Inhibition of miRNA associated with a disease-specific signature and secreted via extracellular vesicles of systemic lupus erythematosus patients suppresses target organ inflammation in a humanized mouse model.

Introduction: Distinct, disease-associated intracellular miRNA (miR) expression profiles have been observed in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematous (SLE) patients. Additionally, we have identified novel estrogenic responses in PBMCs from SLE patients and demonstrated that estrogen upregulates toll-like receptor (TLR)7 and TLR8 expression. TLR7 and TLR8 bind viral-derived single-stranded RNA to stimulate innate inflammatory responses, but recent studies have shown that miR-21, mir-29a, and miR-29b can also bind and activate these receptors when packaged and secreted in extracellular vesicles (EVs).

The therapeutic effects of gingival mesenchymal stem cells and their exosomes in a chimeric model of rheumatoid arthritis.

Background: Rheumatoid arthritis is a chronic systemic autoimmune disease that involves transformation of the lining of synovial joints into an invasive and destructive tissue. Synovial fibroblasts become transformed, invading and destroying the bone and cartilage of the affected joint(s). Due to the significant role these cells play in the progression of the disease process, developing a therapeutic strategy to target and inhibit their invasive destructive nature could help patients who are afflicted with this debilitating disease.

Antigen-driven T cell-macrophage interactions mediate the interface between innate and adaptive immunity in histidyl-tRNA synthetase-induced myositis.

Introduction: Previous work in humans has demonstrated that both innate and adaptive immune signaling pathways contribute to the pathogenesis of idiopathic inflammatory myopathy (IIM), a systemic autoimmune disease targeting muscle as well as extra-muscular organs. To better define interactive signaling networks in IIM, we characterized the cellular phenotype and transcriptomic profiles of muscle-infiltrating cells in our established murine model of histidyl-tRNA synthetase (HRS)-induced myositis.

Methods: Myositis was induced in wild type (WT) and various congenic/mutant strains of C57BL/6 mice through intramuscular immunization with recombinant HRS.

Therapeutic Effects of Gingival Mesenchymal Stem Cells and Their Exosomes in a Chimeric Model of Rheumatoid Arthritis.

Background: Rheumatoid arthritis is a chronic systemic autoimmune disease that involves transformation of the lining of synovial joints into an invasive and destructive tissue. Synovial fibroblasts become transformed, invading and destroying bone and cartilage of the affected joint(s). Due to the significant role these cells play in the progression of the disease process, developing a therapeutic strategy to target and inhibit their invasive destructive nature could help patients who are affiicted with this debilitating disease.

The Utility of Ultrasound in Evaluating Joint Pain in Systemic Lupus Erythematosus: Looking beyond Fibromyalgia.

Background: Systemic lupus erythematosus (SLE) is a complex autoimmune condition with varied clinical presentations, and musculoskeletal pain is one of the most commonly associated symptoms. However, fibromyalgia (FM) is a prevalent co-existing condition in SLE patients that can also cause widespread pain, and in patients with both conditions, it is often difficult to distinguish the underlying cause of musculoskeletal pain and provide optimal therapy.

Methods: A retrospective cohort study was conducted including all adult SLE patients who received musculoskeletal ultrasound (US) examinations for joint pain at the Ohio State University Wexner Medical Center between 1 July 2012, and 30 June 2022.

Association between skeletal muscle mitochondrial dysfunction and insulin resistance in patients with rheumatoid arthritis: a case-control study.

Background: Insulin resistance affects a substantial proportion of patients with rheumatoid arthritis (RA). Skeletal muscle mitochondrial dysfunction results in the accumulation of lipid intermediates that interfere with insulin signaling. We therefore sought to determine if lower oxidative phosphorylation and muscle mitochondrial content are associated with insulin resistance in patients with RA.

Inhibition of BET Proteins Regulates Fcγ Receptor Function and Reduces Inflammation in Rheumatoid Arthritis.

Overactivation of immune responses is a hallmark of autoimmune disease pathogenesis. This includes the heightened production of inflammatory cytokines such as Tumor Necrosis Factor α (TNFα), and the secretion of autoantibodies such as isotypes of rheumatoid factor (RF) and anticitrullinated protein antibody (ACPA). Fcγ receptors (FcγR) expressed on the surface of myeloid cells bind Immunoglobulin G (IgG) immune complexes.

Aromatase-Inhibitor-Induced Musculoskeletal Inflammation Is Observed Independent of Oophorectomy in a Novel Mouse Model.

Aromatase Inhibitors (AIs) block estrogen production and improve survival in patients with hormone-receptor-positive breast cancer. However, half of patients develop aromatase-inhibitor-induced arthralgia (AIIA), which is characterized by inflammation of the joints and the surrounding musculoskeletal tissue. To create a platform for future interventional strategies, our objective was to characterize a novel animal model of AIIA.

Molecular profiling of kidney compartments from serial biopsies differentiate treatment responders from non-responders in lupus nephritis.

The immune pathways that define treatment response and non-response in lupus nephritis (LN) are unknown. To characterize these intra-kidney pathways, transcriptomic analysis was done on protocol kidney biopsies obtained at flare (initial biopsy (Bx1)) and after treatment (second biopsy (Bx2)) in 58 patients with LN. Glomeruli and tubulointerstitial compartments were isolated using laser microdissection.

Pathogenesis and Treatment of T-Large Granular Lymphocytic Leukemia (T-LGLL) in the Setting of Rheumatic Disease.

A complex relationship exists between rheumatic diseases and cancer. This delicate balance between chronic inflammation and malignant cell transformation in hematologic neoplasms has been observed, but is not well defined. Large Granular Lymphocyte (LGL) leukemia is at the intersection of a clonal lymphoproliferative disease, chronic inflammation, and autoimmunity.

Incidence, Treatment, and Survival of Patients With T-Cell Lymphoma, T-Cell Large Granular Leukemia, and Concomitant Plasma Cell Dyscrasias.

T-Cell malignancies are a group of heterogeneous disorders composed of primary cutaneous T-cell lymphomas (CTCLs), peripheral T-cell lymphomas (PTCLs), and T-cell leukemias, including T-cell large granular lymphocytic leukemia (T-LGLL). Cases of patients with combined T-cell malignancies and plasma cell dyscrasias (PCD) are reported in the literature, but these are mostly limited to case reports or small case series with <10 patients. Here, we described the clinical course of 26 patients and report baseline characteristics and clinical outcomes including overall survival (OS), progression-free survival (PFS), and objective response rates (ORRs) in this unique population.

Gut dysbiosis is associated with acceleration of lupus nephritis.

The gut microbiota (GM) exerts a strong influence over the host immune system and dysbiosis of this microbial community can affect the clinical phenotype in chronic inflammatory conditions. To explore the role of the GM in lupus nephritis, we colonized NZM2410 mice with Segmented Filamentous Bacteria (SFB). Gut colonization with SFB was associated with worsening glomerulonephritis, glomerular and tubular immune complex deposition and interstitial inflammation compared to NZM2410 mice free of SFB.

Interaction effect of systemic inflammation and modifiable rheumatoid cachexia risk factors on resting energy expenditure in patients with rheumatoid arthritis.

Background: In rheumatoid cachexia (RC), high resting energy expenditure (REE) is associated with loss of muscle mass driven by proinflammatory cytokines. The objectives of this study were to investigate parameters associated with RC, and the interaction between systemic inflammation and modifiable risk factors for RC on REE.

Methods: Thirty-five rheumatoid arthritis (RA) and nineteen non-RA controls comparable in age, sex, race and BMI underwent measures of REE by indirect calorimetry.

Stabilin receptors clear LPS and control systemic inflammation.

Lipopolysaccharides (LPSs) cause lethal endotoxemia if not rapidly cleared from blood circulation. Liver sinusoidal endothelial cells (LSEC) systemically clear LPS by unknown mechanisms. We discovered that LPS clearance through LSEC involves endocytosis and lysosomal inactivation via Stabilin-1 and 2 (Stab1 and Stab2) but does not involve TLR4.

Human Complement C4B Allotypes and Deficiencies in Selected Cases With Autoimmune Diseases.

Human complement C4 is one of the most diverse but heritable effectors for humoral immunity. To help understand the roles of C4 in the defense and pathogenesis of autoimmune and inflammatory diseases, we determined the bases of polymorphisms including the frequent genetic deficiency of C4A and/or C4B isotypes. We demonstrated the diversities of C4A and C4B proteins and their gene copy number variations (CNVs) in healthy subjects and patients with autoimmune disease, such as type 1 diabetes, systemic lupus erythematosus (SLE) and encephalitis.

Components of tart cherry juice inhibit NFκB activation and inflammation in acute gout.

Objectives: To identify the anthocyanin content in tart cherry juice concentrate (TCJC) and establish the anti-inflammatory effect of in a murine acute gout model.

Methods: The main anthocyanins in the TCJC were identified by liquid chromatography mass spectroscopy (LCMS). TCJC or phosphate-buffered saline (PBS) as control were administered daily by oral gavage to BALB/C-Tg(NFκB-RE-luc)-Xen mice that harbour a firefly luciferase cDNA reporter under the regulation of 3 Nuclear factor-κB (NF-κB) response elements.

Crosslinking Reactions and Substrate Incorporation Assays for The Identification of Transglutaminase-2 Protein Substrates.

Transglutaminase (TG2) catalyzes protein crosslinking between glutamyl and lysyl residues. Catalytic activity occurs via a transamidation mechanism resulting in the formation of isopeptide bonds. Since TG2-mediated transamidation is of mechanistic importance for a number of biological processes, assays that enable rapid and efficient identification and characterization of candidate substrates are an important first-step to uncovering the function of crosslinked proteins.

A Novel Inflammatory Dendritic Cell That Is Abundant and Contiguous to T Cells in the Kidneys of Patients With Lupus Nephritis.

The mechanisms that promote local inflammatory injury during lupus nephritis (LN) flare are largely unknown. Understanding the key immune cells that drive intrarenal inflammation will advance our knowledge of disease pathogenesis and inform the development of new therapeutics for LN management. In this study, we analyzed kidney biopsies from patients with proliferative LN and identified a novel inflammatory dendritic cell (infDC) population that is highly expressed in the LN kidney, but minimally present in healthy human kidneys.

Metaanalysis Reveals Genetic Correlates of Osteoporosis Pathogenesis.

Objective: Osteoporosis is a growing healthcare burden. By identifying osteoporosis-promoting genetic variations, we can spotlight targets for new pharmacologic therapies that will improve patient outcomes. In this metaanalysis, we analyzed mesenchymal stem cell (MSC) biomarkers in patients with osteoporosis.

The role of B7 family members in the generation of Immunoglobulin.

Ig is a Y-shaped protein produced by plasma cells and exerts multiple functions in humoral immunity. There are five groups of Igs including IgA, IgD, IgE, IgG, and IgM, which differ in their heavy chain class. The primary function of Igs includes the neutralization of extrinsic pathogens, agglutination of foreign cells for phagocytosis, precipitation of soluble antigens in serum, and complement fixation.

Cy3-tilmanocept labeling of macrophages in joints of mice with antibody-induced arthritis and synovium of human patients with rheumatoid arthritis.

γ-Tilmanocept ( Tc-tilmanocept) is a receptor-directed, radiolabeled tracer that is FDA-approved for guiding sentinel lymph node biopsy. Tilmanocept binds the C-type lectin mannose receptor (MR, CD206) on macrophages. In this study, nonradioactive, fluorescently-labeled Cy3-tilmanocept was used to detect CD206 mononuclear cells in the cartilage of mice with antibody-induced arthritis and in the synovial fluid and tissue of human subjects with rheumatoid arthritis (RA) for comparison with osteoarthritis (OA), and healthy volunteer (HV) controls.

Pathological manifestation of autoimmune myocarditis is detected prior to glomerulonephritis in a murine model of lupus nephritis.

Objective: Since enhanced cardiac magnetic resonance imaging (cMRI) signals have been associated with lupus disease activity in humans prior to renal failure and novel, cardiac-focused therapeutic strategies could be investigated with an associated animal model, autoimmune myocarditis was characterized in murine lupus nephritis (NZM2410).

Methods: Weekly blood urea nitrogen (BUN) levels and weights were recorded. Cardiac function was assessed by echocardiogram.