Autophagy in the Thymic Epithelium Is Dispensable for the Development of Self-Tolerance in a Novel Mouse Model

The thymic epithelium plays critical roles in the positive and negative selection of T cells. Recently, it was proposed that autophagy in thymic epithelial cells is essential for the induction of T cell tolerance to self antigens and thus for the prevention of autoimmune diseases. Here we have tested this hypothesis using mouse models in which autophagy was blocked specifically in epithelial cells expressing keratin 14 (K14), including the precursor of thymic epithelial cells. While the thymic epithelial cells of mice carrying the floxed Atg7 gene (ATG7 f/f) showed a high level of autophagy, as determined by LC3 Western blot analysis and fluorescence detection of the recombinant green fluorescent protein (GFP)-LC3 reporter protein on autophagosomes, autophagy in the thymic epithelium was efficiently suppressed by deletion of the Atg7 gene using the Cre-loxP system (ATG7 f/f K14-Cre). Suppression of autophagy led to the massive accumulation of p62/sequestosome 1 (SQSTM1) in thymic epithelial cells. However, the structure of the thymic epithelium as well as the organization and the size of the thymus were not altered in mutant mice. The ratio of CD4 to CD8-positive T cells, as well as the frequency of activated (CD69+) CD4 T cells in lymphoid organs, did not differ between mice with autophagy-competent and autophagy-deficient thymic epithelium. Inflammatory infiltrating cells, potentially indicative of autoimmune reactions, were present in the liver, lung, and colon of a similar fraction of ATG7 f/f and ATG7 f/f K14-Cre mice. In contrast to previously reported mice, that had received an autophagy-deficient thymus transplant, ATG7 f/f K14-Cre mice did not suffer from autoimmunity-induced weight loss. In summary, the results of this study suggest that autophagy in the thymic epithelium is dispensable for negative selection of autoreactive T cells

The role of the mitochondria and the endoplasmic reticulum contact sites in the development of the immune responses

Abstract Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are dynamic modules enriched in subset of lipids and specialized proteins that determine their structure and functions. The MERCs regulate lipid transfer, autophagosome formation, mitochondrial fission, Ca2+ homeostasis and apoptosis. Since these functions are essential for cell biology, it is therefore not surprising that MERCs also play a critical role in organ physiology among which the immune system stands by its critical host defense function. This defense system must discriminate and tolerate host cells and beneficial commensal microorganisms while eliminating pathogenic ones in order to preserve normal homeostasis. To meet this goal, the immune system has two lines of defense. First, the fast acting but unspecific innate immune system relies on anatomical physical barriers and subsets of hematopoietically derived cells expressing germline-encoded receptors called pattern recognition receptors (PRR) recognizing conserved motifs on the pathogens. Second, the slower but very specific adaptive immune response is added to complement innate immunity. Adaptive immunity relies on another set of specialized cells, the lymphocytes, harboring receptors requiring somatic recombination to be expressed. Both innate and adaptive immune cells must be activated to phagocytose and process pathogens, migrate, proliferate, release soluble factors and destroy infected cells. Some of these functions are strongly dependent on lipid transfer, autophagosome formation, mitochondrial fission, and Ca2+ flux; this indicates that MERCs could regulate immunity

Effects of baricitinib on lipid, apolipoprotein, and lipoprotein particle profiles in a phase 2b study in patients with active rheumatoid arthritis

Objective: To assess the effects of baricitinib on lipid profile in patients with moderate-to-severe rheumatoid arthritis. Methods: Once-daily baricitinib (1, 2, 4, or 8-mg) or placebo was studied in 301 randomized patients. Changes in lipid profile, particle size, and number were assessed at weeks 12/24; associations with clinical efficacy were evaluated. Apolipoproteins were assessed at weeks 4/12 for the placebo, and 4- and 8-mg baricitinib groups. Results: Baricitinib treatment resulted in dose-dependent increases by week 12 in serum lipids (low-density lipoprotein cholesterol [LDL-C]: 3.4 mg/dL increase from baseline to week 12 (1-mg) to 11.8 mg/dL (8-mg); high-density lipoprotein cholesterol [HDL-C]: 3.3 mg/dL (1-mg) to 8.1 mg/dL (8-mg); triglycerides: 6.4 mg/dL (1-mg) to 15.4 mg/dL (8-mg) baricitinib). Group-wise mean increases in LDL-C were coincident with mean increases in large LDL particles and mean reductions in small dense LDL particles. Increases from baseline to week 12 in apolipoprotein A-I, B, and total CIII were observed with 4-mg (9.5%, 6.8%, and 23.0%, respectively) and 8-mg (12.2%, 7.1%, and 19.7%, respectively) baricitinib with no increase in LDL-associated CIII (4-mg: -4.5%; 8-mg: -9.0). Baricitinib reduced HDL-associated serum amyloid A at 4-mg (-36.0%) and 8-mg (-32.0%); a significant reduction in lipoprotein (a) was observed only with 8-mg (-16.6%). Increased HDL cholesterol at week 12 correlated with improved Disease Activity Scores and Simplified Disease Activity Index; changes in total cholesterol, LDL cholesterol, and triglycerides did not reveal a similar relationship. Conclusion: Baricitinib-associated increases in serum lipids were observed. HDL-C increases correlated with improved clinical outcomes. This article is protected by copyright. All rights reserved.</p

Maintenance of antigen-specific immunological memory through variable regions of heavy and light chains of anti-idiotypic antibody

Immunological memory is characterized by a quick and enhanced immune response after re-exposure to the same antigen. To explain the mechanism involved in generation and maintenance of immunological memory, we had earlier proposed a hypothesis involving the relay of memory by idiotypic and anti-idiotypic B cells. The peptidomimic present in the hypervariable region of anti-idiotypic antibody was hypothesized to carry forward immunological memory. In the present work, we provide evidence supporting a role for the anti-idiotypic antibody in eliciting antigen-specific B-cell and T-cell responses. Employing the idiotypic monoclonal antibody (Ab1) specific for haemagglutinin (H) protein of rinderpest virus, Ab2β was generated, which possesses an internal image of the H protein in the region between amino acids 527 and 556. We demonstrate that antigen-specific memory is perpetuated by immunization with Ab2, as shown by maintenance of antigen-specific T-cell responses upon restimulation in vitro of Ab2 immune splenocytes by antigen-presenting cells expressing H protein or pulsed with H-protein-derived peptides. We have also shown that boosting with antigen-specific anti-idiotypic B cells generates a memory response in antigen-primed mice. Evidence has been provided for the existence of an antigen-specific B-cell idiotypic network in the body that supports the perpetuation of immunological memory as proposed in the relay hypothesis

Ikskile’s transformations and their reflections in virtual space

Maģistra darba „Ikšķiles transformācijas un to atspoguļojums virtuālā telpā” mērķis ir noskaidrot vietas transformācijas izpausmes Ikšķiles pilsētā un lauku teritorijā, kā arī analizēt to cilvēku uztverē un atspoguļojumu virtuālā telpā. Maģistra darba tēmas izvēle ir saistīta ar Ikšķiles kā vietas un telpas straujo attīstību Rīgas pilsētas pievārtē, pieaugošo moderno tehnoloģiju lomu cilvēku ikdienā, kā arī ar autora profesionālo darbību Ikšķiles novadā - gandrīz desmit gadus autors ir strādājis mērniecības jomā. Maģistra darbs rakstīts ar mērķi izpētīt vietas transformācijas izpausmes no cilvēka ģeogrāfijas konceptuālā skatījuma, lielo pilsētu reģionu ietekmē, analizēt ietekmes un atspoguļojumu virtuālā telpā.Master`s thesis „ Ikskile’s transformations and their reflections in virtual space” purpose is to elucidate expressions of place transformations in Ikskile and rural areas, analyze the perception of space transformations and it`s reflections in virtual space. The Masters theme is based on Ikskile`s space rapid development on the outskirts of Riga and the increasing role of modern technologies in everyday life. Based on the experience of the author`s professional activities in Ikskile – nearly ten years author has worked in the sphere of field surveying. The Masters Paper aim is to explore place transformations expressions from conceptual view of human geography, taking into context the influence of growth and development of major urban areas, analyze impact and reflections in virtual space