Ficolin-3 and MASP-2 gene variants in Siberian arctic populations: Summarized evidence of selective pressure for the high frequency of lectin complement pathway deficiency.

Herewith, we provide novel original data about the prevalence of FCN3 rs532781899 and MASP2 rs72550870 variants among the newborns of aboriginal Siberian Arctic populations (Nenets and Dolgan-Nganasans) and Russians of East Siberia. This novel data has been analysed along with the genetic data about other proteins of the lectin pathway of the complement system (mannose-binding lectin and ficolin-2) obtained earlier. A total of 926 specimens of dried blood spots of the newborns were genotyped. The newborns represented four populations: Nenets, Dolgan-Nganasans, Mixed aboriginal population, and Russians (Caucasians) to study the prevalence of single nucleotide polymorphisms of FCN3 rs532781899 and MASP2 rs72550870. The prevalence of the deletion allele of the rs532781899 variant in the FCN3 gene associated with the decreased production of ficolin-3 was found to be increased in Russians compared to the Nenets aboriginal populations (P = .002). The prevalence of the rs72550870*G allele in the MASP2 gene associated with low serum protease activity was found to be increased in Russians compared with Nenets and Dolgan-Nganasans (P < .001 and P = .03, respectively). The results of the current study and our previous findings corroborate with a hypothesis that human evolution has been directed toward the accumulation of genotypes associated with low activity of the lectin complement activation pathway.

Chronic optogenetic stimulation of Bergman glia leads to dysfunction of EAAT1 and Purkinje cell death, mimicking the events caused by expression of pathogenic ataxin-1.

Bergmann glia (BG) are highly specialized radial astrocytes of the cerebellar cortex, which play a key role in the uptake of synaptic glutamate via the excitatory amino acid transporter EAAT1. Multiple lines of evidence suggest that in cerebellar neurodegenerative diseases reactive BG has a negative impact on neuronal function and survival through compromised EAAT activity. A family of such diseases are those caused by expansion of CAG repeats in genes of the ataxin family, resulting in spinocerebellar ataxias (SCA). We investigated the contribution of BG to the pathogenesis of cerebellar neurodegeneration in a model of SCA1, which was induced by expression of a polyglutamine mutant of ataxin-1 (ATXN1[Q85]) in BG specifically. We compared the outcomes with a novel model where we triggered excitotoxicity by a chronic optogenetic activation of BG with channelrhodopsin-2 (ChR2). In both cases we detected evidence of reduced glutamate uptake manifested by prolongation of excitatory postsynaptic currents in Purkinje cells which is consistent with documented reduction of expression and/or function of EAAT1. In both models we detected astroglyosis and Purkinje cells atrophy. Finally, the same pattern was detected in a knock-in mouse which expresses a polyglutamine mutant ataxin-1 ATXN1[Q154] in a non-cell-selective manner. Our results suggest that ATXN1[Q85] and ChR2-induced insult targeted to BG closely mimics SCA1 pathology, where excessive glutamate signaling appears to be a common feature likely being an important contributor to cerebellar neurodegeneration.

Mannose-binding lectin gene polymorphisms in the East Siberia and Russian Arctic populations.

Mannose-binding lectin (MBL) encoded by MBL2 gene is a protein with the ability to form carbohydrate complexes with microbial wall promoting their subsequent elimination. Genetically determined levels of MBL can modify the risk and clinical characteristics of many infectious diseases. The frequency of MBL2 genotypes exhibits significant population differences. The data on the distribution of MBL2 genotypes among the aborigines of the Russian Arctic territories have not yet been published. A total of 880 specimens of dried blood spots of the newborns were genotyped. The newborns represented four populations: Nenets, Dolgan-Nganasans, Mixed aboriginal population, and Russians (Caucasians, Krasnoyarsk). Six polymorphisms of the MBL2 gene were studied: rs11003125, rs7096206, rs7095891, rs5030737, rs1800450, and rs1800451. The frequency of the combined rare O allele (composed of the coding region variants rs5030737, rs1800450, and rs1800451) in the homozygous state was significantly higher in Russians: 10% vs 2% in Nenets and 1% in Dolgan-Nganosans (p < 0.001 for Russians vs other populations). The frequency of the high-producing haplotype (HYPA) was 35.4% in the Russian newborns, in keeping with European populations (27-33%); 64% for Nenets and 56% for Dolgan-Nganasans, similar to the estimates obtained for Eskimos and North Amerinds (64-81%). Our study results are in line with the hypothesis that human evolution has been moving in the direction of accumulation of the genotypes associated with low activity of the lectin complement activation pathway because of the prevalence of some intracellular infections such as tuberculosis, whereby low MBL activity may have a protective effect.

Extracellular S100ß Disrupts Bergman Glia Morphology and Synaptic Transmission in Cerebellar Purkinje Cells.

Astrogliosis is a pathological process that affects the density, morphology, and function of astrocytes. It is a common feature of brain trauma, autoimmune diseases, and neurodegeneration including spinocerebellar ataxia type 1 (SCA1), a poorly understood neurodegenerative disease. S100ß is a Ca2+ binding protein. In SCA1, excessive excretion of S100ß by reactive astrocytes and its uptake by Purkinje cells has been demonstrated previously. Under pathological conditions, excessive extracellular concentration of S100ß stimulates the production of proinflammatory cytokines and induces apoptosis. We modeled astrogliosis by S100ß injections into cerebellar cortex in mice. Injections of S100ß led to significant changes in Bergmann glia (BG) cortical organization and affected their processes. S100ß also changed morphology of the Purkinje cells (PCs), causing a significant reduction in the dendritic length. Moreover, the short-term synaptic plasticity and depolarization-induced suppression of synaptic transmission were disrupted after S100ß injections. We speculate that these effects are the result of Ca2+-chelating properties of S100ß protein. In summary, exogenous S100ß induced astrogliosis in cerebellum could lead to neuronal dysfunction, which resembles a natural neurodegenerative process. We suggest that astrocytes play an essential role in SCA1 pathology, and that astrocytic S100ß is an important contributor to this process.

The prevalence of the variants of the L-ficolin gene (FCN2) in the arctic populations of East Siberia.

L-ficolin encoded by FCN2 gene is a crucial factor of defence against infection in humans. We studied the prevalence of the two common variants (rs17549193 and rs7851696) in aboriginal and alien populations of the Taymyr-Dolgan-Nenets region of Krasnoyarskiy Kray, East Siberia, Russia (Nenets, Dolgans, Nganasans, Russians). We found a decreased prevalence of the rs17549193*T allele in all aboriginal populations as compared to Russians. Also, its frequency was the lowest in the Nenets among the studied populations, while frequency of the rs7851696*T allele was increased in this population. The results suggest that the Arctic populations of East Siberia are characterised by specificity of genetic make-up responsible for the activity of L-ficolin. Clinical and epidemiological studies are required to discover if these genetic features correlate with the infant infectious morbidity in East Siberian populations.

Immunological parameters and gene polymorphisms (C-590T IL4, C-597A IL10) in severe bronchial asthma in children from the Krasnoyarsk region, West Siberia.

BACKGROUND: Bronchial asthma is a common disease caused by interplay between multiple determinants, including genetic and immune variations. OBJECTIVE: To investigate the main indices of humoral and cellular branches of immunity, features of cytokine regulation and cytokine genes in children with atopic bronchial asthma (BA) with different levels of disease control. DESIGN: Fifty children with controlled BA (CBA) and 50 with uncontrolled BA (UBA) were analyzed. Mean age in the sample was 13.36 ± 2.24 years. A control group of healthy children (n = 50) was also studied. All individuals were Russians (Eastern Slavs) from the Krasnoyarsk Territory, West Siberia. Diagnoses, severity and level of disease control were defined according to the Global Initiative for Asthma (GINA) recommendations. The lymphocytes were counted in blood using fluorescent microscopy. Humoral branch indices and cytokine levels (IL-2, IL-4, IL-10 and TNF-α) in blood serum were measured by ELISA. Genotyping of single-nucleotide polymorphism (SNP) in -590 position of the IL4 and -597 position of the IL10 gene was performed by restriction fragment length analysis. RESULTS: No statistically significant differences in total IgE and cytokines blood levels were found in CBA and UBA. However, significant differences between the groups were found for CD(3+), CD(4+) and CD(8+) cell counts. The T-590 allele of the IL4 gene, which is responsible for an increased serum level of IL-4, showed a tendency to an association with UBA. A decreased level of IL-10 enhances control over BA, which proves its association with the allelic variant A-597 IL10. CONCLUSION: Our data show that children with UBA have higher counts of CD(3+) cells and an increase of sub-population of CD(4+)-cells as well as higher levels of IgE, IL-4 and TNF-α in blood serum as compared to CBA. Polymorphisms of the IL4 and IL10 genes are associated with allergic inflammation in UBA.

Association of IL2, TNFA, IL4 and IL10 Promoter Gene Polymorphisms with the Rate of Progression of the HIV Infection.

The rate of transition from one stage to another during the course of HIV infection is characterized by changes in the cytokine network balance. The alterations in the cytokine network balance during HIV infection depend on the individual profile of cytokine production predetermined by the functioning of the genes encoding the immunomodulators. The purpose of this research is to study the distribution in the frequency of allelic variants of the promoter regions of the genes encoding pro-inflammatory (T-330G IL2 and G-308A TNFA) and anti-inflammatory (C-590T IL4 and C-597A IL10) cytokines among healthy individuals of European origin and in HIV-infected patients with various rates of HIV progression (fast and slow). Four polymorphic loci of the promoter regions were analyzed in 127 HIV-infected patients and 52 healthy individuals using the polymerase chain reaction - restriction light fragment polymorphism (PCR-RLFP) methodology. We have obtained data indicating an increased allelic content of genotypes T/T IL2 (OR = 1.67), G/A TNFA (OR = 4.21), T/T IL4 (OR = 3.43), C/A IL10 (OR = 1.34) in HIV-infected patients as compared to healthy individuals. The correlation between the genotypes and allelic combinations of the investigated cytokines, and the rate of the infection progression in AIDS has been investigated. The association of T/G IL2, G/A TNFA, T/T IL4, A/A IL10 allelic variants of the immunomodulator genes with a fast rate of HIV infection has been established.

Polymorphism of Immune Response Genes as a Factor for Predisposition to Development of Diseases.

The association of particular allelic variants of genes coding proteins, such as transporter associated with processing (TAP) and heat shock protein (HSP), involved in endocellular processing of endogenous antigens, with synovium pathology accompanied with urogenital infection was observed. The particular alleles of TAP1 and TAP2 genes appeared to be the factor of predisposition or resistance for Chlamidia trachomatis but not for Mycoplasma hominis. At the same time, the relative risk for C. trachomatis and M. hominis infection development was increased among persons with HSP70-2*A/B phenotype. Some TAP2 gene allelic variants were determined as the factor of an increased relative risk to develop synovium pathology, especially accompanied with urogenital infection. The preliminary data concerning gene polymorphism of some proinflammatory cytokines in human immunodeficiency virus (HIV) infected patients are presented. We observed an increased frequency of C/T allele of IL-4 gene among HIV patients. None of patients showed A/A homozygous variant of IL-10 and TNF-alpha genes. Our obtained results may be used as informative criteria for prognosis of resistance or predisposition to different diseases.