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Human leukocyte antigen G (HLA-G) is a non-classical MHC class I molecule that regulates many immune functions. The physiologic HLA-G expression is restricted to foetal tissues such as: amniotic cells, erythroid precursors, and cytotrophoblasts, and, in adults, to immune-privileged organs. The ectopic expression in tumours could point out to a strategy used by malignant cells to escape the immune surveillance. There are two forms of HLA-G, membrane-bound and soluble. The structure of the soluble and membrane bound isoforms differs at the C-terminus. The extracellular domain and the intracytoplasmic tail are replaced in the secreted isoforms by a short hydrophilic tail. These differences could serve as a marker to distinguish shed or proteolytically cleaved HLA-G isoforms from secreted HLA-G isoforms. HLA-G induces tolerance by inhibiting different cells and this function is mediated by binding of both soluble and membrane-bound HLA-G to the inhibitory receptors. There exists a consistent evidence in literature that HLA-G represents an important factor in determining prognosis in various types of cancer. In this review, we will focus on soluble form of HLA-G (sHLA-G) in cancers and its association with the prognosis of cancer patients, because this immune check-point molecule appears as a promising relevant target for cancer immunotherapy (Fig. 2, Ref. 115). Keywords: cancer, diagnosis, HLA-G, soluble HLA-G, tumour.

Neuroinflammation represents one of the two major pathological components of multiple sclerosis (MS). The aim of our study was to find the role of the late pro-inflammatory cytokine HMGB1 (high mobility group box) in MS pathogenesis. A total of 165 patients from three MS centers in Slovakia were enrolled in the study. Patients underwent a complex clinical investigation and their plasma levels of HMGB1 were analyzed by a sandwich ELISA test. MS patients had 4.5 times higher plasma level of HMGB1 (median, 13.529 ng/mL; IQR = 2.330-113.45) than healthy controls (median, 2.999 ng/mL; IQR = 1.686-9.844; P < 0.0001). The concentrations of HMGB1 were significantly associated with increased number of affected areas diagnosed by MRI (P < 0.0001) (the median for one affected area, 4.205 ng/mL; median for five affected areas, 17.843 ng/mL; P < 0.05). Patients with at least one active lesion in any of the affected areas in the brain had significantly higher plasma levels of HMGB1 (median, 20.118 ng/mL; IQR, 3.693–100.12) than those without any active lesion (median, 16.695 ng/mL; IQR, 3.255–113.45; P < 0.0235). We found also a very highly significant association of HMGB1 plasma levels with clinical condition expressed as EDSS (expanded disability status scale) (P < 0.0001); patients with higher EDSS had higher levels of HMGB1 (EDSS ≤ 2.5, 11.648 ng/mL vs. EDSS ≥ 3, 17.549 ng/mL; P = 0.0115). Our results suggest chronic low-grade inflammation in MS patients that correlates with clinical conditions of MS patients, and for HMGB1 as a possible target molecule in future therapy.

Background: Human leukocyte antigen G (HLA-G) belongs to nonclassical HLA I molecule involving in the suppression of immune response. Besides its profound effect to induce fetal tolerance, HLA-G ex...

OBJECTIVES Multiple sclerosis is a chronic inflammatory and autoimmune demyelinating disease of the brain and spinal cord. Vitamin D has anti-inflammatory and anti-Th1, Th17 activities, activates the function of regulatory T cells, shifts the immune response towards Th2, so it might be favorable for downregulation of the disease pathogenesis, and if inflammation and Th1 and Th17 immunity are hyperactivated. The aim of our study was to highlight the role of vitamin D in multiple sclerosis pathogenesis. METHODS We investigated 178 patients with multiple sclerosis. Plasma levels of 25(OH)D and HMGB1 were investigated. RESULTS Despite a regular use of VD by patients, the plasma levels of 25(0H)D were significantly decreased in 57% of them, 14.1% had VD deficiency (level of 25(OH)D < 20 ng/mL) and more than 6 % of patients had VD severe deficiency with the plasma level of 25(OH)D < 12 ng/mL. The level of 25(OH)D negatively correlated with the severity of the disease (EDSS, index of progression, duration of the disease) and negative association was found also with Herbert´s six severity grades. HMGB1 levels were higher in patients (p < 0.0001). CONCLUSION Our result showed that vitamin D deficiency plays a role in multiple sclerosis pathogenesis. We believe that administration of vitamin D to patients at a sufficient dose providing a physiological level of vitamin D could have a positive effect on the course of the disease. However, regular monitoring of vitamin D levels is required, which should be at least within 30-75 ng/mL, and even more, but below the toxicity limit (Tab. 6, Ref. 66).

Human leukocyte antigen G (HLA-G) is a non-classical HLA class I protein with various immunosuppressive functions. Besides its profound effect to induce fetal tolerance, HLA-G has been also found to enhance graft acceptance. The aim of the study was to analyse the association between HLA-G 14 bp insertion/deletion polymorphism, soluble HLA-G level and kidney graft outcome in the Slovak population. We investigated 69 kidney transplant recipients aged 27–65 years. Out of this group, 37 recipients developed acute rejection, confirmed by biopsy, and 32 patients had stable allograft function. Plasma was obtained from recipients at 1 day before transplantation and analyzed by ELISA. Genotyping of HLA-G polymorphism was performed by PCR. Significantly higher pre-transplantation levels of sHLA-G were found in the group with stable allograft function in comparison to group with acute rejection (P = 0.0409). In the homozygous −14/−14 recipients with stable allograft function, significantly higher values of sHLA-G were determined in comparison to the recipients with acute rejection (P = 0.0052). The study revealed an association between 14 bp deletion polymorphism and soluble HLA-G level that is proportional to kidney graft acceptance. It is suggested that pre-transplantation levels of soluble HLA-G should be monitored as additional marker to predict kidney graft outcome.

Alzheimer’s disease (AD) is the most prevalent cause of dementia in elderly people worldwide. Many studies support the hypothesis that the inflammation of the CNS contributes to the neurodegeneration and disease progression. The integrin moleculeα4β1, also known as very late antigen 4 (VLA-4), belongs to adhesion molecules that activate the inflammatory process through the migration of immune cells into the CNS. Therefore, the objective of our study was to analyze the association between two polymorphisms located in theITGA4gene encoding theα4 subunit of VLA-4 and the risk of AD. 104 late-onset AD patients and 206 control subjects from Slovakia were genotyped forITGA4gene SNP polymorphism rs113276800 (−269C/A) and rs1143676 (+3061A/G). The same study cohorts were also genotyped for theAPOE-ε4, which is a known genetic factor associated with increased risk of AD developing.ITGA4polymorphism analysis revealed significantly higher frequency of the +3061AG carriers in AD group compared to the controls (P≤0.05). Following theAPOE-ε4 stratification of study groups, the association remained significant only inAPOE-ε4 noncarriers. Our study suggests a novel association ofITGA4+3061A/G polymorphism with AD and its possible contribution to the disease pathology.

Pregnancy loss (abortion) and pre-eclampsia represent the most common disorders in pregnant women. Besides infection, there are anatomical, endocrinological, genetic and immunological factors that can induce pregnancy disorders. Because the exact mechanisms of physiological pregnancy maintenance are still not clearly understood, the search for genes and proteins fulfilling this role is still in progress. One of the immune molecules that plays a beneficial role in pregnancy is the nonclassical HLA-G molecule. The molecule is mainly expressed on trophoblast cells in the foetal placenta and induces the immune tolerance of the foetus via its interaction with inhibitory receptors on maternal NK cells and CD8+ T lymphocytes. In relation to pregnancy disorders, associations between HLA-G polymorphism, HLA-G level and HLA-G function were described. Thus, the HLA-G molecule can be used as a new diagnostic marker and, potentially, for the future therapy of pregnancy disorders.

The knowledge that asthma is an inflammatory disorder has prompted us to investigate the plasma levels of a new inflammatory marker sTREM-1 that is released from the surfaces of activated neutrophils and monocytes. The plasma levels of sTREM-1 were analysed by a sandwich ELISA test in the cohort of 76 patients with allergic asthma bronchiale and 39 healthy controls. Our results revealed more than 3.5 times higher levels of sTREM-1 in AB patients (92.3 pg/mL ± 125.6) compared with healthy subjects (25.7 pg/mL ± 9.2;P=0.0001). Higher levels of sTREM-1 were found also in patients with exacerbated AB (170.5 pg/mL ± 78.2) compared with nonexacerbated AB patients (59.1 ± 78.2;P<0.0001), patients with respiratory tract obstruction (176.4 pg/mL ± 177.8), than those without obstruction (51.99 pg/mL ± 64.0;P<0.0001) and patients with anti-IgE therapy (P<0.0001). Levels of sTREM-1 correlated with number of leucocytes (P=0.002), and absolute number of neutrophils (P=0.001). Elevated plasma levels of sTREM-1 reflect the severity, state of exacerbation, presence of respiratory tract obstruction in AB patients and together with increased number of neutrophils point to the role of neutrophils in inflammation accompanying AB.