Therapy Of Autoimmune Diseases Research Articles

Mesenchymal Stem Cells in the Pathogenesis and Therapy of Autoimmune and Autoinflammatory Diseases.

Mesenchymal stem cells (MSCs) modulate immune responses and maintain self-tolerance. Their trophic activities and regenerative properties make them potential immunosuppressants for treating autoimmune and autoinflammatory diseases. MSCs are drawn to sites of injury and inflammation where they can both reduce inflammation and contribute to tissue regeneration. An increased understanding of the role of MSCs in the development and progression of autoimmune disorders has revealed that MSCs are passive targets in the inflammatory process, becoming impaired by it and exhibiting loss of immunomodulatory activity. MSCs have been considered as potential novel cell therapies for severe autoimmune and autoinflammatory diseases, which at present have only disease modifying rather than curative treatment options. MSCs are emerging as potential therapies for severe autoimmune and autoinflammatory diseases. Clinical application of MSCs in rare cases of severe disease in which other existing treatment modalities have failed, have demonstrated potential use in treating multiple diseases, including rheumatoid arthritis, systemic lupus erythematosus, myocardial infarction, liver cirrhosis, spinal cord injury, multiple sclerosis, and COVID-19 pneumonia. This review explores the biological mechanisms behind the role of MSCs in autoimmune and autoinflammatory diseases. It also covers their immunomodulatory capabilities, potential therapeutic applications, and the challenges and risks associated with MSC therapy.

CD19-Targeted CAR-T Cells in Refractory Systemic Autoimmune Diseases: A Monocentric Experience from the First Fifteen Patients

Background: CD19-targeting chimeric antigen receptor (CAR) T cells are highly efficient in B cell malignancies. However, CD19 CAR T cells also target autoreactive B cells that trigger autoimmune diseases (AID) including systemic lupus erythematosus (SLE), idiopahtic inflammatory myositis (IIM) and systemic sclerosis (SSc). Achieving long-term remission in AID with standard therapy remains challenging and usually necessitates long-term treatment. Aim: To test whether CD19 CAR T cells achieve a deeper reset of B cells, eradicate autoimmunity, and achieve lasting drug-free remission in autoantibody-dependent AID. Methods: Patients with treatment-refractory SLE, IIM and SSc were eligible if they had signs of active organ involvement, failure of multiple immunomodulatory therapies, and serious or immediately life-threatening disease. CAR T cell therapy was offered via an expanded access program. Autologous CD19 CAR T cells MB-CART19.1 were produced with the Miltenyi prodigy platform. After leukapheresis on day -13, manufacturing commenced in house and lymphodepletion was started with fludarabine 25 mg/m2/d intravenously (i.v.) on days -5 to -3 and cyclophosphamide 1000 mg/m2/d i.v. on day -3. On day 1, all patients received 1x106 CAR T cells / kg body weight. Results: 15 patients (8 SLE, 4 SSc, and 3 IIM) were apheresed and were treated with a single infusion of CD19 CAR T cells. Median disease duration before CAR T was 3 years [1-20], median follow-up after CAR T was 12 months [2-28]. All patients failed on a median of 5 [2-14] previous treatments. Except for a maximum of 10 mg prednisolone daily, all immunomodulatory drugs were stopped prior to leukapheresis. After infusion, CAR T cells rapidly expanded till day 8.6 ± 0.8. CD19+ B cells were rapidly eliminated from peripheral blood after a mean of 5.9 ± 2.2 days. In 12/15 patients, B cells reoccurred at day 111±50. The last three patients with 77, 51 and 16 days follow-up are still B cell aplastic. All 8 SLE patient reached a complete remission after 3 months and maintain a SLE Disease Activity Index (SLEDAI) of 0 since. 3/3 IIM patients experienced major improvement and normalization of CK after 3 months which is ongoing. Of 4 SSc patients, 3 patients with >3 months follow-up show a decreased disease activity by EULAR AI by -4.3 [-4.3; -3.6]. All 15 patients entirely stopped immunosuppressive drugs. Overall safety of CAR T Cell therapy in AID was very favourable with cytokine-release syndrome (CRS) of grade 0 in 4, grade 1 in 10, and grade 2 in 1 patient. 6/15 patients received tocilizumab. One grade 1 immune-effector cell associated neurotoxicity syndrome (ICANS) presented as vertigo two weeks after CAR T infusion. No prolonged (>28 days) bone marrow suppression occurred. The Five SLE patients with a follow-up of 14-24 months stayed in remission despite reconstitution of B cells. In line, complement factor C3 stayed normal, proteinuria remained absent or at very low levels, and autoantibody seroconversion persisted. IgG responses to standard vaccines remained stable up to month 24 and were boosted by re-vaccination. Total B cell numbers gradually increased to a median of 230 cells/µl [183; 886] at month 12 and were mostly of a naïve phenotype. The early drop of CD19+CD27+ memory B cells increased again at month 12 indicating maturation of the B cells emerging after CAR T treatment. Conclusion: CD19 CAR T cells induce persistent, drug-free remission in three distinct autoantibody dependent AID with very good tolerability. Though hypothetical cure appears possible, longer follow up is needed. This unprecedented drug-free remission is remarkable as B cells functionally reconstitute. An investigator-initiated trial is currently expanding our experience of efficacy and safety.

Clinical Research Progress of BTK Inhibitors in the Treatment of Autoimmune Diseases.

Bruton tyrosine kinase (BTK) is an important protein of the tyrosine kinase family and plays a key role in signal transduction, proliferation, migration, and survival in B lymphocytes. The inhibition of BTK is a promising therapy for various autoimmune diseases (AD) involving abnormal B cell function, such as rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE). This article briefly summarizes the role of BTK in the BCR signaling pathway, the development process of BTK inhibitors, and especially the latest progress of their clinical trials for the treatment of AD.

MRNA Lipid Nanoparticles for Ex Vivo Engineering of Immunosuppressive T Cells for Autoimmunity Therapies.

Cell-based therapies for autoimmune diseases have gained significant traction, with several approaches centered around the regulatory T (Treg) cell─a well-known immunosuppressive cell characterized by its expression of the transcription factor Foxp3. Unfortunately, due to low numbers of Treg cells available in circulation, harvesting and culturing Treg cells remains a challenge. It has been reported that engineering Foxp3 expression in CD4+ T cells can result in a Treg-like phenotype; however, current methods result in the inefficient engineering of these cells. Here, we develop an ionizable lipid nanoparticle (LNP) platform to effectively deliver Foxp3 mRNA to CD4+ T cells. We successfully engineer CD4+ T cells into Foxp3-T (FP3T) cells that transiently exhibit an immunosuppressive phenotype and functionally suppress the proliferation of effector T cells. These results demonstrate the promise of an LNP platform for engineering immunosuppressive T cells with potential applications in autoimmunity therapies.

Therapy-Related Myeloid Neoplasms: Predisposition and Clonal Evolution.

Therapy-related Myeloid Neoplasm (t-MN) represents one of the worst long-term consequences of cytotoxic therapy for primary tumors and autoimmune disease. Poor survival and refractoriness to current treatment strategies characterize affected patients from a clinical point of view. In our aging societies, where newer therapies and ameliorated cancer management protocols are improving the life expectancy of cancer patients, therapy-related Myeloid Neoplasms are an emerging problem. Although several research groups have contributed to characterizing the main risk factors in t-MN development, the multiplicity of primary tumors, in association with the different therapeutic strategies available and the new drugs in development, make interpreting the current data still complex. The main risk factors involved in t-MN pathogenesis can be subgrouped into patient-specific, inherited, and acquired predispositions. Although t-MN can occur at any age, the risk tends to increase with advancing age, and older patients, characterized by a higher number of comorbidities, are more likely to develop the disease. Thanks to the availability of deep sequencing techniques, germline variants have been reported in 15-20% of t-MN patients, highlighting their role in cancer predisposition. It is becoming increasingly evident that t-MN with driver gene mutations may arise in the background of Clonal Hematopoiesis of Indeterminate Potential (CHIP) under the positive selective pressure of chemo and/or radiation therapies. Although CHIP is generally considered benign, it has been associated with an increased risk of t-MN. In this context, the phenomenon of clonal evolution may be described as a dynamic process of expansion of preexisting clones, with or without acquisition of additional genetic alterations, that, by favoring the proliferation of more aggressive and/or resistant clones, may play a crucial role in the progression from preleukemic states to t-MN.

Rituximab bij auto-immune blaarziekten

Rituximab for autoimmune bullous diseases For a long time, the treatment of autoimmune blistering diseases consisted of classical immunosuppressants. Recently, biologicals, including rituximab, directed against the pan B-cell marker CD20, are used. Currently, practical guidelines for the optimal use of rituximab in the treatment of autoimmune blistering diseases are still under discussion. This literature review provides an overview of the efficacy, side effects, indication, optimal dosage and administration interval of rituximab in this population. In total, 37 publications were included, based on a systematic search strategy and selection procedure. The reported efficacy of rituximab in pemphigoid, expressed as complete remission without further therapy, ranges from 20% to 79%. For pemphigus, this amounts to 89% in the RITUX-3 study, which formed the basis for approval as first-line therapy. Side effects occur in 24% to 85% of the cases. The most important are infusion-related reactions and infections. In general, the safety profile corresponds to the known side effects of rituximab in other indications. The evidence for the practical guidelines is mainly built around pemphigus. Currently, the ‘high-dose rheumatoid arthritis protocol’ is preferred, although randomised, comparative studies are lacking. The high relapse rate justifies the need for repeated administrations. Further research should clarify whether repeated administration should be done systematically or based on different parameters. Rituximab is an effective and relatively safe therapy in autoimmune blistering diseases in both first and second line. In terms of practical use, further research is recommended.

Retrospective analysis of autoimmune bullous diseases in Middle Franconia.

Autoimmune bullous diseases (AIBDs) are a group of rare cutaneous disorders affecting cornified skin and mucous membranes. They are characterized by tense or flaccid blistering and erosions due to autoantibodies against desmosomal and hemidesmosomal structural proteins of the skin. This group of disorders can be divided into those of pemphigoid and those of pemphigus diseases. If left untreated, these autoimmune diseases can cause serious or even life-threatening complications such as loss of fluid, superinfections or impaired food intake. Due to modern standardized serological assays, the diagnosis of AIBDs can usually be confirmed in combination with their clinical appearance. Whereas for a long time corticosteroids were the major players in the treatment of these diseases, with the approval of rituximab and other immunosuppressive agents, the therapy has increasingly improved. In this study, we aimed to investigate epidemiologic and clinical features as well as diagnostics and therapy of bullous autoimmune diseases in Middle Franconia, a governorate within the German federal state of Bavaria. Patients diagnosed or treated because of a AIBDs between 01.04.2013 and 31.03.2019 at the dermatological department of the university hospital Erlangen were included in this retrospective study (n = 242). Patients were either diagnosed for the first time (n=176) or the diagnosis has been confirmed (n=66) at the department. The respective incidence was calculated among the 176 subjects who had been diagnosed at the center in this period. Data was taken from patient records and analyzed with Microsoft® Excel. The evaluation included the diagnoses of pemphigus vulgaris (PV), pemphigus foliaceus (PF), bullous pemphigoid (BP), mucous membrane pemphigoid (MMP), linear IgA dermatosis (LAD), epidermolysis bullosa acquisita (EBA), and dermatitis herpetiformis (DH). This study shows that the incidence of each AIBDs in Middle Franconia is low and comparable (PV, PF, LAD, EBA) or lower (BP, MMP, DH) than in other studies and regions. BP is the most common newly diagnosed AIBD in Middle Franconia. Due to the chronic and sometimes severe course of AIBDs, repeated in-house treatments are often necessary. To date, mainly topically and systemically applied corticosteroids in combination with immunomodulators are used as first-line therapy.

Thrombin in the Crossroad Hemostasis and Inflammation

Hemostasis and immune responses are evolutionarily and functionally related systems on the coordinated work of which vital processes – protection from blood loss and pathogens, depend. Thrombin is the central enzyme of the coagulation system, which has pronounced pro–inflammatory activity and plays an important role in the pathogenesis of a wide range of infectious and non-infectious diseases. Many humoral immune factors regulating inflammation (IL-1α, C3 and C5 complement components) and cell migration to the lesion site (osteopontin, chimerin) are thrombin targets and become activated by proteolytic cleavage. The main thrombin receptors – protease-activating receptors (PARs), are expressed on many cells of the immune system and are considered as non–classical pattern-recognizing receptors (PRRs). The effect of thrombin on innate immune cells may not be related to its enzymatic effects. Thrombin action on adaptive immunity is just beginning to be studied. Recent studies show that thrombin can act as an alarmin, stimulate the maturation of dendritic cells and adaptive immune responses. The production of this factor also affects Th cell polarization, which determines immune response strategy. The study of the immune functions of the components of the coagulation system reveals new pathogenetic mechanisms of the development of sterile inflammation and expands existing possibilities of allergic, autoimmune and neuroinflammatory disease therapy.

Myeloid-derived suppressor cells in the therapy of autoimmune diseases.

Myeloid-derived suppressor cells (MDSCs) are well recognized as critical factors in the pathology of tumors. However, their roles in autoimmune diseases are still unclear, which hampers the development of efficient immunotherapies. The role of different MDSCs subsets in multiple sclerosis, inflammatory bowel diseases, rheumatoid arthritis, type 1 diabetes, and systemic lupus erythematosus displayed different mechanisms of immune suppression, and several studies pointed to MDSCs' capacity to induce T-helper (Th)17 cells and tissue damage. These results also suggested that MDSCs could be present in different functional states and utilize different mechanisms for controlling the activity of T and B cells. Therefore, various therapeutic strategies should be employed to restore homeostasis in autoimmune diseases. The therapies harnessing MDSCs could be designed either as cell therapy or rely on the expansion and activation of MDSCs in vivo, or their depletion. Cumulatively, MDSCs are inevitable players in autoimmunity, and rational approaches in developing therapies are required to avoid the adverse effects of MDSCs and harness their suppressive mechanisms to improve the overall efficacy of autoimmunity therapy.

Organoruthenium 9E1 and APL Altered Collagen II263-272 Peptide as Therapy for Autoimmune Diseases

Therapy for autoimmune diseases such as rheumatoid arthritis and multiple sclerosis (MS) is currently available in symptom management, pain-relieving, and mitigation of disease. Currently, prescribed drugs for patients with the disease work in specific mechanisms, regardless of failure to determine the most effective medication. We use a literature review to highlight two newly examined substances: organoruthenium 9E1 and APL altered collagen II263-272 peptide, and elaborate substances mentioned above' potential to be used in rheumatoid arthritis and MS therapy. Several studies show positive effects from 9E1 and altered CII263-272 peptides on experimented mice. Altered CII263-272 peptide can elicit Th cells to produce neurotrophic factors, decrease the body amount of pro-inflammatory T cells, increase the body amount of anti-inflammatory T cells, and alleviate collagen-induced arthritis symptoms. Meanwhile, 9E1 can inhibit Mst1 kinase effectively (IC50=45nM), giving consequences of decreasing Th1 cells' cytokines, increasing Th2 cells' cytokines, decreasing body amount's IgG1 and IgG2a, slowing down EAE and collagen-induced arthritis' manifestation, increasing IL-10 and IL-4-producing T cells. Organoruthenium and altered CII263-272 peptide possess positive and multiple effects as therapies for EAE and collagen-induced arthritis, hence potential to be prescribed to patients with rheumatoid arthritis and MS. This literature review suggests further research concerning 9E1 and altered CII263-272 peptide usage in the community to examine their effectivity, side effects, and suitable dose.

Peptide-based immunotherapy in lupus: Where are we now?

In autoimmune rheumatic diseases, immune hyperactivity and chronic inflammation associate with immune dysregulation and the breakdown of immune self-tolerance. A continued, unresolved imbalance between effector and regulatory immune responses further exacerbates inflammation that ultimately causes tissue and organ damage. Many treatment modalities have been developed to restore the immune tolerance and immmunoregulatory balance in autoimmune rheumatic diseases, including the use of peptide-based therapeutics or the use of nanoparticles-based nanotechnology. This review summarizes the state-of-the-art therapeutic use of peptide-based therapies in autoimmune rheumatic diseases, with a specific focus on lupus.

Polymer-Based Nanoparticles as Drug Delivery Systems for Purines of Established Importance in Medicine.

Many purine derivatives are active pharmaceutical ingredients of significant importance in the therapy of autoimmune diseases, cancers, and viral infections. In many cases, their medical use is limited due to unfavorable physicochemical and pharmacokinetic properties. These problems can be overcome by the preparation of the prodrugs of purines or by combining these compounds with nanoparticles. Herein, we aim to review the scientific progress and perspectives for polymer-based nanoparticles as drug delivery systems for purines. Polymeric nanoparticles turned out to have the potential to augment antiviral and antiproliferative effects of purine derivatives by specific binding to receptors (ASGR1-liver, macrophage mannose receptor), increase in drug retention (in eye, intestines, and vagina), and permeation (intranasal to brain delivery, PEPT1 transport of acyclovir). The most significant achievements of polymer-based nanoparticles as drug delivery systems for purines were found for tenofovir disoproxil in protection against HIV, for acyclovir against HSV, for 6-mercaptopurine in prolongation of mice ALL model life, as well as for 6-thioguanine for increased efficacy of adoptively transferred T cells. Moreover, nanocarriers were able to diminish the toxic effects of acyclovir, didanosine, cladribine, tenofovir, 6-mercaptopurine, and 6-thioguanine.

<i>In vitro</i> production of myeloid-derived suppressor cells from peripheral blood monocytes

Myeloid-derived suppressor cells (MDSCs) are of interest as key regulators of the immune response for the development and improvement of cellular technologies in biomedicine. Enhancing the suppressive activity of these cells is important for developing therapies for autoimmune diseases and miscarriages, and their suppression may be useful in the treatment of cancer, since MDSCs are known to suppress antitumor immunity. However, there is a problem that prevents the active study of MDSCs, i.e., the difficulty in obtaining sufficient numbers of this cell population. Isolation of MDSCs in cancer patients poses an ethical challenge. Moreover, these MDSC may differ in subpopulation composition and suppressive activity due to individual factors. Researchers who generate human MDSC from bone marrow cells may also face similar problems. Therefore, finding a reliable and affordable source of these cells to facilitate the study of their functions is extremely important. Attempts to obtain human MDSCs in vitro have been ongoing for a long time. GM- CSF, IL-6, IL- 1β, IL-4, PGE2, LPS, M-CSF, IFNγ are described as factors that induce the ex vivo MDSC differentiation. However, despite multiple factors used, not all protocols are clearly reproducible, leading to generation of a sufficient number of cells in the target population. Previously, we had also developed a scheme for MDSC differentiation from CD11b+ cells derived from human peripheral blood, which made it possible to obtain a tangible but still insufficient percentage of cells to study functional activity.
 To increase the number of MDSCs in cultures, we developed a protocol aimed for differentiation of these cells from peripheral blood monocytes (CD14+ cells) previously transformed into PCMO (programmed cells of monocytic origin). The monocytes isolated by immunomagnetic separation were cultured in a de-differentiating medium (complete culture medium supplemented with M-CSF, IL-3 and β-mercaptoethanol) for one week. Later on, the medium was replaced by the addition of GM-CSF, being cultured for three days, followed by addition of LPS and IL-1β in order to induce suppressive activity. We have found that culturing CD14+ cells on a two-week schedule with prior creation of dedifferentiation conditions resulted in a slightly decreased percentage of viable cells in culture. However, there was a trend towards an increased ratio of MDSCs in culture (from an average of 34 to 40%) and an increase in their suppressive activity (arginase and IDO expression). The percentage of Arg+ cells increased by average of 10%, and IDO+ cells, by 16%. Moreover, the percentage of mature M-MDSCs was significantly (several-fold) higher when compared with differentiation protocol using CD11b+ cells. Hence, this method of MDSCs production enables us to increase the number of cells belonging to the conditionally “mature” monocyte subpopulation of MDSCs, as well as the percentage of functional suppressor cells in the population. The described scheme may be used to improve the quality of studies aimed at modulating MDSC functions in order to develop new therapeutic approaches.

Engineered plant extracellular vesicles for autoimmune diseases therapy

Engineered plant extracellular vesicles for autoimmune diseases therapy

Combining docking, molecular dynamics simulations, AD-MET pharmacokinetics properties, and MMGBSA calculations to create specialized protocols for running effective virtual screening campaigns on the autoimmune disorder and SARS-CoV-2 main protease.

The development of novel medicines to treat autoimmune diseases and SARS-CoV-2 main protease (Mpro), a virus that can cause both acute and chronic illnesses, is an ongoing necessity for the global community. The primary objective of this research is to use CoMFA methods to evaluate the quantitative structure-activity relationship (QSAR) of a select group of chemicals concerning autoimmune illnesses. By performing a molecular docking analysis, we may verify previously observed tendencies and gain insight into how receptors and ligands interact. The results of the 3D QSAR models are quite satisfactory and give significant statistical results: Q_loo∧2 = 0.5548, Q_lto∧2 = 0.5278, R∧2 = 0.9990, F-test = 3,101.141, SDEC = 0.017 for the CoMFA FFDSEL, and Q_loo∧2 = 0.7033, Q_lto∧2 = 0.6827, Q_lmo∧2 = 0.6305, R∧2 = 0.9984, F-test = 1994.0374, SDEC = 0.0216 for CoMFA UVEPLS. The success of these two models in exceeding the external validation criteria used and adhering to the Tropsha and Glorbaikh criteria's upper and lower bounds can be noted. We report the docking simulation of the compounds as an inhibitor of the SARS-CoV-2 Mpro and an autoimmune disorder in this context. For a few chosen autoimmune disorder receptors (protein tyrosine phosphatase, nonreceptor type 22 (lymphoid) isoform 1 (PTPN22), type 1 diabetes, rheumatoid arthritis, and SARS-CoV-2 Mpro, the optimal binding characteristics of the compounds were described. According to their potential for effectiveness, the studied compounds were ranked, and those that demonstrated higher molecular docking scores than the reference drugs were suggested as potential new drug candidates for the treatment of autoimmune disease and SARS-CoV-2 Mpro. Additionally, the results of analyses of drug similarity, ADME (Absorption, Distribution, Metabolism, and Excretion), and toxicity were used to screen the best-docked compounds in which compound 4 scaled through. Finally, molecular dynamics (MD) simulation was used to verify compound 4's stability in the complex with the chosen autoimmune diseases and SARS-CoV-2 Mpro protein. This compound showed a steady trajectory and molecular characteristics with a predictable pattern of interactions. These findings suggest that compound 4 may hold potential as a therapy for autoimmune diseases and SARS-CoV-2 Mpro.

The developing role of extracellular vesicles in autoimmune diseases: special attention to mesenchymal stem cell-derived extracellular vesicles.

Autoimmune diseases are complex, chronic inflammatory conditions initiated by the loss of immunological tolerance to self-antigens. Nowadays, there is no effective and useful therapy for autoimmune diseases, and the existing medications have some limitations due to their nonspecific targets and side effects. During the last few decades, it has been established that mesenchymal stem cells (MSCs) have immunomodulatory functions. It is proposed that MSCs can exert an important therapeutic effect on autoimmune disorders. In parallel with these findings, several investigations have shown that MSCs alleviate autoimmune diseases. Intriguingly, the results of studies have demonstrated that the effective roles of MSCs in autoimmune diseases do not depend on direct intercellular communication but on their ability to release a wide spectrum of paracrine mediators such as growth factors, cytokines and extracellular vehicles (EVs). EVs that range from 50 to 5,000nm were produced by almost any cell type, and these nanoparticles participate in homeostasis and intercellular communication via the transfer of a broad range of biomolecules such as modulatory proteins, nucleic acids (DNA and RNA), lipids, cytokines, and metabolites. EVs derived from MSCs display the exact properties of MSCs and can be safer and more beneficial than their parent cells. In this review, we will discuss the features of MSCs and their EVs, EVs biogenesis, and their cargos, and then we will highlight the existing discoveries on the impacts of EVs from MSCs on autoimmune diseases such as multiple sclerosis, arthritis rheumatic, inflammatory bowel disease, Type 1 diabetes mellitus, systemic lupus erythematosus, autoimmune liver diseases, Sjögren syndrome, and osteoarthritis, suggesting a potential alternative for autoimmune conditions therapy.

Discovery of novel aporphine alkaloid derivative as potent TLR2 antagonist reversing macrophage polarization and neutrophil infiltration against acute inflammation.

Toll-like receptor 2 (TLR2) mediated macrophages regulate the protective immune response to infectious microorganisms, but the aberrant activation of macrophages often leads to pathological inflammation, including tissue damage. In this study, we identified antagonists of TLR2 by screening 2100 natural products and subsequently identified Taspine, an aporphine alkaloid, as an excellent candidate. Furthermore, analysis of the 10 steps chemical synthesis route and structural optimization yielded the Taspine derivative SMU-Y6, which has higher activity, better solubility, and improved drug-feasible property. Mechanistic studies and seq-RNA analysis revealed that SMU-Y6 inhibited TLR2 over other TLRs, hindered the formation of TLR2/MyD88 complex, and blocked the downstream NF-κB and MAPK signaling pathway, thus suppressing the release of inflammatory cytokines. SMU-Y6 could stabilize TLR2 and bind to TLR2 protein with a Kd of 0.18μmol/L. Additionally, SMU-Y6 could efficiently reverse the M1 phenotype macrophage polarization, reduce the production of cytokines as well as infiltration of neutrophiles and alleviate the local inflammation in mice with acute paw edema and colitis. Collectively, we reported the first aporphine alkaloid derivative that selectively inhibits TLR2 with high binding affinity and superior drug-feasible property, thus providing an urgently-needed molecular probe and potential drug candidate for inflammatory and autoimmune disease therapy.

Modern concept of autoimmunity in rheumatology

Two fundamental pathologic processes are central to the spectrum of chronic inflammation mechanisms: autoimmunity and autoinflammation. Autoimmunity and autoinflammation are mutually potent pathologic processes; their development is considered within the framework of the “immunoinflammatory” continuum, reflecting the close relationship between innate and acquired types of immune response. Autoimmunity is the leading mechanism of pathogenesis of a large group of chronic inflammatory human diseases, defined as autoimmune diseases, the frequency of which in the population exceeds 10%. Advances in molecular biology, pharmacogenetics and bioinformatics have created prerequisites for individualization of therapy of autoimmune rheumatic diseases within the concept of personalized medicine. The study of immunopathogenesis mechanisms, improvement of diagnostics, deciphering the nature of molecular taxonomy, development of approaches to prevention and personalized therapy of human autoimmune diseases is among the priority directions of medicine of the 21st century.

B cell metabolism in autoimmune diseases: signaling pathways and interventions.

Autoimmune diseases are heterogeneous disorders believed to stem from the immune system's inability to distinguish between auto- and foreign- antigens. B lymphocytes serve a crucial role in humoral immunity as they generate antibodies and present antigens. Dysregulation of B cell function induce the onset of autoimmune disorders by generating autoantibodies and pro-inflammatory cytokines, resulting in an imbalance in immune regulation. New research in immunometabolism shows that cellular metabolism plays an essential role in controlling B lymphocytes immune reactions by providing the energy and substrates for B lymphocytes activation, differentiation, and function. However, dysregulated immunometabolism lead to autoimmune diseases by disrupting self-tolerance mechanisms. This review summarizes the latest research on metabolic reprogramming of B lymphocytes in autoimmune diseases, identifying crucial pathways and regulatory factors. Moreover, we consider the potential of metabolic interventions as a promising therapeutic strategy. Understanding the metabolic mechanisms of B cells brings us closer to developing novel therapies for autoimmune disorders.

Effect of pregnancy-specific β1-glycoprotein on the expression of arginase-1 and indolamine-2,3-dioxygenase by myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSC) - a population of immature cells of myeloid origin with inhibitory functions, mainly related to T lymphocytes. Normally, MDSC account for less than 1% of leukocytes in peripheral blood. The number of these cells increases during healthy pregnancy. However, MDSC have been shown to play a critical role in the maintenance of tumor growth and in autoimmune diseases.
 Because MDSC are now considered important regulators of immunity, finding ways to manipulate their functions is important for the development of therapies for malignant and autoimmune diseases, as well as for pregnancy pathologies and post-transplant complications. The immunosuppressive mechanisms of these cells are mediated by their expression of the surface molecules CD73, ADAM17, PD -L1, the enzymes arginase 1 (Arg 1), inducible nitric oxide synthase (iNOS), and indoleamine 2,3-dioxygenase (IDO), reactive oxygen species, and the production of the anti-inflammatory cytokines IL -10 and TGF-1.
 Pregnancy-specific 1-glycoprotein (PSG) is a pregnancy glycoprotein that has immunomodulatory effects on natural (dendritic cells and macrophages) and adaptive (T cells) immunity cells. At the same time, the effect of PSG on MDSC has not been investigated so far. Since this glycoprotein has promising pharmacological applications, it is necessary to study not only the native variant of PSG but also its recombinant form.
 Since the main function of MDSC is immunosuppression, the aim of our work was to evaluate one of its mechanisms, namely the intracellular expression of amino acid degradation enzymes Arg1 and IDO under the influence of native and recombinant PSG in vitro.
 MDSC differentiation was performed from CD11b+ cells isolated from peripheral blood of healthy volunteers. Cells were cultured for 7 days with stepwise addition of GM-CSF, IL -1, and LPS. Native (n) (1, 10, and 100 g/mL) and recombinant (r) (1 and 10 g/mL) PSG was added to the cultures three days before the end of incubation. The percentage of MDSCs (Lin- HLA-DR -CD11b+CD33+) intracellularly expressing Arg1 and IDO was determined by flow cytometry.
 It was found that nPSG and rPSG did not alter the amount of Arg1-expressing MDSCs at all concentrations examined. However, at a concentration of 10 g/mL, both types of proteins caused a statistically significant increase in the percentage of cells expressing IDO.
 We have already established that nPSG and rPSG affect MDSC differentiation by increasing the proportion of these cells belonging to the monocytic subpopulation. However, now we can say that PSG, in addition, enhances the suppressive function of the studied cells.
 The obtained data are novel and open perspectives for targeting myeloid suppressor cells to improve cellular technologies in science and medicine.