Background Endophenotypes are simple biological aspects of a disease that can be observed in unaffected relatives at a higher rate than in the general population; an “autism endophenotype” justifies ...the observation that a mild reduction in ideational fluency and nonverbal generativity might be observed in healthy, unaffected relatives of children with autism. Because it is becoming apparent that autism is associated with given alleles encoding within the human leukocyte antigens region, a region of pivotal importance in immunity, we examined whether the “autism endophenotype” would extend its effects on the immune system. Methods Multiple immune parameters were analyzed in autistic children (AC) ( n = 20), their siblings (HSAC) ( n = 15), and age- and gender-comparable healthy control subjects (HC) ( n = 20) without any familiarity for autism. Results The immune profiles of HSAC were significantly more similar to those of their autistic siblings than to what was observed in HC. Thus, in AC and HSAC compared with HC: 1) proinflammatory and interleukin-10–producing immune cells were augmented ( p < .01 in both comparisons); 2) CD8+ naïve (CD45RA+ /CCR7+) T lymphocytes were increased ( p < .0001 and p = .001); and 3) CD8+ effector memory (CD45RA− /CCR7−) ( p < .0001 and p = .03) as well as CD4+ terminally differentiated (CD45RA− /CCR7+) ( p < .05 in both comparisons) lymphocytes were diminished. Serum autoantibodies (GM1) could be detected in 10% of AC children alone. Conclusions Results of this pilot study indicate that a complex immune dysfunction is present both in autistic children and in their non-autistic siblings and show the presence of an “autism endophenotype” that expands its effects on immunologic functions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The activation of natural killer (NK) cells is modulated by surface molecules. We analyzed NK cells in human immunodeficiency virus (HlV)-exposed seronegative (HESN) individuals by means of molecular ...typing of HLA B, Cw, and killer cell immunoglobulin-like receptor (KIR) molecules. In HESN individuals, compared with HIV patients, the frequency of the inhibitory KIR3DL1 allele and of the KIR3DL1⁺/Bw4⁺ inhibitory complex was reduced, whereas that of the activatory KIR3DS1⁺ ligand and the activatory Bw4⁺/3DL1⁻/3DS1⁺ complex was increased, resulting in a statistically significant diversion from Hardy-Weinberg equilibrium (KIR3DS1 homozygote) in HESN individuals. The reciprocal equilibrium between inhibitory and activatory NK receptors and their ligands favors NK activation in HESN individuals.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Vitamin D modulates immune responses and its deficiency has been observed in more than 60% of bronchiectasis patients. Vitamin D binding protein (DBP) is coded by the GC gene, is involved in the ...transport of vitamin D, and includes a number of isoforms based on single nucleotide polymorphisms (SNPs) in the coding region at rs7041 and rs4855. We evaluated the possible clinical impact of DBP polymorphisms and isoforms in an observational, cross-sectional study conducted in 116 bronchiectasis patients, who were genetically characterized for rs4588 and rs7041 SNPs. Results showed that the GC1f isoform (rs7041/rs4588 A/G) correlated with a more severe disease (18.9% vs. 6.3%, p = 0.038), a higher incidence of chronic infections (63.6% vs. 42%, p = 0.041), and a lower BACI score (0.0 (0.0, 2.5) vs. 3.0 (0.0, 3.0), p = 0.035). Moreover, blood concentration of vitamin D was higher in patients carrying GC1s (median (IQR): 20.5 (14.3, 29.7 vs. 15.8 (7.6, 22.4), p = 0.037)). Patients carrying GC1f isoform have a more severe disease, more chronic infections and lower asthmatic comorbidity in comparison to those without the GC1f isoform. Presence of the GC1s isoform (rs7041/rs4588 C/G) seems to be associated to a milder clinical phenotype with increased vitamin D levels and lower comorbidities score.
Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease's estimated heritability, whereas low-frequency and rare variants may partly account for the missing ...heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italian MS multiplex family with five affected members. For this purpose, we combined linkage analysis and next-generation sequencing (NGS)-based whole exome and whole genome sequencing (WES and WGS, respectively). The genetic burden attributable to known common MS variants was also assessed by weighted genetic risk score (wGRS). We found a significantly higher burden of common variants in the affected family members compared to that observed among sporadic MS patients and healthy controls (HCs). We also identified 34 genes containing at least one low-frequency functional variant shared among all affected family members, showing a significant enrichment in genes involved in specific biological processes-particularly mRNA transport-or neurodegenerative diseases. Altogether, our findings point to a possible pathogenic role of different low-frequency functional MS variants belonging to shared pathways. We propose that these rare variants, together with other known common MS variants, may account for the high number of affected family members within this MS multiplex family.
In HIV-infected individuals, mechanisms underlying unsatisfactory immune recovery during effective combination antiretroviral therapy (cART) have yet to be fully understood. We investigated whether ...polymorphism of genes encoding immune-regulating molecules, such as killer immunoglobulin-like receptors (KIR) and their ligands class I human leukocyte antigen (HLA), could influence immunological response to cART.
KIR and HLA frequencies were analyzed in 154 HIV-infected and cART-treated patients with undetectable viral load divided into two groups: 'immunological non responders' (INR, N = 50, CD4(+) T-cell count <200/mm(3)) and full responders (FR, N = 104, CD4(+) T-cell count >350/mm(3)). Molecular KIR were typed using polymerase chain reaction-based genotyping. Comparisons were adjusted for baseline patient characteristics.
The frequency of KIR2DL3 allele was significantly higher in FR than in INR (83.7% vs. 62%, P = 0.005). The functional compound genotype HLA-C1(+)/KIR2DL3(+), even at multivariable analysis, when adjusted for nadir CD4(+) T-cell count, was associated with reduced risk of INR status: odds ratio (95% Confidence Intervals) 0.34 (0.13-0.88), P = 0.03.
Reduced presence of the inhibitory KIR2DL3 genotype detected in INR might provoke an imbalance in NK function, possibly leading to increased immune activation, impaired killing of latently infected cells, and higher proviral burden. These factors would hinder full immune recovery during therapy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The aim of this investigation was to determine if particular immunoglobulin GM (γ marker) alleles and genotypes were associated with Parkinson's disease (PD) and whether they contributed to the ...interindividual differences in the level of antibodies to herpes simplex virus type 1 (HSV1), which has been implicated in PD pathology. Using a case-control study design, 94 PD patients and 157 controls were characterized for anti-HSV1 IgG antibodies and genotyped for GM alleles expressed on IgG1 (3,17) and IgG2 (23 +, 23-). The homozygosity for the GM 3 and GM 23 alleles was significantly associated with susceptibility to PD (p = 0.004, 0.018, respectively). Also, GM 23 genotypes were significantly associated with anti-HSV1 IgG antibody levels in patients (p = 0.0021), but not in controls. These results suggest that GM genes may act as effect modifiers of the reported HSV1-PD association.
•GM alleles are risk/protective factors for Parkinson's disease (PD).•GM alleles influence antibody responsiveness to herpes simplex virus type 1 (HSV1), which has been implicated in PD pathology.•These results suggest that GM genes may act as effect modifiers of the reported HSV1-PD association.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Autism spectrum disorders (ASD) can present with different onset and timing of symptom development; children may manifest symptoms early in their first year of life, i.e., early onset (EO-ASD), or ...may lose already achieved skills during their second year of life, thus showing a regressive-type onset (RO-ASD). It is still controversial whether regression represents a neurobiological subtype of ASD, resulting from distinct genetic and environmental causes. We focused this study on the 25 kD synaptosomal-associated protein (SNAP-25) gene involved in both post-synaptic formation and adhesion and considered a key player in the pathogenesis of ASD. To this end, four single nucleotide polymorphisms (SNPs) of the SNAP-25 gene, rs363050, rs363039, rs363043, and rs1051312, already known to be involved in neurodevelopmental and psychiatric disorders, were analyzed in a cohort of 69 children with EO-ASD and 58 children with RO-ASD. Both the rs363039 G allele and GG genotype were significantly more frequently carried by patients with EO-ASD than those with RO-ASD and healthy controls (HC). On the contrary, the rs1051312 T allele and TT genotype were more frequent in individuals with RO-ASD than those with EO-ASD and HC. Thus, two different SNAP-25 alleles/genotypes seem to discriminate between EO-ASD and RO-ASD. Notably, rs1051312 is located in the 3′ untranslated region (UTR) of the gene and is the target of microRNA (miRNA) regulation, suggesting a possible epigenetic role in the onset of regressive autism. These SNPs, by discriminating two different onset patterns, may represent diagnostic biomarkers of ASD and may provide insight into the different biological mechanisms towards the development of better tailored therapeutic and rehabilitative approaches.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Vitamin D binding protein (DBP) gene encodes for Gc, an α2 globulin that transports vitamin D metabolites in serum. Given the role of vitamin D in MS onset and disease progression we ...analyzed the frequencies of three polymorphisms (rs7041, rs4588 and rs2282679) within DBP gene in 701 Italian multiple sclerosis (MS) patients and 831 healthy controls (HC). None of the polymorphisms showed any association with MS onset and progression. Our results suggest that DBP is not involved in the pathogenesis of MS in Italians.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract Indoleamine 2,3 dioxygenase (IDO)1 and IDO2 are enzymes playing a pivotal role in the metabolism of tryptophan and in immune modulation. IDO2, in particular, was recently suggested to drive ...B cell-mediated autoimmune diseases. Two functional polymorphisms within the IDO2 gene are described that result in the production of enzymes with suppressed activity; we analyzed these polymorphisms in a cohort of Italian multiple sclerosis patients (MS). R248W (rs10109853) and Y359STOP (rs4503083) IDO2 polymorphisms were analyzed in 1355 Caucasian Italians (675 MS patients and 680 healthy controls) using Allelic discrimination Real-time approach with predesigned TaqMan probes. No significant differences in the distributions of rs10109853 and rs4503083 IDO2 polymorphisms could be observed between MS patients and the control group, even when patients were stratified according to disease phenotype (relapsing remitting - RRMS or primary progressive -PPMS) or sex. Moreover, the analyzed SNPs were not associated with age at onset or disease progression measured by EDSS (expanded disability status scale) and MSSS (multiple sclerosis severity score) scores. IDO2 rs10109853 and rs4503083 polymorphisms are not associated with MS risk, age at onset and disease progression in Italian MS patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Alzheimer's disease (AD) is a multifactorial disease with a still barely understood etiology. Herpes simplex virus 1 (HSV-1) has long been suspected to play a role in the pathogenesis of AD because ...of its neurotropism, high rate of infection in the general population, and life-long persistence in neuronal cells, particularly in the same brain regions that are usually altered in AD. The goal of this study was to evaluate HSV-1-specific humoral immune responses in patients with a diagnosis of either AD or amnestic mild cognitive impairment (aMCI), and to verify the possible relation between HSV-1-specific antibody (Ab) titers and cortical damage; results were compared to those obtained in a group of healthy controls (HC). HSV-1 serum IgG titers were measured in 225 subjects (83 AD, 68 aMCI, and 74 HC). HSV-specific Ab avidity and cortical gray matter volumes analyzed by magnetic resonance imaging (MRI) were evaluated as well in a subgroup of these individuals (44 AD, 23 aMCI, and 26 HC). Results showed that, whereas HSV-1 seroprevalence and IgG avidity were comparable in the three groups, increased Ab titers (p < 0.001) were detected in AD and aMCI compared to HC. Positive significant correlations were detected in AD patients alone between HSV-1 IgG titers and cortical volumes in orbitofrontal (region of interest, ROI1 RSp0.56; p = 0.0001) and bilateral temporal cortices (ROI2 RSp0.57; p < 0.0001; ROI3 RSp0.48; p = 0.001); no correlations could be detected between IgG avidity and MRI parameters. Results herein suggest that a strong HSV-1-specific humoral response could be protective toward AD-associated cortical damage.
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