Effectiveness of immunosuppressive therapy for lymphocytic myocarditis according: data from actual clinical practice

Aim. To compare the effectiveness of standard heart failure therapy with and without combined immunosuppressive therapy in patients with documented lymphocytic myocarditis (LM) based on data from actual clinical practice.Material and methods. This observational study included 70 patients with documented LM, 40% (n=28) of whom received immunosuppressive therapy. All patients underwent standard echocardiographic and laboratory investigations, endomyocardial biopsy with histological, immunohistochemical and molecular genetic analysis. Contrast-enhanced cardiac magnetic resonance imaging was performed in 74% of patients. All patients received standard therapy for heart failure at baseline.Results. The groups did not differ in demographic and echocardiographic characteristics. The appointment of immunosuppressive therapy was accompanied by an increase in ejection fraction by 12,2% compared to 6,4% (p=0,02). There were no significant differences in combined endpoints (survival and the need for heart transplantation) depending on therapy regimen (log-rank p=0,97).Conclusion. The prognosis of patients with chronic LM depends on the process activity, the severity of impaired hemodynamics and ventricular arrhythmias, as well as on the presence of persistent viral infection. Compliance with patient selection algorithm before prescribing immunosuppressive therapy is associated with the improvement in myocardial global contractility.

Computational methods for the discovery and annotation of viral integrations

The transfer of genetic material between viruses and eukaryotic cells is pervasive. Somatic integrations of DNA viruses and retroviruses have been linked to persistent viral infection and genotoxic effects. Integrations into germline cells, referred to as Endogenous Viral Elements (EVEs), can be co-opted for host functions. Besides DNA viruses and retroviruses, EVEs can also derive from nonretroviral RNA viruses, which have often been observed in piRNA clusters. Here, we describe a bioinformatic framework to annotate EVEs in a genome assembly, study their widespread occurrence and polymorphism and identify sample-specific viral integrations using whole-genome sequencing data.

Some issues in pathogenesis of premalignant lesions of the uterine cervix

Aetiological and pathogenetic aspects in uterine cervix pathology associated with persistent viral infection by the high-risk human papillomavirus (HR HPV) are considered in this scientific review. The article provides a concise description of the biological structure and life processes of the virus. The main stages of uterine cervix impairment by the viral agent crucial for cancer development are described. Additionally, some mechanisms in the escape of viral progression from the immune control are given insight into. It is considered that, alongside with the aggression of the virus toward the host cells, there is a decline of cellular and humoral immunity in the female’s genitourinary tract, which may determine the growth and development of the neoplasm as well. The article puts a large emphasis on the defensive mechanisms appearing in the female organism as a response to the invasion and the persistence of the human papillomavirus. It is assumed that complete knowledge of pathogenetic mechanisms in development of oncogenic potential of the virus would imply the absence of rampant CIN and cervical cancer development induced by invasion of the agent into the organism

IL-21 from high-affinity CD4 T cells drives differentiation of brain-resident CD8 T cells during persistent viral infection

Development of tissue-resident memory (TRM) CD8 T cells depends on CD4 T cells. In polyomavirus central nervous system infection, brain CXCR5hi PD-1hi CD4 T cells produce interleukin-21 (IL-21), and CD8 T cells lacking IL-21 receptors (IL21R−/−) fail to become bTRM. IL-21+ CD4 T cells exhibit elevated T cell receptor (TCR) affinity and higher TCR density. IL21R−/− brain CD8 T cells do not express CD103, depend on vascular CD8 T cells for maintenance, are antigen recall defective, and lack TRM core signature genes. CD4 T cell–deficient and IL21R−/− brain CD8 T cells show similar deficiencies in expression of genes for oxidative metabolism, and intrathecal delivery of IL-21 to CD4 T cell–depleted mice restores expression of electron transport genes in CD8 T cells to wild-type levels. Thus, high-affinity CXCR5hi PD-1hi CD4 T cells in the brain produce IL-21, which drives CD8 bTRM differentiation in response to a persistent viral infection.

ISG15 drives immune pathology and respiratory failure during viral infection

Cytokine storm during respiratory viral infection is an indicator of disease severity and poor prognosis. Type 1 interferon (IFN-I) production and signaling has been reported to be causal in cytokine storm-associated pathology in several respiratory viral infections, however, the mechanisms by which IFN-I promotes disease pathogenesis remain poorly understood. Here, using Usp18-deficient, USP18 enzymatic-inactive and Isg15-deficient mouse models, we report that lack of deISGylation during persistent viral infection leads to severe immune pathology characterized by hematological disruptions, cytokine amplification, lung vascular leakage and death. This pathology requires T cells but not T cell-intrinsic deletion of Usp18. However, lack of Usp18 in myeloid cells mimicked the pathological manifestations observed in Usp18-/- or Usp18C61A mice which were dependent on Isg15. We further mechanistically demonstrate that interrupting the ISGylation/deISGylation circuit increases extracellular levels of ISG15 which is accompanied by inflammatory neutrophil accumulation to the lung. Importantly, neutrophil depletion reversed morbidity and mortality in Usp18C61A mice. In summary, we reveal that the enzymatic function of Usp18 is crucial for regulating extracellular release of ISG15. This is accompanied by altered neutrophil differentiation, cytokine amplification and mortality following persistent viral infection. Moreover, our results suggest that extracellular ISG15 may drive the inflammatory pathology observed and could be both a prospective predictor of disease outcome and a therapeutic target during severe respiratory viral infections.

IMMUNOGLOBULIN INDICATORS TO VIRUSES CYTOMEGAL AND GENITAL HERPES IN THE BLOOD SERUM OF WOMEN WITH NON-ATIPICAL ENDOMETRIAL HYPERPROLIFETATIVE PATHOLOGY

The aim of the study was to analyze the level of Ig M- and Ig G-antibody (Ab) for cytomegalovirus (CMV) and herpes simplex virus type 2 (HSV-2) in serum of women with non-atypical endometrial hyperproliferative pathology. Materials and methods: The analysis of immunoglobulin indices to CMV and HSV-2 in serum of women with non-atypical endometrial hyperproliferative pathology. In women with uterine body polyps the presence of CMV in the uterine cavity was found in 54.8% of cases, in women with non-atypical endometrial hyperplasia in 38.3% of cases. The levels of Ig G-Ab and Ig M-Ab to CMV in serum have a clear dependence on the degree of antigen expression in endometrial tissue. HSV-2 antigens were determined in 22.58 ± 5.31% of women with uterine body polyps and in 8.33 ± 3.57% of patients with non-atypical endometrial hyperplasia while increasing serum specific antibodies to HSV-2. Results: The results indicate that there is a clear link between viral infection of hyperproliferatively altered endometrium and the determination of positive immunoglobulin levels in peripheral blood, which may be a reliable marker of chronic persistent viral infection in a woman’s body. Conclusions: In women with uterine body polyps, the presence of CMV in the uterine cavity was found in 54.84 ± 6.32% of cases, in women with non-atypical endometrial hyperplasia in 38.33 ± 6.28% of cases. The levels of Ig G-Ab and and Ig M-Ab to CMV in serum have a clear dependence on the degree of antigen expression in endometrial tissue. HSV-2 antigens were determined in 22.58 ± 5.31% of women with uterine body polyps and in 8.33 ± 3.57% of patients with non-atypical endometrial hyperplasia while increasing serum specific antibodies to HSV-2. The results indicate that there is a clear link between viral infection of the target tissue (hyperproliferatively altered endometrium) and the determination of a positive level of peripheral blood immunoglobulin, which may be a reliable marker of chronic persistent viral infection in a woman.