Changes In Immune Homeostasis Research Articles

Substantiation for the relationship and «closed loop effect» between post-traumatic stress disorder and recurrent pregnancy loss

The objective: to identify and evaluate the changes in immune homeostasis in women with recurrent pregnancy loss (RPL) who had posttraumatic stress disorder (PTSD), and to establish the relationship between psycho-emotional status, the immune system and the role of chronic stress in the pathogenesis of autoimmune disorders as a cause of RPL.Materials and methods. An examination of 150 women of reproductive age was carried out, who were divided into three groups: I group (main group) – 100 patients with RPL and PTSD; II group (comparison one) – patients with RPL without PTSD (30 women) and the III group (control one) – 20 patients with PTSD who are planning pregnancy.Indicators of cellular immunity were studied and antiphospholipid syndrome was diagnosed. The electronic database of primary data was created using the Microsoft Excel 2016 spreadsheet program. Statistical data analysis was performed using the Statistica10.0 statistical analysis package.Results. Based on the results of the screening it was found that there are non-specific antibodies to anionic phospholipids, also known as antiphospholipid antibodies, in some patients of the main group. In the presence of antiphospholipid antibodies, the number of NK cells (CD3-CD16/56+) doubled, increasing the probability of the pregnancy interruption that had already occurred. There was also an increased number of NK cells (CD3-CD16/56+) in the blood of patients with PTSD compared to the control group – the patients with PTSD who are planning pregnancy.Conclusions. The results of the study confirmed the connection between PTSD and RPL and demonstrated significant immune homeostasis disorders, as well as the structural and morphological changes in the reproductive system.Women with RPL may have PTSD, which affects the pathogenesis of autoimmune disorders and RPL. These results lead to more deep understanding of RPL and will help in the development of new preventive and therapeutic measures.

Sex Variations in the Oral Microbiomes of Youths with Severe Periodontitis.

Objective Periodontitis is an inflammatory disease of microbial etiology caused primarily by dysbiosis of the oral microbiota. Our aim was to compare variations in the composition of the oral microbiomes of youths with severe periodontitis according to gender. Methods Subgingival plaque samples collected from 17 patients with severe periodontitis (11 males and 6 females) were split for 16S rRNA gene sequencing. The composition, α-diversity, and β-diversity of the patients' oral microbiomes were compared between the males and the females. Linear discriminant analysis effect size (LEfSe) was used to analyze the specific taxa enriched in the two groups. Functional profiles (KEGG pathways) were obtained using PICRUSt based on 16S rRNA gene sequencing data. Results The Chao1 index and phylogenetic diversity whole tree were significantly higher in males than in females. The Simpson and Shannon indices were not significantly different between the two groups. β-Diversity suggested that the samples were reasonably divided into groups. The Kruskal-Wallis test based on the relative abundance of species, combined with the LEfSe analysis showed that the dominant bacteria in males were Pseudomonas and Papillibacter, whereas the dominant bacteria in women were Fusobacteriales and Tannerella. KEGG analysis predicted that the variation in the oral microbiome may be related to the immune system in women, whereas immune system diseases were the dominant pathway in men. Conclusion We found sex-specific differences in the oral microbiome in a sample of youths with severe periodontitis. The differences may be related to changes in immune homeostasis and lead to a better understanding of periodontitis.

The value of azoximer bromide for optimization of therapy for HPV-associated cervical precancerous diseases

A significant increase in human papillomavirus-associated cervical oncological diseases, a high rate of recurrence of the process (4862.4%) after surgical treatment, changes in the local immune microenvironment in cervical biopsy specimens with (HSIL) created the prerequisites for studying the clinical efficacy of local immunocorrection in complex HSIL therapy.
 Aim. To study the clinical efficacy of local immunocorrection of azoximer with bromide in the complex therapy of cervical intraepithelial neoplasias.
 Materials and methods. Examination and treatment of 40 patients with HSIL was carried out. The study of the effectiveness of azoximer bromide in complex therapy in patients with cervical intraepithelial neoplasias of a high degree of oncogenic risk was carried out on the basis of an immunohistochemical study of cervicobioptates to markers CD3, CD56, CD20, CD138, M-CSF.
 Results and discussion. It was revealed that cervical intraepithelial neoplasias of a high degree of oncogenic risk are accompanied by changes in the local immune microenvironment in the epithelium and stroma of neoplastic altered tissues, which may contribute to the development of neoplasia progression. The inclusion of a local immunomodulator azoximer bromide in the complex therapy helped to reduce the recurrence of the process by 2 times, the elimination of the human papillomavirus by 3.5 times relative to the comparison group.
 Conclusion. 1. In cervico-biopsy specimens of patients with HSIL, there is an increase in the proportion of cells with expression of receptors CD20, CD3, CD138 (in stromal cells) and a decrease in epithelial infiltration with M-CSF, which indicates significant changes in immune homeostasis in cells of the affected epithelium. Based on the results obtained, at the stage of preparation for surgical treatment of patients with HSIL, it is advisable to include local immunocorrection to improve the outcome of therapy. 2. The inclusion of a local immunomodulator azoximer bromide in the complex therapy helped to reduce the recurrence of the process by 2 times, the elimination of the human papillomavirus by 3.5 times, which dictates the need for complex immunomodulation in the treatment of HSIL at the stage of preparation for surgery.

Potential Determinants of Gastrointestinal Dysfunction in Autism Spectrum Disorders

Gastrointestinal (GI) dysfunction is a common comorbidity of autism spectrum disorders (ASD) and is associated with increased severity of characteristic autism-associated symptoms. However, the underlying biological mechanisms for GI dysfunction symptoms in children with ASD are unknown. This review explores potential explanations for these symptoms including altered enteric microbiota, impaired intestinal permeability, changes in immune homeostasis, and genetic factors such as single nucleotide polymorphisms. It was shown that genetic factors not only influence the development of altered enteric microbiota and impaired intestinal permeability, but also are a strong, independent contributor to GI dysfunction in ASD patients.

Immune Responses to Broad-Spectrum Antibiotic Treatment and Fecal Microbiota Transplantation in Mice.

Compelling evidence demonstrates the pivotal role of the commensal intestinal microbiota in host physiology and the detrimental effects of its perturbations following antibiotic treatment. Aim of this study was to investigate the impact of antibiotics induced depletion and subsequent restoration of the intestinal microbiota composition on the murine mucosal and systemic immunity. To address this, conventional C57BL/6j mice were subjected to broad-spectrum antibiotic treatment for 8 weeks. Restoration of the intestinal microbiota by peroral fecal microbiota transplantation (FMT) led to reestablishment of small intestinal CD4+, CD8+, and B220+ as well as of colonic CD4+ cell numbers as early as 7 days post-FMT. However, at d28 following FMT, colonic CD4+ and B220+ cell numbers were comparable to those in secondary abiotic (ABx) mice. Remarkably, CD8+ cell numbers were reduced in the colon upon antibiotic treatment, and FMT was not sufficient to restore this immune cell subset. Furthermore, absence of gut microbial stimuli resulted in decreased percentages of memory/effector T cells, regulatory T cells, and activated dendritic cells in the small intestine, colon, mesenteric lymph nodes (MLN), and spleen. Concurrent antibiotic treatment caused decreased cytokine production (IFN-γ, IL-17, IL-22, and IL-10) of CD4+ cells in respective compartments. These effects were, however, completely restored upon FMT. In summary, broad-spectrum antibiotic treatment resulted in profound local (i.e., small and large intestinal), peripheral (i.e., MLN), and systemic (i.e., splenic) changes in the immune cell repertoire that could, at least in part, be restored upon FMT. Further studies need to unravel the distinct molecular mechanisms underlying microbiota-driven changes in immune homeostasis subsequently providing novel therapeutic or even preventive approaches in human immunopathologies.

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner.

Demethylation of CpG motifs in the Foxp3 intronic element, conserved noncoding sequence 2 (CNS2), is indispensable for the stable expression of Foxp3 in regulatory T cells (Tregs). In this study, we found that vitamin C induces CNS2 demethylation in Tregs in a ten-eleven-translocation 2 (Tet2)-dependent manner. The CpG motifs of CNS2 in Tregs generated in vitro by TGF-β (iTregs), which were methylated originally, became demethylated after vitamin C treatment. The conversion of 5-methylcytosin into 5-hydroxymethylcytosin was more efficient, and the methyl group from the CpG motifs of Foxp3 CNS2 was erased rapidly in iTregs treated with vitamin C. The effect of vitamin C disappeared in Tet2(-/-) iTregs. Furthermore, CNS2 in peripheral Tregs in vivo, which were demethylated originally, became methylated after treatment with a sodium-dependent vitamin C transporter inhibitor, sulfinpyrazone. Finally, CNS2 demethylation in thymic Tregs was also impaired in Tet2(-/-) mice, but not in wild type mice, when they were treated with sulfinpyrazone. Collectively, vitamin C was required for the CNS2 demethylation mediated by Tet proteins, which was essential for Foxp3 expression. Our findings indicate that environmental factors, such as nutrients, could bring about changes in immune homeostasis through epigenetic mechanisms.

The Cytomegaloviral Protein pUL138 Acts as Potentiator of Tumor Necrosis Factor (TNF) Receptor 1 Surface Density To Enhance ULb′-Encoded Modulation of TNF-α Signaling

Human cytomegalovirus is a ubiquitous herpesvirus that establishes lifelong latent infection. Changes in immune homeostasis induce the reactivation of lytic infection, which is mostly inapparent in healthy individuals but often causes overt disease in immunocompromised hosts. Based on discrepant tumor necrosis factor receptor 1 surface disposition between human cytomegalovirus AD169 variants differing in the ULb' region, we identified the latency-associated gene product pUL138, which also is expressed during productive infection, as a selective potentiator of tumor necrosis factor receptor 1, one of the key receptors of innate immunity. Ectopically expressed pUL138 coprecipitated with tumor necrosis factor receptor 1, extended the protein half-life, and enhanced its signaling responses, thus leading to tumor necrosis factor receptor 1 hyperresponsiveness. Conversely, the targeted deletion of UL138 from the human cytomegaloviral genome strongly reduced tumor necrosis factor receptor 1 surface densities of infected cells. Remarkably, the comparison of UL138 deficiency to ULb' deficiency revealed the presence of further positive modulators of tumor necrosis factor alpha signal transduction encoded within the human cytomegalovirus ULb' region, identifying this region as a hub for multilayered tumor necrosis factor alpha signaling regulation.

Loss of Roquin induces early death and immune deregulation but not autoimmunity

The substitution of one amino acid in the Roquin protein by the sanroque mutation induces a dramatic autoimmune syndrome in mice. This is believed to occur through ectopic expression of inducible T cell co-stimulator (ICOS) and unrestrained differentiation of follicular T helper cells, which induce spontaneous germinal center reactions to self-antigens. In this study, we demonstrate that tissue-specific ablation of Roquin in T or B cells, in the entire hematopoietic system, or in epithelial cells of transplanted thymi did not cause autoimmunity. Loss of Roquin induced elevated expression of ICOS through T cell-intrinsic and -extrinsic mechanisms, which itself was not sufficient to break self-tolerance. Instead, ablation of Roquin in the hematopoietic system caused defined changes in immune homeostasis, including the expansion of macrophages, eosinophils, and T cell subsets, most dramatically CD8 effector-like T cells, through cell-autonomous and nonautonomous mechanisms. Germline Roquin deficiency led to perinatal lethality, which was partially rescued on the genetic background of an outbred strain. However, not even complete absence of Roquin resulted in overt self-reactivity, suggesting that the sanroque mutation induces autoimmunity through an as yet unknown mechanism.

Neuroendocrine peptide receptors on cells of the immune system.

The functional role of neuropeptide receptors in the immune system seems to be sensory and regulatory. Signaling molecules (i.e. neuropeptides/neurotransmitters) secreted by immune or neuroendocrine cells can interact with specificity to immunocyte membrane bound neuroendocrine peptide receptors resulting in changes in immune homeostasis. At the onset of this review, three criteria were established in order to formally define the existence of a receptor including the pharmacologic, biochemical, and biological profiles. Applying these criteria, at least ten neuroendocrine peptide/peptide neurotransmitter receptors have met the requirements (table 1). Perhaps more striking, many of these receptors have characteristics which are nearly identical to those receptors found on neuroendocrine tissue. This observation implies irregularities in the physiology of a receptor system in one tissue compartment (neuroendocrine or immune) may be mirrored by the receptors found in the other compartment (neuroendocrine or immune) as well. This rather hypothetical concept is, in fact, supported by data studying ACTH, CRH, and TRH receptors on immune cells relative to the expression or function of these receptors in neuroendocrine tissue taken from patients with neuroendocrine disorders. It is likely that future work will use this relationship to further study the dynamic interaction between the immune and neuroendocrine systems in defining neurologic, neuroendocrine, and autoimmune disorders.

Neuroendocrine peptide receptors on cells of the immune system.

The functional role of neuropeptide receptors in the immune system seems to be sensory and regulatory. Signaling molecules (i.e. neuropeptides/neurotransmitters) secreted by immune or neuroendocrine cells can interact with specificity to immunocyte membrane bound neuroendocrine peptide receptors resulting in changes in immune homeostasis. At the onset of this review, three criteria were established in order to formally define the existence of a receptor including the pharmacologic, biochemical, and biological profiles. Applying these criteria, at least ten neuroendocrine peptide/peptide neurotransmitter receptors have met the requirements (table 1). Perhaps more striking, many of these receptors have characteristics which are nearly identical to those receptors found on neuroendocrine tissue. This observation implies irregularities in the physiology of a receptor system in one tissue compartment (neuroendocrine or immune) may be mirrored by the receptors found in the other compartment (neuroendocrine or immune) as well. This rather hypothetical concept is, in fact, supported by data studying ACTH, CRH, and TRH receptors on immune cells relative to the expression or function of these receptors in neuroendocrine tissue taken from patients with neuroendocrine disorders. It is likely that future work will use this relationship to further study the dynamic interaction between the immune and neuroendocrine systems in defining neurologic, neuroendocrine, and autoimmune disorders.