Expression of MHC II genes

Innate and adaptive immunity are connected via antigen processing and presentation (APP), which results in the presentation of antigenic peptides to T cells in the complex with the major histocompatibility (MHC) determinants. MHC class II (MHC II) determinants present antigens to CD4+ T cells, which are the main regulators of the immune response. Their genes are transcribed from compact promoters that form first the MHC II enhanceosome, which contains DNA-bound activators and then the MHC II transcriptosome with the addition of the class II transactivator (CIITA). CIITA is the master regulator of MHC II transcription. It is expressed constitutively in dendritic cells (DC) and mature B cells and is inducible in most other cell types. Three isoforms of CIITA exist, depending on cell type and inducing signals. CIITA is regulated at the levels of transcription and post-translational modifications, which are still not very clear. Inappropriate immune responses are found in several diseases, including cancer and autoimmunity. Since CIITA regulates the expression of MHC II genes, it is involved directly in the regulation of the immune response. The knowledge of CIITA will facilitate the manipulation of the immune response and might contribute to the treatment of these diseases

Cataract and optic disk drusen in a patient with glycogenosis and di George syndrome: clinical and molecular report

Background We report the ophthalmic findings of a patient with type Ia glycogen storage disease (GSD Ia), DiGeorge syndrome (DGS), cataract and optic nerve head drusen (ONHD). Case presentation A 26-year-old white woman, born at term by natural delivery presented with a post-natal diagnosis of GSD Ia. Genetic testing by array-comparative genomic hybridization (CGH) for DGS was required because of her low levels of serum calcium. The patient has been followed from birth, attending the day-hospital every six months at the San Paolo Hospital, Milan, outpatient clinic for metabolic diseases and previously at another eye center. During the last day-hospital visit, a complete eye examination showed ONHD and cataract in both eyes. Next Generation Sequencing (NGS) was subsequently done to check for any association between the eye problems and metabolic aspects. Conclusions This is the first description of ocular changes in a patient with GSD Ia and DGS. Mutations explaining GSD Ia and DGS were found but no specific causative mutation for cataract and ONHD. The metabolic etiology of her lens changes is known, whereas the pathogenesis of ONHD is not clear. Although the presence of cataract and ONHD could be a coincidence; the case reported could suggest that hypocalcemia due to DGS could be the common biochemical pathway

The prolate-to-oblate shape transition of phospholipid vesicles in response to frequency variation of an AC electric field can be explained by the dielectric anisotropy of a phospholipid bilayer

The external electric field deforms flaccid phospholipid vesicles into spheroidal bodies, with the rotational axis aligned with its direction. Deformation is frequency dependent: in the low frequency range (~ 1 kHz), the deformation is typically prolate, while increasing the frequency to the 10 kHz range changes the deformation to oblate. We attempt to explain this behaviour with a theoretical model, based on the minimization of the total free energy of the vesicle. The energy terms taken into account include the membrane bending energy and the energy of the electric field. The latter is calculated from the electric field via the Maxwell stress tensor, where the membrane is modelled as anisotropic lossy dielectric. Vesicle deformation in response to varying frequency is calculated numerically. Using a series expansion, we also derive a simplified expression for the deformation, which retains the frequency dependence of the exact expression and may provide a better substitute for the series expansion used by Winterhalter and Helfrich, which was found to be valid only in the limit of low frequencies. The model with the anisotropic membrane permittivity imposes two constraints on the values of material constants: tangential component of dielectric permittivity tensor of the phospholipid membrane must exceed its radial component by approximately a factor of 3; and the membrane conductivity has to be relatively high, approximately one tenth of the conductivity of the external aqueous medium.Comment: 17 pages, 6 figures; accepted for publication in J. Phys.: Condens. Matte

Affinity enrichment and functional characterization of TRAX1, a novel transcription activator and X1-sequence-binding protein of HLA-DRA.

The promoters of all class II major histocompatibility (MHC) genes contain a positive regulatory motif, the X element. The DNA-binding proteins specific for this element are presumed to play a critical role in gene expression, although there is a paucity of functional studies supporting this role. In this study, the X-box-binding proteins of HLA-DRA were affinity purified from HeLa nuclear extracts. Fractions 46 to 48 contained an X-box-binding activity and were determined by electrophoretic mobility shift assays to be specific for the X1 element. This X1 sequence-binding-protein, transcriptional activator X1 (TRAX1), was shown to be a specific transcriptional activator of the HLA-DRA promoter in an in vitro transcription assay. By UV cross-linking analysis, the approximate molecular mass of TRAX1 including the bound DNA was determined to be 40 kDa. When the TRAX1 complex was incubated with antibodies against a known recombinant X-box-binding protein, RFX1, and tested in electrophoretic mobility shift assays, TRAX1 was neither shifted nor blocked by the antibody. Further analysis with methylation interference showed that TRAX1 bound to the 5' end of the X1 sequence at -109 and -108 and created hypersensitive sites at -114, -113, and -97. This methylation interference pattern is distinct from those of the known X1-binding proteins RFX1, RFX, NF-Xc, and NF-X. Taken together, our results indicate that TRAX1 is a novel X1-sequence-binding protein and transcription activator of HLA-DRA

Binding and cooperative interactions between two B cell-specific transcriptional coactivators.

International audienceThe class II transactivator (CIITA) and B cell octamer-binding protein 1/octamer-binding factor 1/Oct coactivator from B cells (Bob1/OBF-1/OCA-B) represent two B cell-specific transcriptional coactivators. CIITA and Bob1 interact with proteins that bind to conserved upstream sequences in promoters of class II major histocompatibility genes and octamer-binding transcription factors Oct-1 and Oct-2, respectively. Both CIITA and Bob1 increase the expression from the DRA promoter, which is a prototypic class II promoter. Moreover, in the presence of CIITA, interactions between class II promoters and Bob1 are independent of the octamer-binding site. Using in vivo and in vitro binding assays, we confirm that Bob1 binds to CIITA. Thus, CIITA not only activates the expression of class II genes but recruits another B cell-specific coactivator to increase transcriptional activity of class II promoters in B cells

The challenges of the expanded availability of genomic information: an agenda-setting paper

Rapid advances in microarray and sequencing technologies are making genotyping and genome sequencing more affordable and readily available. There is an expectation that genomic sequencing technologies improve personalized diagnosis and personalized drug therapy. Concurrently, provision of direct-to-consumer genetic testing by commercial providers has enabled individuals’ direct access to their genomic data. The expanded availability of genomic data is perceived as influencing the relationship between the various parties involved including healthcare professionals, researchers, patients, individuals, families, industry, and government. This results in a need to revisit their roles and responsibilities. In a 1-day agenda-setting meeting organized by the COST Action IS1303 “Citizen’s Health through public-private Initiatives: Public health, Market and Ethical perspectives,” participants discussed the main challenges associated with the expanded availability of genomic information, with a specific focus on public-private partnerships, and provided an outline from which to discuss in detail the identified challenges. This paper summarizes the points raised at this meeting in five main parts and highlights the key cross-cutting themes. In light of the increasing availability of genomic information, it is expected that this paper will provide timely direction for future research and policy making in this area.Funding Deborah Mascalzoni is supported under Grant Agreement number 305444. Álvaro Mendes is supported by the FCT—The Portuguese Foundation for Science and Technology under postdoctoral grant SFRH/BPD/88647/2012. Isabelle Budin-Ljøsne receives support from the National Research and Innovation Platform for Personalized Cancer Medicine funded by The Research Council of Norway (NFR BIOTEK2021/ES495029) and Biobank Norway funded by The Research Council of Norway—grant number 245464. Heidi Carmen Howard is partly supported by supported by the Swedish Foundation for Humanities and Social Science under grant M13-0260:1), the Biobanking and Molecular Resource Infrastructure of Sweden (BBMRI.se) and the BBMRI-ERIC. Brígida Riso is supported by the Portuguese Foundation for Science and Technology (FCT) under the PhD grant SFRH/BD/100779/2014. Heidi Beate Bentzen receives support from the project Legal Regulation of Information Processing relating to Personalized Cancer Medicine funded by The Research Council of Norway BIOTEK2021/238999

Favorable outcome of early treatment of new onset child and adolescent migraine-implications for disease modification.

There is evidence that the prevalence of migraine in children and adolescents may be increasing. Current theories of migraine pathophysiology in adults suggest activation of central cortical and brainstem pathways in conjunction with the peripheral trigeminovascular system, which ultimately results in release of neuropeptides, facilitation of central pain pathways, neurogenic inflammation surrounding peripheral vessels, and vasodilatation. Although several risk factors for frequent episodic, chronic, and refractory migraine have been identified, the causes of migraine progression are not known. Migraine pathophysiology has not been fully evaluated in children. In this review, we will first discuss the evidence that early therapeutic interventions in the child or adolescent new onset migraineur, may halt or limit progression and disability. We will then review the evidence suggesting that many adults with chronic or refractory migraine developed their migraine as children or adolescents and may not have been treated adequately with migraine-specific therapy. Finally, we will show that early, appropriate and optimal treatment of migraine during childhood and adolescence may result in disease modification and prevent progression of this disease

Integrative transcriptomic analysis in human and mouse model of anaphylaxis identifies gene signatures associated with cell movement, migration and neuroinflammatory signalling

Background: Anaphylaxis is an acute life-threatening allergic reaction and a concern at a global level; therefore, further progress in understanding the underlying mechanisms and more effective strategies for diagnosis, prevention and management are needed. Objective: We sought to identify the global architecture of blood transcriptomic features of anaphylaxis by integrating expression data from human patients and mouse model of anaphylaxis. Methods: Bulk RNA-sequencings of peripheral whole blood were performed in: i) 14 emergency department (ED) patients with acute anaphylaxis, predominantly to Hymenoptera venom, ii) 11 patients with peanut allergy undergoing double-blind, placebo-controlled food challenge (DBPCFC) to peanut, iii) murine model of IgE-mediated anaphylaxis. Integrative characterisation of differential gene expression, immune cell-type-specific gene expression profiles, and functional and pathway analysis was undertaken. Results: 1023 genes were commonly and significantly dysregulated during anaphylaxis in ED and DBPCFC patients; of those genes, 29 were also dysregulated in the mouse model. Cell-type-specific gene expression profiles showed a rapid downregulation of blood basophil and upregulation of neutrophil signature in ED and DBPCFC patients and the mouse model, but no consistent and/or significant differences were found for other blood cells. Functional and pathway analysis demonstrated that human and mouse blood transcriptomic signatures of anaphylaxis follow trajectories of upregulation of cell movement, migration and neuroinflammatory signalling, and downregulation of lipid activating nuclear receptors signalling. Conclusion: Our study highlights the matched and extensive blood transcriptomic changes and suggests the involvement of discrete cellular components and upregulation of migration and neuroinflammatory pathways during anaphylaxis

Cellular latency in human immunodeficiency virus-infected individuals with high CD4 levels can be detected by the presence of promoter-proximal transcripts

We have investigated the molecular basis of human immunodeficiency virus type 1 (HIV-1) latency in a tissue culture model and in HIV-infected people. We show that increased levels of Tat, but not Rev, can release the proviruses from latency in U1 cells. The absence of Tat in these cells is manifested by the accumulation of promoter-proximal viral transcripts, whereas the presence of Tat correlates with increased expression of viral proteins and an increase in promoter-distal transcripts. The presence of promoter-proximal transcripts also serves as a marker for latency in humans. We observed the exclusive presence of promoter-proximal viral transcripts in peripheral mononuclear cells from the majority (10/11) of asymptomatic HIV-infected individuals examined. Activation of these cells in vitro, and viremia in vivo, correlated with a switch from promoter-proximal transcription to promoter-distal transcription. These results suggest that the control between latency and replication of HIV in vivo is at the level of transcription elongation

Computational exploration of molecular receptive fields in the olfactory bulb reveals a glomerulus-centric chemical map

© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Progress in olfactory research is currently hampered by incomplete knowledge about chemical receptive ranges of primary receptors. Moreover, the chemical logic underlying the arrangement of computational units in the olfactory bulb has still not been resolved. We undertook a large-scale approach at characterising molecular receptive ranges (MRRs) of glomeruli in the dorsal olfactory bulb (dOB) innervated by the MOR18-2 olfactory receptor, also known as Olfr78, with human ortholog OR51E2. Guided by an iterative approach that combined biological screening and machine learning, we selected 214 odorants to characterise the response of MOR18-2 and its neighbouring glomeruli. We found that a combination of conventional physico-chemical and vibrational molecular descriptors performed best in predicting glomerular responses using nonlinear Support-Vector Regression. We also discovered several previously unknown odorants activating MOR18-2 glomeruli, and obtained detailed MRRs of MOR18-2 glomeruli and their neighbours. Our results confirm earlier findings that demonstrated tunotopy, that is, glomeruli with similar tuning curves tend to be located in spatial proximity in the dOB. In addition, our results indicate chemotopy, that is, a preference for glomeruli with similar physico-chemical MRR descriptions being located in spatial proximity. Together, these findings suggest the existence of a partial chemical map underlying glomerular arrangement in the dOB. Our methodology that combines machine learning and physiological measurements lights the way towards future high-throughput studies to deorphanise and characterise structure-activity relationships in olfaction.Peer reviewe