazilian population but also identified six possible lncRNAs that may interfere in LOAD development. The results lead us to emphasize the importance of functional exploration of associations found in large-scale association studies in different populations to base personalized and inclusive medicine in the future.

Neutrophil Extracellular Traps: A Perspective of Neuroinflammation and Complement Activation in Alzheimer's Disease.

Complement system (CS) components are associated with Alzheimer's disease (AD), the commonest cause of dementia in the world. Neutrophils can be attracted to amyloid-ß plaques by several pro-inflammatory factors, including the complement anaphylatoxin C5a. They may release neutrophil extracellular traps (NETs), which are chromatin nets associated with myeloperoxidase, elastase, and other enzymes. Some CS molecules, such as C5a, C1q, and CR1, are associated with increased neutrophil recruitment and NETs release. However, the relationship between CS molecules and NETs in AD is poorly understood. In this work, we detected higher NET concentrations in plasma and serum of Brazilian AD patients, than in elderly controls (medians = 2.78 [2.07-6.19] vs. 2.23 [0.33-4.14] ng/mL, p = 0.0005). We discussed these results within the context of our former findings on complement and AD and the context of the literature on complement and NET release, suggesting both as possible therapeutic targets to prevent the progress of the disease.

Genetic variability of immune-related lncRNAs: polymorphisms in LINC-PINT and LY86-AS1 are associated with pemphigus foliaceus susceptibility.

Pemphigus foliaceus (PF) is an autoimmune blistering disease of the skin, clinically characterized by erosions and, histopathologically, by acantholysis. PF is endemic in the Brazilian Central-Western region. Numerous single nucleotide polymorphisms (SNPs) have been shown to affect the susceptibility for PF, including SNPs at long non-coding RNA (lncRNA) genes, which are known to participate in many physiological and pathogenic processes, such as autoimmunity. Here, we investigated whether the genetic variation of immune-related lncRNA genes affects the risk for endemic and sporadic forms of PF. We analysed 692 novel SNPs for PF from 135 immune-related lncRNA genes in 227 endemic PF patients and 194 controls. The SNPs were genotyped by Illumina microarray and analysed by applying logistic regression at additive model, with correction for sex and population structure. Six associated SNPs were also evaluated in an independent German cohort of 76 sporadic PF patients and 150 controls. Further, we measured the expression levels of two associated lncRNA genes (LINC-PINT and LY86-AS1) by quantitative PCR, stratified by genotypes, in peripheral blood mononuclear cells of healthy subjects. We found 27 SNPs in 11 lncRNA genes associated with endemic PF (p < .05 without overlapping with protein-coding genes). Among them, the LINC-PINT SNP rs10228040*A (OR = 1.47, p = .012) was also associated with increased susceptibility for sporadic PF (OR = 2.28, p = .002). Moreover, the A+ carriers of LY86-AS1*rs12192707 mark lowest LY86-AS1 RNA levels, which might be associated with a decreasing autoimmune response. Our results suggest a critical role of lncRNA variants in immunopathogenesis of both PF endemic and sporadic forms.

COVID-19: The question of genetic diversity and therapeutic intervention approaches.

Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2), is the largest pandemic in modern history with very high infection rates and considerable mortality. The disease, which emerged in China's Wuhan province, had its first reported case on December 29, 2019, and spread rapidly worldwide. On March 11, 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a pandemic and global health emergency. Since the outbreak, efforts to develop COVID-19 vaccines, engineer new drugs, and evaluate existing ones for drug repurposing have been intensively undertaken to find ways to control this pandemic. COVID-19 therapeutic strategies aim to impair molecular pathways involved in the virus entrance and replication or interfere in the patients' overreaction and immunopathology. Moreover, nanotechnology could be an approach to boost the activity of new drugs. Several COVID-19 vaccine candidates have received emergency-use or full authorization in one or more countries, and others are being developed and tested. This review assesses the different strategies currently proposed to control COVID-19 and the issues or limitations imposed on some approaches by the human and viral genetic variability.

Lack of Association between LCT_rs140433552*CA>del Indel Polymorphism and Lactose Intolerance in a Southern Brazilian Population.

BACKGROUND/AIMS: Polymorphisms in the enhancer of the lactase gene (LCT) are strongly associated with lactase persistence, but not always predictive of the phenotype. We investigated a possible association between the regulatory rs140433552*CA>del variant of LCT and lactose intolerance (LI). METHODS: We genotyped 122 individuals for rs140433552 and rs4988235 (-13910*C>T). RESULTS: Associations of rs140433552*CA>del with LI depend on -13910*C>T. Homozygous individuals for the C-CA haplotype, as well as C-CA+/C individuals, seem more likely to manifest LI (OR 3.33 [95% CI 1.32-8.35], p = 0.011, and OR 3.93 [95% CI 1.61-9.61], p = 0.003, respectively), while homozygous individuals for the T-CA haplotype seem more likely to be lactose tolerant (OR 0.04 [95% CI 0.002-0.70], p = 8 × 10-4). CONCLUSIONS: rs140433552*CA>del is not independently associated with LI.

Natural killer cell receptor variants and chronic hepatitis B virus infection in the Vietnamese population.

OBJECTIVES: Genes of host immunity play an important role in disease pathogenesis and are determinants of clinical courses of infections, including hepatitis B virus (HBV). Killer-cell immunoglobulin-like receptor (KIR), expressed on the surface of natural killer cells (NK), regulate NK cell cytotoxicity by interacting with human leukocyte antigen (HLA) class I molecules and are candidates for influencing the course of HBV. This study evaluated whether variations in KIR gene content and HLA-C ligands are associated with HBV and with the development of liver cirrhosis and hepatocellular carcinoma. METHODS: A Vietnamese study cohort (HBV n = 511; controls n = 140) was genotyped using multiplex sequence-specific polymerase chain reaction (PCR-SSP) followed by melting curve analysis. RESULTS: The presence of the functional allelic group of KIR2DS4 was associated with an increased risk of chronic HBV (OR = 1.86, pcorr = 0.02), while KIR2DL2+HLA-C1 (OR = 0.62, pcorr = 0.04) and KIR2DL3+HLA-C1 (OR = 0.48, pcorr = 0.04) were associated with a decreased risk. The pair KIR2DL3+HLA-C1 was associated with liver cirrhosis (OR = 0.40, pcorr = 0.01). The presence of five or more activating KIR variants was associated with hepatocellular carcinoma (OR = 0.53, pcorr = 0.04). CONCLUSIONS: KIR gene content variation and combinations KIR-HLA influence the outcome of HBV infection.