Cellular Immunity in Human Herpes Viruses 6 and 7 Infected Gastrointestinal Cancer Patients
CD4+ T lymphocytes appear to be the preferential target for replication of HHV-6 (human herpes virus) as well as HHV-7 viruses in vivo. In addition, CD8+ T cells, monocytes/macrophages, natural killer cells, epithelial, endothelial, neural cells and fibroblasts may be infected. By definition, however, even a tumour designated by pathologists to be early stage may be late stage when considered by the immune system. Certainly, even early stage tumours have evaded immune control, suggesting that they have acquired many immunosuppressive characteristics. The aim of the study was to clarify the influence of beta-herpes viruses on cellular immune response. In 95 gastrointestinal cancer patients we determined the immunocompetent cell level CD3, CD4, CD8, CD19, CD38, CD95, CD25 using laser flow cytofluorimeter and B- herpes viruses HHV-6, HHV-7 presence using a nested polymerase chain reaction method. Our data showed no statistically significant difference in immunocompetent cell level between negative, latent and active HHV-6, HHV-7 infection. Patients with immunocompromised immune status (lymphopenia) had a tendency to decreased CD4+, CD19+ absolute count. It may be suggested that virus-mediated immune response inhibition seems to be similar to cancer mediated, but differences in immune response among the same group of individuals had no influence on the average number of the immunocompetent cells in the group. Therefore, to characterise host-virus-tumour interactions, individual interpretation of each case is needed.
BK virus (BKV) infection was studied prospectively in 50 unselected consecutive patients who had undergone kidney transplantation. Infection was monitored for one year after transplantation. Viral DNA in urine (viruria) and plasma (viremia) samples was detected by nested, qualitative polymerase chain reaction. BKV screening data was available for 92% (n = 46) of patients enrolled in the study. Four groups of patients were distinguished: uninfected patients (group 1, n = 30), patients with viruria (group 2, n = 3), patients with viremia (group 3, n = 6) and patients with developed BKV nephropathy (group 4, n = 7). Infection was observed starting form the first month, and the maximum number of patients with active BKV infection occurred at six months after transplantation. Five-year graft survival was 69% for patients with any evidence of BKV infection, compared with 80.0% (P = NS) for patients without BKV infection. The best graft function was observed in group one patient (mean serum creatinine 130 mkmol/l and glomerular filtration rate (GFR) 60.9 ml/min) and the worst in group 4 (mean serum creatinine 180 mkmol/l and GFR 52.31 ml/min) at five years after transplantation. Five-year patient survival was 82.6% and was not affected by presence of BKV infection.
Human herpesviruses HHV-6 and HHV-7 reactivation in transplantation is associated with indirect immunomodulatory effects, such as cytomegalovirus (CMV) disease, increased opportunistic infections, graft dysfunction and acute rejection (AR). In this study, we analysed the clinical and immunological outcomes in renal transplant recipients (RTR) with active HHV-6 and HHV-7 infection. Between January 2007 and December 2007, clinical, virological and immunological tests were carried out in 46 RTR. The patients were divided into three groups: with active HHV-6 infection; with active HHV-7 infection; and without infection (control). The mean follow-up was 14 ± 2.5 months. At three months after renal transplantation (RT), active CMV infection was present in 12 (26%); HHV-6 in four (8.6%); and HHV-7 in nine (19.5%) of RTR. Active ß-herpesviruses infection was not associated with more frequent AR and worsening of graft function in recipients at different times after RT. The lymphocyte subsets (CD3+; CD4+ and CD8+ cell count) were considerably lower in RTR before RT. At 3 months after RT CD19+ and CD25+ cell counts were significantly increased in the HHV-7 group compared with the control group (P < 0.05). Significant differences were not found in clinical and immunological outcomes between patients with active ß-herpesviruses infection and those without active ß-herpesviruses infection.
Svetlana Čapenko, Marija Mihailova, Santa Rasa, Angelika Krūmiņa, Zane Zazerska, Ināra Logina and Modra Murovska
Fibromyalgia (FM) is a chronic widespread pain disorder that impacts 0.5%-7% of the general population worldwide. The aetiology and pathogenesis of the disease are still unknown. Human herpesvirus-6 and -7 belong to the family Herpesviridae, subfamily Betaherpesvirinae, and genus Roseolovirus and are immunomodulating viruses potentially pathogenic to the nervous system. Presence of anti-HHV-6 and -HHV-7 antibodies and viral genomic sequences, viral loads, HHV-6 variant-specificity, and TNF-α level were studied in 41 FM patients and 50 healthy individuals using polymerase chain reactions, restriction endonuclease analysis and ELISA. There was no difference in the presence of anti-HHV-6 and anti-HHV-7 IgG class antibodies between FM patients and control group individuals. Viral sequences were found in 80.5% of FM patients and in 62.0% of controls. Significantly higher rate of concurrent HHV-6 and HHV-7 infection and higher viral loads in peripheral blood were detected in FM patients compared to the control group individuals. Plasma viremia was detected only in FM patients. Significantly higher TNF-α levels were detected in virus positive FM patients. From all positive cases only in two FM patients HHV-6A was revealed. Significantly higher detection frequency of concurrent HHV-6 and HHV-7 infection, simultaneous HHV-6 and HHV-7 activation, higher viral loads and TNF-α expression levels in primary FM patients than in control group individuals indicate the potential involvement of Roseoloviruses in development of this disorder.
Maksims Čistjakovs, Alina Sultanova, Olga Jermakova, Svetlana Čapenko, Baiba Lesiņa-Korne, Rafails Rozentāls, Modra Murovska and Ieva Ziediņa
Kidney transplant recipients have higher incidence of human papillomavirus (HPV)-related malignancies, but studies on the natural history of HPV infection are insufficient, especially regarding in male recipients. The aim of this study was to evaluate the course of high-risk HPV (HR-HPV) infection after kidney allograft transplantation in male recipients: to estimate frequency and activity of HR-HPV infection under immune system suppression. Twenty male renal recipients (age 20 - 68) were enrolled in this investigation and examined in dynamics. Peripheral EDTA-blood samples and urine samples were collected from each patient 2 weeks, 6 months and 12 months after transplantation. Polymerase chain reaction (PCR) with consensus primers was used for initial detection of high range HPV types, a commercial qPCR kit for detection of HR-HPV load in urine samples and ELISA for detection of serum IgG class antibodies to HR-HPV L1-capsid protein. Overall, combining molecular (HR-HPV genomic sequences detected by real-time PCR) and serological studies (IgG class antibodies to HR-HPV L1-capsids’ protein), high frequency of HRHPV infection among male kidney transplant recipients (9/20; 45%) was showed. However, the majority of HR-HPV positive recipients (7/9; 78%) showed signs of infection clearance. It means that, despite the applied immune suppressive therapy, the host’s immune system is capable of dealing with HR-HPV infection up to the 12th month after transplantation. However, the sample size should be increased to enable through statistical analysis before final conclusions are made.
Santa Rasa-Dzelzkalēja, Svetlana Čapenko, Angelika Krūmiņa, Yung-Cheng Lin and Modra Murovska
Our aim was to estimate the presence of B19V infection markers, the level of cytokines and time period since the appearance of infection in association with ME/CFS clinical symptoms. In 200 ME/CFS patients and 104 control group individuals the presence of B19V-specific IgG/IgM class antibodies, B19V NS1 gene sequence, mRNA expression, viral load and level of cytokines were determined. B19V-specific IgG-antibodies were found in 70% of ME/CFS patients and 67.4% of controls, IgM-antibodies in 8% of patients and in none of controls, B19V genomic sequences in 29% of patients and 3.8% of controls. 58.6% of positive patients had active and 41.4% had latent/persistent B19V infection. B19V NS1 gene expression was detected in 43% of patients. B19V load varied from < 0.2 copies to median 38.2 copies/µg of DNA. According to the antibody pattern, 36% of patients had a recent, and 43% had sustained B19V infection. Patients with the B19V genomic sequence and NS1 specific antibodies significantly more often had lymphadenopathy and multi-joint pain. Onset of the symptoms corresponded to time of appearance of B19V infection. IL-10 and TNF-levels were higher in patients with elevated B19V load. B19V genome 1 was identified in Latvian ME/CFS patients. The results indicated that at least in some cases B19V infection plays an important role in ME/CFS development
Marija Mihailova, Ināra Logina, Santa Rasa, Svetlana Čapenko, Modra Murovska and Angelika Krūmiņa
Fibromyalgia (FM) is a chronic disorder manifested by diffuse musculoskeletal pain, fatigue, sleep, and emotional disturbance. The disorder is probably associated with dysfunction of C and A delta peripheral nerve fibres. Thermal quantitative sensory testing (QST) was used to analyse thinly myelinated A delta fibres and nonmylinated C fibres, which function in the nociceptive sensory system, and the spinothalamic pathway. The observation that FM pain has neuropathic nature increased the value of QST as an additional diagnostic tool. The research group included 51 patients. Somatic symptoms were assessed using the Fatigue Severity Score (FSS), Fibromyalgia Impact Questionnaire (FIQ) and American College of Rheumatology (ACR) 2010 year diagnostic criteria. QST was performed by using thermal stimulus at wrist and feet. QST results were compared with 20 non-FM controls matched for age and sex. FM patients showed significant alteration of thermal perception and pain threshold compared with that in healthy controls, which demonstrated possible neuropathic pain nature in FM patients. Changes were more expressed in warm perception and heat pain threshold, which probably indicates that in FM patients C fibres are more damaged and warm perception and warm pain threshold are more sensitive, which may be used as FM diagnostics. We also found statistically significant negative correlations between warm and cold perception thresholds and between heat and cold pain thresholds, reflecting central sensitization or a defective pain inhibitory system.
Dmitrijs Užameckis, Svetlana Čapenko, Ināra Logina, Modra Murovska and Jonas Blomberg
Multiple sclerosis (MS) is a neurological disease of unknown aetiology. Several research groups reported an increased level of human endogenous retroviruses HERV-W and HERV-H RNAs in cerebrospinal fluid, plasma and supernatants of cell cultures from MS individuals. To quantify the abundance of extracellular virion-associated HERV, RNAs in blood, plasma samples from Latvian MS patients, patients with other neurological diseases (OND), as well as blood donors (BD), were retrospectively studied by using both our previously published and newly developed quantitative Real-time reverse transcription PCR assays (QPCRs) targeting different polymerase (pol) gene regions of HERV-W and HERV-H. Unspecific signals due to incomplete removal of DNA were monitored by running the assays with and without reverse transcription (RT±) in parallel. According to our score, a few MS, OND and healthy controls gave borderline signals simultaneously with both newly developed HERV-H and HERV-W QPCRs, but the rest were negative. All borderline positive samples also had small amounts of non-retroviral cellular mRNA with possible origin from cell-free circulating RNA fragments, apoptotic bodies or exosomes, which can mimic the previously described virus-like particles. The results do not confirm the previous reports on prevalence of HERV-H or -W virion-associated RNA in plasma of MS patients.