Publications by authors named "Yuriy Baglaenko"

T-cells recognize antigens and induce specialized gene expression programs (GEPs) enabling functions including proliferation, cytotoxicity, and cytokine production. Traditionally, different classes of helper T-cells express mutually exclusive responses - for example, Th1, Th2, and Th17 programs. However, new single-cell RNA sequencing (scRNA-Seq) experiments have revealed a continuum of T-cell states without discrete clusters corresponding to these subsets, implying the need for new analytical frameworks.

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Precision Medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle. Autoimmune diseases are those in which the body's natural defense system loses discriminating power between its own cells and foreign cells, causing the body to mistakenly attack healthy tissues. These conditions are very heterogeneous in their presentation and therefore difficult to diagnose and treat.

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Fine-mapping and functional studies implicate rs117701653, a non-coding single nucleotide polymorphism in the CD28/CTLA4/ICOS locus, as a risk variant for rheumatoid arthritis and type 1 diabetes. Here, using DNA pulldown, mass spectrometry, genome editing and eQTL analysis, we establish that the disease-associated risk allele is functional, reducing affinity for the inhibitory chromosomal regulator SMCHD1 to enhance expression of inducible T-cell costimulator (ICOS) in memory CD4 T cells from healthy donors. Higher ICOS expression is paralleled by an increase in circulating T peripheral helper (Tph) cells and, in rheumatoid arthritis patients, of blood and joint fluid Tph cells as well as circulating plasmablasts.

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Invariant Natural Killer T (iNKT) cells are unconventional T cells that respond to microbe-derived glycolipid antigens. iNKT cells exert fast innate effector functions that regulate immune responses in a variety of contexts, including during infection, cancer, or inflammation. The roles these unconventional T cells play in intestinal inflammation remain poorly defined and vary based on the disease model and species.

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Article Synopsis
  • - Liver failure can disrupt the Blood CNS Barrier (BCB), leading to damage in the Central Nervous System (CNS), but the exact mechanisms are not yet fully understood.
  • - Researchers developed advanced imaging techniques to study the integrity of the BCB, discovering that specific genetic changes in mice lead to BCB breakdown and subsequent brain damage.
  • - The study highlights a potential protective role of a molecule called HFE2, which could prevent BCB dysfunction and offers insights into treating conditions like multiple sclerosis related to blood-brain barrier issues.
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Psoriasis is a chronic, systemic inflammatory condition primarily affecting skin. While the role of the immune compartment (e.g.

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  • * The study utilized mouse models and specific knockout techniques to show that the disruption of B cell tolerance is dependent on the presence of the IFNα receptor and requires CD4+ T cells and Myd88 signaling.
  • * Findings suggest that targeting IFNα signaling could be a potential therapeutic strategy for managing SLE by mitigating its effects on B cells and auto-antibody production.
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  • * This study focused on single-cell eQTLs in memory T cells, analyzing over 500,000 cells from 259 individuals and finding that about one-third of eQTLs were linked to complex cell states like cytotoxicity.
  • * The research highlighted that considering continuous cell states offers better insights than traditional categories (e.g., CD4 vs. CD8), emphasizing the importance of cell-state context in understanding autoimmune diseases and eQTL pathogenicity.
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  • Recent advancements in human genetics have greatly enhanced our understanding of rheumatic and autoimmune diseases, identifying numerous genetic loci and variants linked to these conditions.
  • Despite these discoveries, pinpointing the specific genetic variations that cause diseases and how they operate remains a challenge, especially with variants located in non-coding regions of the genome.
  • The emergence of genome editing technologies like CRISPR-Cas offers new methods to explore and clarify the mechanisms behind these genetic risks, paving the way for improved therapeutic strategies in autoimmune diseases.
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Multimodal T cell profiling can enable more precise characterization of elusive cell states underlying disease. Here, we integrated single-cell RNA and surface protein data from 500,089 memory T cells to define 31 cell states from 259 individuals in a Peruvian tuberculosis (TB) progression cohort. At immune steady state >4 years after infection and disease resolution, we found that, after accounting for significant effects of age, sex, season and genetic ancestry on T cell composition, a polyfunctional type 17 helper T (T17) cell-like effector state was reduced in abundance and function in individuals who previously progressed from Mycobacterium tuberculosis (M.

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Background: Systemic lupus erythematosus (SLE) is a severe autoimmune disease in which immune tolerance defects drive production of pathogenic anti-nuclear autoantibodies. Anergic B cells are considered a potential source of these autoantibodies due to their autoreactivity and overrepresentation in SLE patients. Studies of lupus-prone mice have shown that genetic defects mediating autoimmunity can breach B cell anergy, but how this breach occurs with regards to endogenous nuclear antigen remains unclear.

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Spondyloarthritis (SpA) represents a family of inflammatory diseases of the spine and peripheral joints. Ankylosing spondylitis (AS) is the prototypic form of SpA in which progressive disease can lead to fusion of the spine. Therapeutically, knowledge of type 3 immunity has translated into the development of IL-23- and IL-17A-blocking antibodies for the treatment of SpA.

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Genetic studies have revealed that autoimmune susceptibility variants are over-represented in memory CD4 T cell regulatory elements. Understanding how genetic variation affects gene expression in different T cell physiological states is essential for deciphering genetic mechanisms of autoimmunity. Here, we characterized the dynamics of genetic regulatory effects at eight time points during memory CD4 T cell activation with high-depth RNA-seq in healthy individuals.

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The emerging diversity of single-cell RNA-seq datasets allows for the full transcriptional characterization of cell types across a wide variety of biological and clinical conditions. However, it is challenging to analyze them together, particularly when datasets are assayed with different technologies, because biological and technical differences are interspersed. We present Harmony (https://github.

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Of the 1.8 billion people worldwide infected with Mycobacterium tuberculosis, 5-15% will develop active tuberculosis (TB). Approximately half will progress to active TB within the first 18 months after infection, presumably because they fail to mount an effective initial immune response.

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Single-cell methods have revolutionized the study of T cell biology by enabling the identification and characterization of individual cells. This has led to a deeper understanding of T cell heterogeneity by generating functionally relevant measurements - like gene expression, surface markers, chromatin accessibility, T cell receptor sequences - in individual cells. While these methods are independently valuable, they can be augmented when applied jointly, either on separate cells from the same sample or on the same cells.

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Background: Diagnosis of systemic autoimmune rheumatic diseases (SARD) relies on the presence of hallmark anti-nuclear antibodies (ANA), many of which can be detected years before clinical manifestations. However, ANAs are also seen in healthy individuals, most of whom will not develop SARD. Here, we examined a unique cohort of asymptomatic ANA individuals to determine whether they share any of the cellular immunologic features seen in SARD.

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The transcription factor AhR modulates immunity at multiple levels. Here we report that phagocytes exposed to apoptotic cells exhibited rapid activation of AhR, which drove production of the cytokine IL-10. Activation of AhR was dependent on interactions between apoptotic-cell DNA and the pattern-recognition receptor TLR9 that was required for the prevention of immune responses to DNA and histones in vivo.

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Article Synopsis
  • Researchers have developed a method for genome editing specifically in primary human B cells using CRISPR-Cas9 ribonucleoproteins (RNPs), achieving high gene knockout efficiencies over 80%.
  • The method also allows for targeted gene modifications through the insertion of specific nucleotides, with a success rate exceeding 10% using oligonucleotide templates for repair.
  • This approach is applicable in both undifferentiated and activated B cells, making it a versatile tool for studying B cell biology and potentially enhancing engineered B cell therapies.
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  • Lupus is caused by a breakdown in B cell tolerance, leading to the production of autoantibodies, and this study investigates the mechanisms behind this loss of tolerance using specific mouse models.
  • Researchers found that mice with a certain chromosome region (c1(96-100)) produced more anti-HEL antibodies and showed increased B cell activity, indicating a failure in B cell self-regulation.
  • The study suggests that both B and T cell defects play a role in breaking germinal center tolerance, supported by experiments showing enhanced autoantibody production when both B and T cell abnormalities are present.
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Invariant NKT (iNKT) cells are innate lymphocytes that respond to glycolipids presented by the MHC class Ib molecule CD1d and are rapidly activated to produce large quantities of cytokines and chemokines. iNKT cell development uniquely depends on interactions between double-positive thymocytes that provide key homotypic interactions between signaling lymphocyte activation molecule (SLAM) family members. However, the role of SLAM receptors in the differentiation of iNKT cell effector subsets and activation has not been explored.

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Objective: Ankylosing spondylitis (AS) is a chronic inflammatory disease of unknown origin in which interleukin (IL) 17 has been genetically and therapeutically recognised as a key player. Identification of the cellular sources and inducers of IL-17 is crucial in our understanding of the drivers of inflammation in AS. Recently, mucosal-associated invariant T (MAIT) cells have been implicated in autoimmune diseases.

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The development and progression of systemic lupus erythematosus is mediated by the complex interaction of genetic and environmental factors. To decipher the genetics that contribute to pathogenesis and the production of pathogenic autoantibodies, our lab has focused on the generation of congenic lupus-prone mice derived from the New Zealand Black (NZB) strain. Previous work has shown that an NZB-derived chromosome 4 interval spanning 32 to 151 Mb led to expansion of CD5+ B and Natural Killer T (NKT) cells, and could suppress autoimmunity when crossed with a lupus-prone mouse strain.

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Objective: To identify an immunologic basis for the male sex bias in ankylosing spondylitis (AS).

Methods: Cohorts of male and female patients with AS and age- and sex-matched healthy control subjects were selected, and the levels of serum cytokines (interferon-γ [IFNγ], tumor necrosis factor α, interleukin-17A [IL-17A], and IL-6) were examined by enzyme-linked immunosorbent assay, the frequencies of Th1 and Th17 cells were assessed by flow cytometry, and whole blood gene expression was analyzed using both microarray and NanoString approaches.

Results: The frequency of IL-17A and Th17 cells, both of which are key factors in the inflammatory Th17 axis, was elevated in male patients with AS but not in female patients with AS.

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Protective immunity to the pathogen Chlamydia is dependent on a robust IFN-γ response generated by innate and adaptive lymphocytes. Here we assess the role of the macrophage in orchestrating a protective response in vivo to the murine pathogen, Chlamydia muridarum. During acute pulmonary and peritoneal infection, resident macrophages in both sites are infected with C.

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