Interstitial Lung Disease in Connective Tissue Disease: A Common Lesion With Heterogeneous Mechanisms and Treatment Considerations.

Connective tissue disease (CTD) related interstitial lung disease (CTD-ILD) is one of the leading causes of morbidity and mortality of CTD. Clinically, CTD-ILD is highly heterogenous and involves rheumatic immunity and multiple manifestations of respiratory complications affecting the airways, vessels, lung parenchyma, pleura, and respiratory muscles. The major pathological features of CTD are chronic inflammation of blood vessels and connective tissues, which can affect any organ leading to multi-system damage.

Diagnosis of fish and shellfish allergies.

Seafood allergy is a hypersensitive disorder with increasing prevalence worldwide. Effective and accurate diagnostic workup for seafood allergy is essential for clinicians and patients. Parvalbumin and tropomyosin are the most common fish and shellfish allergens, respectively.

Junctional adhesion molecules JAM-B and JAM-C promote autoimmune-mediated liver fibrosis in mice.

Fibrosis remains a serious health concern in patients with chronic liver disease. We recently reported that chemically induced chronic murine liver injury triggers increased expression of junctional adhesion molecules (JAMs) JAM-B and JAM-C by endothelial cells and de novo synthesis of JAM-C by hepatic stellate cells (HSCs). Here, we demonstrate that biopsies of patients suffering from primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) or autoimmune hepatitis (AIH) display elevated levels of JAM-C on portal fibroblasts (PFs), HSCs, endothelial cells and cholangiocytes, whereas smooth muscle cells expressed JAM-C constitutively.

Characterization of Blimp-1 function in effector regulatory T cells.

Regulatory T (T) cells maintain immunological tolerance in steady-state and after immune challenge. Activated T cells can undergo further differentiation into an effector state that highly express genes critical for T cell function, including ICOS, TIGIT and IL-10, although how this process is controlled is poorly understood. Effector T cells also specifically express the transcriptional regulator Blimp-1 whose expression overlaps with many of the canonical markers associated with effector T cells, although not all ICOSTIGIT T cells express Blimp-1 or IL-10.

Proteomic analysis reveals distinctive protein profiles involved in CD8 T cell-mediated murine autoimmune cholangitis.

Autoimmune cholangitis arises from abnormal innate and adaptive immune responses in the liver, and T cells are critical drivers in this process. However, little is known about the regulation of their functional behavior during disease development. We previously reported that mice with T cell-restricted expression of a dominant negative form of transforming growth factor beta receptor type II (dnTGFβRII) spontaneously develop an autoimmune cholangitis that resembles human primary biliary cholangitis (PBC).

Environmental basis of primary biliary cholangitis.

Autoimmunity is a consequence of both genetic and environmental factors, occurring in genetically susceptible hosts with environmental triggers. While genome-wide association studies have revealed a number of susceptible genes contributing to etiology, the environmental triggers remain poorly understood. Primary biliary cholangitis, formally known as primary biliary cirrhosis, is considered a model autoimmune disease for which our group has extensively evaluated environmental factors involved in its etiology.

Toward solving the etiological mystery of primary biliary cholangitis.

Primary biliary cholangitis (PBC) is considered a model autoimmune disease due to its signature AMA autoantibody, female predominance and relatively specific portal infiltration and cholestasis. The identification and cloning of the major mitochondrial autoantigens, recognized by AMA, have served as an immunologic platform to identify the earliest events involved in loss of tolerance. Despite the relative high concordance rate in identical twins, genome wide association studies have not proven clinically useful and have led to suggestions of epigenetic events.

Trichloroethylene Exposure Reduces Liver Injury in a Mouse Model of Primary Biliary Cholangitis.

Trichloroethylene (TCE) is a persistent environmental contaminant proposed to contribute to autoimmune disease. Experimental studies in lupus-prone MRL+/+ mice have suggested that TCE exposure can trigger autoimmune hepatitis. The vast majority of studies examining the connection between TCE and autoimmunity utilize this model, and the impact of TCE exposure in other established models of autoimmune liver disease is not known.

Th17 cell differentiation proceeds independently of IRF8.

The transcriptional repressor/activator interferon regulatory factor 8 (IRF8) modulates the differentiation of a multitude of hematopoietic lineages. However, the role of IRF8 in CD4(+) T-cell development is less well defined, with a recent study implicating IRF8 as an intrinsic repressor of interleukin-17 (IL-17) expressing T helper type 17 (Th17) cell differentiation. Using an IRF8-EGFP reporter strain we have confirmed that IRF8 is expressed in all T helper lineages, including Th17 cells.

Autotaxin, Pruritus and Primary Biliary Cholangitis (PBC).

Autotaxin (ATX) is a 125-kD type II ectonucleotide pyrophosphatase/phosphodiesterase (ENPP2 or NPP2) originally discovered as an unknown "autocrine motility factor" in human melanoma cells. In addition to its pyrophosphatase/phosphodiesterase activities ATX has lysophospholipase D (lysoPLD) activity, catalyzing the conversion of lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). ATX is the only ENPP family member with lysoPLD activity and it produces most of the LPA in circulation.

Deletion of Galectin-3 Enhances Xenobiotic Induced Murine Primary Biliary Cholangitis by Facilitating Apoptosis of BECs and Release of Autoantigens.

Galectin-3 (Gal-3) is a carbohydrate binding lectin, with multiple roles in inflammatory diseases and autoimmunity including its antiapoptotic effect on epithelial cells. In particular, increased expression of Gal-3 in epithelial cells is protective from apoptosis. Based on the thesis that apoptosis of biliary epithelial cells (BECs) is critical to the pathogenesis of Primary Biliary Cholangitis (PBC), we have analyzed the role of Gal-3 in the murine model of autoimmune cholangitis.

Adaptive immunity in the liver.

The anatomical architecture of the human liver and the diversity of its immune components endow the liver with its physiological function of immune competence. Adaptive immunity is a major arm of the immune system that is organized in a highly specialized and systematic manner, thus providing long-lasting protection with immunological memory. Adaptive immunity consists of humoral immunity and cellular immunity.

A contemporary perspective on the molecular characteristics of mitochondrial autoantigens and diagnosis in primary biliary cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune hepatobiliary disease characterized by immune mediated destruction of the intrahepatic small bile ducts and the presence of antimitochondrial antibodies (AMAs). The mitochondrial autoantigens have been identified as the E2 subunits of the 2-oxo-acid dehydrogenase complex, including the E2 subunits of pyruvate dehydrogenase, branched-chain 2-oxo acid dehydrogenase complex, oxoglutarate dehydrogenase complex, E3 binding protein and PDC E1 alpha subunit. The AMA epitope is mapped within the E2 lipoic acid binding domain, which is particularly important for oxidative phosphorylation.

Transgenic Overexpression of Aryl Hydrocarbon Receptor Repressor (AhRR) and AhR-Mediated Induction of CYP1A1, Cytokines, and Acute Toxicity.

Background: The aryl hydrocarbon receptor repressor (AhRR) is known to repress aryl hydrocarbon receptor (AhR) signaling, but very little is known regarding the role of the AhRR in vivo.

Objective: This study tested the role of AhRR in vivo in AhRR overexpressing mice on molecular and toxic end points mediated through a prototypical AhR ligand.

Methods: We generated AhRR-transgenic mice (AhRR Tg) based on the genetic background of C57BL/6J wild type (wt) mice.

Chemokine and chemokine receptors in autoimmunity: the case of primary biliary cholangitis.

Chemokines represent a major mediator of innate immunity and play a key role in the selective recruitment of cells during localized inflammatory responses. Beyond critical extracellular mediators of leukocyte trafficking, chemokines and their cognate receptors are expressed by a variety of resident and infiltrating cells (monocytes, lymphocytes, NK cells, mast cells, and NKT cells). Chemokines represent ideal candidates for mechanistic studies (particularly in murine models) to better understand the pathogenesis of chronic inflammation and possibly become biomarkers of disease.

Xenobiotics and loss of tolerance in primary biliary cholangitis.

Data from genome wide association studies and geoepidemiological studies established that a combination of genetic predisposition and environmental stimulation is required for the loss of tolerance in primary biliary cholangitis (PBC). The serologic hallmark of PBC are the presence of high titer anti-mitochondrial autoantibodies (AMA) that recognize the lipoyl domain of the mitochondrial pyruvate dehydrogenase E2 (PDC-E2) subunit. Extensive efforts have been directed to investigate the molecular basis of AMA.

The modulation of co-stimulatory molecules by circulating exosomes in primary biliary cirrhosis.

Exosomes are nanoparticles of endocytic origin, secreted by a myriad of cell populations that are attracting increased attention by virtue of their ability to modulate cell-to-cell communications. They are also attracting attention in a variety of immunological issues, including autoimmunity and, in particular, their ability to regulate cytokine and chemokine activation. Primary biliary cirrhosis (PBC) is considered a model autoimmune disease, which has a highly focused cytotoxic response against biliary epithelial cells.

The Significance of Autoantibody Changes Over Time in Primary Biliary Cirrhosis.

Objectives: In primary biliary cirrhosis (PBC), the antimitochondrial antibody is a cornerstone of diagnosis, but there have been conflicting reports about the correlation of autoantibodies with disease stage and prognosis. We studied whether autoantibody levels changed over time and sought correlations with clinical outcomes in a cohort of patients with PBC.

Methods: We tested serial serum samples from patients with PBC at a research institution for several autoantibodies.

Screening and identification of mimotopes of the major shrimp allergen tropomyosin using one-bead-one-compound peptide libraries.

The one-bead-one-compound (OBOC) combinatorial peptide library is a powerful tool to identify ligand and receptor interactions. Here, we applied the OBOC library technology to identify mimotopes specific to the immunoglobulin E (IgE) epitopes of the major shellfish allergen tropomyosin. OBOC peptide libraries with 8-12 amino acid residues were screened with serum samples from patients with shellfish allergy for IgE mimotopes of tropomyosin.

Gastrointestinal Immune Response to the Shrimp Allergen Tropomyosin: Histological and Immunological Analysis in an Animal Model of Shrimp Tropomyosin Hypersensitivity.

Background: Shellfish hypersensitivity is among the most common food allergies. A murine model of IgE-mediated shrimp allergy has been established in our laboratory. The aim of this study is to determine the intestinal histological changes and cytokine expression profile of this model sensitized with the major shellfish allergen tropomyosin.

Environmental Basis of Autoimmunity.

The three common themes that underlie the induction and perpetuation of autoimmunity are genetic predisposition, environmental factors, and immune regulation. Environmental factors have gained much attention for their role in triggering autoimmunity, with increasing evidence of their influence as demonstrated by epidemiological studies, laboratory research, and animal studies. Environmental factors known to trigger and perpetuate autoimmunity include infections, gut microbiota, as well as physical and environmental agents.

Innate immunity drives the initiation of a murine model of primary biliary cirrhosis.

Invariant natural killer T (iNKT) cells play complex roles in bridging innate and adaptive immunity by engaging with glycolipid antigens presented by CD1d. Our earlier work suggested that iNKT cells were involved in the initiation of the original loss of tolerance in primary biliary cirrhosis (PBC). To address this issue in more detail and, in particular, to focus on whether iNKT cells activated by a Th2-biasing agonist (2s,3s,4r)-1-O-(α-D-galactopyranosyl)-N-tetracosanoyl-2-amino-1,3,4-nonanetriol (OCH), can influence the development of PBC in a xenobiotic-induced PBC murine model.

Animal models of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is characterized histologically by the presence of chronic non-suppurative destructive cholangitis of the small interlobular bile duct, leading to chronic progressive cholestasis. Most PBC patients are asymptomatic and have a reasonable prognosis, but a few develop esophageal varices or jaundice, rapidly leading to liver failure within a short period. As multiple factors appear to be involved in the onset of PBC, its clinical course may be complicated.

IL-35 and Autoimmunity: a Comprehensive Perspective.

Interleukin 35 (IL-35) is the most recently identified member of the IL-12 family of cytokines and offers the potential to be a target for new therapies for autoimmune, inflammatory, and infectious diseases. Similar to other members of the IL-12 family including IL-12, IL-23, and IL-27, IL-35 is composed of a heterodimer of α and β chains, which in the case of IL-35 are the p35 and Epstein-Barr virus-induced gene 3 (EBI3) proteins. However, unlike its proinflammatory relatives, IL-35 has immunosuppressive effects that are mediated through regulatory T and B cells.