A degradatory fate for CCR4 suggests a primary role in Th2 inflammation.

CCR4 is the sole receptor for the chemokines CCL22 and CCL17. Clinical studies of asthmatic airways have shown levels of both ligands and CCR4 Th2 cells to be elevated, suggestive of a role in disease. Consequently, CCR4 has aroused much interest as a potential therapeutic target and an understanding of how its cell surface expression is regulated is highly desirable.

Identification of regulators of the myofibroblast phenotype of primary dermal fibroblasts from early diffuse systemic sclerosis patients.

Systemic sclerosis (SSc or scleroderma) is an auto-immune disease characterized by skin fibrosis. While primary cells from patients are considered as a unique resource to better understand human disease biology, the effect of in vitro culture on these cells and their evaluation as a platform to identify disease regulators remain poorly characterized. The goal of our studies was to provide insights into the utility of SSc dermal fibroblast primary cells for therapeutic target discovery.

Pristane-Accelerated Autoimmune Disease in (SWR X NZB) F1 Mice Leads to Prominent Tubulointerstitial Inflammation and Human Lupus Nephritis-Like Fibrosis.

Mouse models lupus nephritis (LN) have provided important insights into disease pathogenesis, although none have been able to recapitulate all features of the human disease. Using comprehensive longitudinal analyses, we characterized a novel accelerated mouse model of lupus using pristane treatment in SNF1 (SWR X NZB F1) lupus prone mice (pristane-SNF1 mice). Pristane treatment in SNF1 mice accelerated the onset and progression of proteinuria, autoantibody production, immune complex deposition and development of renal lesions.

Discovery of biaryl carboxylamides as potent RORγ inverse agonists.

RORγt is a pivotal regulator of a pro-inflammatory gene expression program implicated in the pathology of several major human immune-mediated diseases. Evidence from mouse models demonstrates that genetic or pharmacological inhibition of RORγ activity can block the production of pathogenic cytokines, including IL-17, and convey therapeutic benefit. We have identified and developed a biaryl-carboxylamide series of RORγ inverse agonists via a structure based design approach.

Anti-BDCA2 monoclonal antibody inhibits plasmacytoid dendritic cell activation through Fc-dependent and Fc-independent mechanisms.

Type I interferons (IFN-I) are implicated in the pathogenesis of systemic lupus erythematosus (SLE). In SLE, immune complexes bind to the CD32a (FcγRIIa) receptor on the surface of plasmacytoid dendritic cells (pDCs) and stimulate the secretion of IFN-I from pDCs. BDCA2 is a pDC-specific receptor that, when engaged, inhibits the production of IFN-I in human pDCs.

CXCR3 antagonist VUF10085 binds to an intrahelical site distinct from that of the broad spectrum antagonist TAK-779.

Background And Purpose: The chemokine receptor CXCR3 is implicated in a variety of clinically important diseases, notably rheumatoid arthritis and atherosclerosis. Consequently, antagonists of CXCR3 are of therapeutic interest. In this study, we set out to characterize binding sites of the specific low MW CXCR3 antagonist VUF10085 and the broad spectrum antagonist TAK-779 which blocks CXCR3 along with CCR2 and CCR5.

Immune modulation by butyrophilins.

The B7 family of co-stimulatory molecules has an important role in driving the activation and inhibition of immune cells. Evolving data have shown that a related family of molecules - the butyrophilins - have similar immunomodulatory functions to B7 family members and may represent a novel subset of co-stimulatory molecules. These studies have taken the field by surprise, as the butyrophilins were previously thought to only be important in lactation and milk production.

Distinct conformations of the chemokine receptor CCR4 with implications for its targeting in allergy.

CC chemokine receptor 4 (CCR4) is expressed by Th2 and regulatory T cells and directs their migration along gradients of the chemokines CCL17 and CCL22. Both chemokines and receptor are upregulated in allergic disease, making CCR4 a therapeutic target for the treatment of allergy. We set out to assess the mechanisms underlying a previous report that CCL22 is a dominant ligand of CCR4, which may have implications for its therapeutic targeting.

Genetic architecture of human fibrotic diseases: disease risk and disease progression.

Genetic studies of human diseases have identified multiple genetic risk loci for various fibrotic diseases. This has provided insights into the myriad of biological pathways potentially involved in disease pathogenesis. These discoveries suggest that alterations in immune responses, barrier function, metabolism and telomerase activity may be implicated in the genetic risks for fibrotic diseases.

Human labour is associated with a decline in myometrial chemokine receptor expression: the role of prostaglandins, oxytocin and cytokines.

Problem: Human labour is an inflammatory process with a heavy infiltration of immune cells into the myometrium and cervix induced by local chemokine production. Myometrial cells also express chemokine receptors, but there is little information about their behaviour or function during pregnancy and labour.

Method Of Study: We studied the behaviour of the receptors (CCR2, CXCR1 and CXCR2) for the CCL2 and CXCL8 in human myometrium, because both have been shown to be important in labour.

Structure of the cyanobacterial Magnesium Chelatase H subunit determined by single particle reconstruction and small-angle X-ray scattering.

The biosynthesis of chlorophyll, an essential cofactor for photosynthesis, requires the ATP-dependent insertion of Mg(2+) into protoporphyrin IX catalyzed by the multisubunit enzyme magnesium chelatase. This enzyme complex consists of the I subunit, an ATPase that forms a complex with the D subunit, and an H subunit that binds both the protoporphyrin substrate and the magnesium protoporphyrin product. In this study we used electron microscopy and small-angle x-ray scattering to investigate the structure of the magnesium chelatase H subunit, ChlH, from the thermophilic cyanobacterium Thermosynechococcus elongatus.

Stretch and inflammatory cytokines drive myometrial chemokine expression via NF-κB activation.

Both human preterm labor (PTL) and term labor are consistently associated with a chemokine-induced inflammatory infiltration of the myometrium. However, what regulates myometrial chemokine expression and whether the increase in expression precedes the onset of labor, and so may have a role in its causation, or occurs after, and is simply a consequence of labor, is uncertain. Therefore, we assessed 1) chemokine expression in nonlaboring and laboring myometrial samples obtained at and before term and 2) the factors that regulate myometrial chemokine expression.

The tale of TL1A in inflammation.

TL1A (also known as TNFSF15) is a tumor necrosis factor (TNF) family member expressed by monocytes, macrophages, dendritic cells (DCs), synovial fibroblasts, and endothelial cells in response to stimulation by cytokines, immune complexes, and microorganisms. Its cell surface receptor, DR3 (also known as TNFSF25, WSL-1, TRAMP, and LARD), is mainly expressed by T cells.

Metastatic carcinoid presenting as a breast lesion.

Metastasis to the breast is a rare occurrence, constituting fewer than 2% of all breast tumours. Of all metastatic tumours in the breast, most arise from contralateral breast primaries. Other reported primary solid tumour sites include melanoma; lung, gastric, and renal cancers; and approximately 29 cases of carcinoid tumour.

A metabolic signature of long life in Caenorhabditis elegans.

Background: Many Caenorhabditis elegans mutations increase longevity and much evidence suggests that they do so at least partly via changes in metabolism. However, up until now there has been no systematic investigation of how the metabolic networks of long-lived mutants differ from those of normal worms. Metabolomic technologies, that permit the analysis of many untargeted metabolites in parallel, now make this possible.

Gatekeepers of intestinal inflammation.

The intestine is subjected to a barrage of insults from food, bacterial flora, and pathogens. Despite this constant antigenic challenge, the mucosal tissues lining the intestinal tract remain largely under control. The mechanisms regulating the homeostatic balance in the gut have been investigated for many years by many groups, but the precise nature of the regulatory control remains elusive.

Methods of inducing inflammatory bowel disease in mice.

Animal models of experimentally induced inflammatory bowel disease (IBD) are useful for understanding more about the mechanistic basis of disease, identifying new targets for therapeutic intervention, and testing novel therapeutic agents. This unit provides detailed protocols for four of the most commonly used mouse models of experimentally induced intestinal inflammation: chemical induction of colitis by dextran sodium sulfate (DSS), hapten-induced colitis via 2,4,6-trinitrobenzene sulfonic acid (TNBS), Helicobacter-induced colitis in mdr1a(-/-) mice, and the CD4(+) CD45RB(hi) SCID transfer colitis model.

Overview of mouse models of inflammatory bowel disease and their use in drug discovery.

Inflammatory bowel disease (IBD), a condition that affects millions of individuals, encompasses two distinct conditions: Crohn's disease (CD) and ulcerative colitis (UC). CD is an inflammatory condition affecting any part of the digestive tract between the mouth and anus, but, most commonly, the ileum and colon. It is distinguished by the presence of granulomas in the mucosal tissue and patchy areas of transmural inflammation.

Recent developments in IBD and the B7 family of costimulatory molecules.

The cells and tissues of the intestinal tract are subjected to a constant onslaught of antigenic challenge from both beneficial and harmful pathogens. Despite this constant stimulation, the host is able to maintain a relatively stable environment, often referred to as 'a controlled state of inflammation'. In patients with chronic inflammatory bowel disease, this controlled state of inflammation is lost.

Regulation of costimulation in the era of butyrophilins.

The butyrophilin and butyrophilin-like superfamily of molecules has garnered attention in the immunology world in the past few years as a result of the observation that the butyrophilin-like 2 molecule, BTNL2, can alter T cell responsiveness. Additional interest in this superfamily solidified following the discovery that genetic polymorphisms in BTNL2 are associated with predisposition to many human diseases. In this review, we will provide an overview of the members comprising the butyrophilin superfamily of molecules.

Serum biomarkers in a mouse model of bacterial-induced inflammatory bowel disease.

Background: The diagnosis and classification of inflammatory bowel disease (IBD) require both clinical and histopathologic data. Serum biomarkers would be of considerable benefit to noninvasively monitor the progression of disease, assess effectiveness of therapies, and assist in understanding disease pathogenesis. Currently, there are limited noninvasive biomarkers for monitoring disease progression in animal IBD models, which are used extensively to develop new therapies and to understand IBD pathogenesis.

Direct measurement of metal-ion chelation in the active site of the AAA+ ATPase magnesium chelatase.

Magnesium chelatase catalyzes the first committed step in chlorophyll biosynthesis. This complex enzyme has at least three substrates and couples ATP hydrolysis to the insertion of Mg2+ into protoporphyrin IX. We directly observed metal-ion chelation fluorometrically, providing the first data describing the on-enzyme reaction.