Method of training examples in solving inverse ill-posed problems of spectroscopy

Further development of the method of computational experiments for solving ill-posed problems is given. The effective (unoverstated) estimate for solution error of the first-kind equation is obtained using the truncating singular numbers spectrum of an operator. It is proposed to estimate the magnitude of the truncation by results of solving model (training, learning) examples close to the initial example (problem). This method takes into account an additional information about the solution and gives a new principle for choosing the regularization parameter and error estimate for equation solution by the Tikhonov regularization method. The method is illustrated by a numerical example from the inverse problem of spectroscopy.Comment: 9 pages, 3 figure

TNF, SOLUBLE RECEPTORS AND AUTOANTIBODIES TO TNF OF PATIENTS WITH RHEUMATOID ARTHRITIS AND HEALTHY DONORS

The content of autoantibodies to TNF in the sera of patients with rheumatoid arthritis (RA) in conjunction with the definition of soluble receptors and TNF was investigated. A significant increase in the content of TNF and I and II types soluble receptors to TNF in sera of RA patients in the acute stage and of responding to therapy RA patients compared with relatively healthy donors was demonstrated. In determining autoantibodies subclasses a significant increase in the relative content of subclasses IgG2, IgG3 and IgG4 autoantibodies in sera of RA patients in the acute stage compared with relatively healthy donors, as well as a significant increase in the relative content of subclasses IgG2 and IgG4 autoantibodies in RA patients in the acute stage compared with RA patients, responding to therapy were shown. Thus we have shown the presence of antibodies, soluble receptors to TNF and cytokine in the serum of relatively healthy donors and RA patients, herewith taking into account significant changes in the relative content of the subclasses of autoantibodies and in the content of TNF and soluble receptors we can talk about the functional role of the autoantibodies and soluble receptors to TNF in the pathology

Comparative analysis of the expression of the soluble IL-7 receptor in patients with arthropathy

Arthropathy is one of the most prevalent diseases, which are based on the destruction and remodeling of cartilage and bone tissue. The inflammation that precedes destruction can be caused by mechanical stress on the joints, or by autoimmune reactions. Recently, IL-7 is considered as one of the key cytokines that promote the production of matrix metalloproteinases, catabolic enzymes, T cell-mediated activation of monocytes, and maturation of osteoclasts. The soluble form of the IL-7 receptor can help prolong the lifespan of IL-7 and thereby it ensures the bioavailability of the cytokine and mediates effect of IL-7 on cells. The aim of this study was to determine the soluble form of the IL-7 receptor (sIL-7R) in the blood plasma of patients with rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PsA) and psoriasis vulgaris (PS), as well as healthy individuals. The RA patients included in the study had moderate to high disease activity according to the DAS28 index. Patients with PsA predominantly had moderate and low disease activity (DAS28) and were characterized by mild to moderate disease severity (PASI). In accordance with the PASI index, patients with PS with mild and severe severity of the disease were included in the study. All patients with OA had a metabolic phenotype that is accompanied by an elevated body mass index.sIL-7R was determined in blood plasma by enzyme-linked immunosorbent assay. It was found that in patients with arthropathy, the level of soluble form of IL-7 was increased relative to healthy individuals, with the exception of the group of patients with PsA. Also, a high concentration of sIL-7R was observed in patients with PS. Analyzing the clinical characteristics of the patients, we found that sIL-7R levels were elevated in RA and PsA patients with high disease activity by DAS28. In addition, positive correlations were found between the concentration of sIL-7R and DAS28 in RA and PsA. In patients with PsA with moderate severity of the disease (PASI), the concentration of sIL-7R was also increased relative to donor's values. On the contrary, in patients with PS, a high level of sIL-7R was noted regardless of the severity of the disease. In patients with OA, no relationship was found between sIL-7R levels and clinical parameters.Thus, an elevated level of sIL-7R in patients with arthropathy may indicate the involvement of IL-7 and its receptor system in the pathogenesis of joint diseases. The IL-7 receptor may become a promising target both in the treatment of joint diseases and other autoimmune diseases, including psoriasis

Myeloid-derived suppressor cells as biomarkers of the effectiveness of therapy with new biological agents in axial spondyloarthritis

Innate immune cells, including myeloid cells — myeloid derived suppressor cells (MDSCs) — are supposed to play an important role in the pathogenesis of axial spondyloarthritis (AxSp). Myeloid derived suppressor cells represent a heterogeneous population of immature cells capable of suppressing innate and adaptive immune responses with the most pronounced suppressor activity against T cells. Biological disease-modifying antirheumatic drugs (bDMARDs) can reduce the clinical and laboratory disease activity, but their effectiveness varies widely in different patients with AxSp. The present study is aimed at studying MDSCs subpopulations and their suppressive function depending on the response to bDMARD therapy in AxSp. The study included AxSp patients with a disease duration of 16.5 years (median); HLA-B27 (+) status was detected in 79% of cases. All patients received bDMARDs at least the past 12 weeks, including TNF inhibitors (etanercept, certolizumab pegol, adalimumab, or golimumab) or IL-17 inhibitors (secukinumab, ixekizumab, or netakimab). Percentage of granulocytic MDSCs (G-MDSCs, Lin-HLA-DR-CD33+CD66b+), monocytic MDSCs (M-MDSCs, HLA-DRlow/-CD14+), MDSCs of early stage differentiation (E-MDSCs, Lin-HLA-DR- CD33+CD66b-), as well as intracellular expression of arginase-1 was assessed by flow cytometry. Frequency of circulating MDSC subpopulations of patients with a stable response to bDMARDs (responders) did not differ significantly compared to healthy donors. Patients not responding to bDMARDs therapy showed increased relative and absolute number of E-MDSCs compared to healthy donors (pU = 0.01 and pU = 0.02, respectively) and the responders (pU = 0.03 and pU = 0.07, respectively). Increased percentage of E-MDSCs was positively correlated to disease activity — ESR (Rs = 0.821; p = 0.023), CRP (Rs = 0.714; p = 0.07) and ASDASCRP (Rs = 0.829; p = 0.042) in the non-responder group. Responder patients exhibited no correlation between disease activity and circulating MDSCs. The suppressor potential of MDSCs was analyzed by the intracellular expression of arginase-1 molecule which is involved in the inhibition of T cell response. Patients with the stable response were characterized by increased expression of arginase-1 in E-MDSCs compared to donors (pU = 0.02). Non-responders did not demonstrate significant changes in Arg-1 expression, however, the percentage of arginase-1-expressing G-MDSCs was positively correlated to indexes ASDASESR (Rs = 0.857; p = 0.014) and BASDAI (Rs = 0.785; p = 0.036). Thus, E-MDSCs as well as arginase-1 expression in MDSCs may serve as biomarkers of effectiveness bDMARD therapy, and act as potential candidate predictors of response to therapy in AxSp

Studies of non-autonomous effects of apoptosis in the course of in vitro apoptotic cell death initiation in healthy persons and patients with rheumatoid arthritis

The process of apoptosis is known that play an important role in cellular homeostasis, and the altered cell death may lead to development of pathological disorders. Evolving autoimmune conditions, in particular, rheumatoid arthritis, are associated with decreased rates of apoptosis as a form of programmed cell death. The aim of this study was to evaluate expression of activation and proliferation markers on T lymphocytes during initiation of apoptotic cell death under the conditions of “cell neighborhood” in healthy individuals and patients with rheumatoid arthritis. Patients and methods. The study was performed with blood samples of the patients with rheumatoid arthritis (RA) and healthy women of comparable age. During the study, we conducted experiments aimed to identify the in vitro influence of non-stimulated apoptosis-induced cells, as well as aCD3- and dexamethasone (Dexa)-stimulated apoptosis-induced cells upon autologous T lymphocytes cultured under physiological conditions. Development of a “cell neighborhood” model, i.e., co-cultures of CFSE- T cells subjected to incubation under crowding condition and depletion of the culture medium which is the most physiological variant of apoptosis activation, and CFSE+ autologous cells placed in the complete culture medium, has revealed some relationships. We have revealed an opportunity of secondary induction of early and late apoptosis by means of humoral and cellular components of autologous cell culture subjected to activation apoptosis. We determined the features of apoptosis in unstimulated, as well as aCD3- and dexamethasone-stimulated cultures, compared with controls. There were no differences in these parameters of apoptosis between RA patients and healthy people for all variants of cultures. An increased proportion of viale cells was found in the CFSE- culture of patients with RA when compared to donors. The donor group had more lymphocytes with activation parameters CD25+, CD69+ and low level of proliferation marker Ki-67 than patients. In contrast to healthy, the RA patients demonstrated a significantly increased expression of Ki 67 in T lymphocytes when co-culturing CFSE- and CFSE+ cells. An increased number of living cells in apoptotic cultures of patients with RA relative to healthy people, in absence of significant differences in the parameters of apoptosis and activation markers in dynamics, as well as pattern of changes in the Ki-67+ cell contents suggested a contribution of the non-autonomous effects of apoptosis to cellular homeostasis in RA patients

EFFECT OF DEXAMETHASONE ON INTERFERON-α-INDUCED DIFFERENTIATION OF MONOCYTES TO DENDRITIC CELLS

Type I Interferons are potent inducers of monocyte’s differentiation into dendritic cells (DCs). However, sensitivity of these DCs to tolerogenic effect of glucocorticoids has not been previously investigated. The aim of this study was to investigate the effect of dexamethasone upon maturation and functions of interferonalpha-induced DCs (IFN-DC) derived from healthy donors. DCs were generated from blood monocytes cultured for 5 days with GM-CSF and IFNα, in absence or with addition of dexamethasone (10-6 M), applied on the 3rd day. Addition of dexamethasone inhibited IFN-DC maturation, which manifested with increasing numbers of CD14+ cells and decreased percentage of CD83+ DCs. Dexamethasone did not significantly influence HLA-DR, CD86 and B7H1 expression. However, it caused a 2-fold increase of tolerogenic TLR-2 molecule expression. Along with suppression of IFN-DC maturation, dexamethasone inhibited production of proinflammatory/Th1 cytokines (TNFα, IL-1, IL-2, IFNγ, IL-12), and some chemokines (MIP-1α, RANTES). Dexamethasone-treated IFN-DCs exhibited a 2-fold lower allostimulatory activity in mixed lymphocyte culture (MLC). Worth of note, the capacity of IFN-DCs to stimulate T cell proliferative response in allo-MLC showed direct correlation with CD83 expression on DCs, and an inverse correlation with CD14 and TLR-2. Evaluation of Th1/Th2-polarizing activity of IFN-DCs showed that dexamethasone exerted a pronounced inhibitory effect upon ability of DCs to stimulate T cells for IFNγ production, along with lowgrade suppressive effect upon ability of DCs to induce IL-6 production, thus being indicative for a dominance of Th2-polarizing activity of IFN-DCs under the influence of dexamethasone. In general, the data obtained show that IFN-DCs are sensitive to tolerogenic action of dexamethasone, and, hence, the IFN-DCs may mediate the immunomodulatory effect of glucocorticosteroids and represent novel candidate cells for the development of therapeutic tolerogenic DC-based vaccines applicable for management of autoimmune disorders