Publications by authors named "Teresa K Tarrant"

36 Publications

Paget's Disease of Bone: Osteoimmunology and Osteoclast Pathology.

Curr Allergy Asthma Rep 2021 Mar 25;21(4):23. Epub 2021 Mar 25.

Division of Rheumatology and Immunology, Department of Medicine, Duke University, DUMC #3874, 200 Trent Dr, Durham, NC, 27710, USA.

Purpose Of Review: The purpose of this review is to recognize clinical features of Paget's disease of bone and to describe how the osteoclast, a myeloid-derived cell responsible for bone resorption, contributes to the disease.

Recent Findings: Recent studies have identified several variants in SQSTM1, OPTN, and other genes that may predispose individuals to Paget's disease of bone; studies of these genes and their protein products have elucidated new roles for these proteins in bone physiology. Understanding the pathologic mechanisms in the Pagetic osteoclast may lead to the identification of future treatment targets for other inflammatory and autoimmune diseases characterized by abnormal bone erosion and/or osteoclast activation.
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http://dx.doi.org/10.1007/s11882-021-01001-2DOI Listing
March 2021

A Mimic of Ankylosing Spondylitis, Ochronosis: Case Report and Review of the Literature.

Curr Allergy Asthma Rep 2021 Mar 5;21(3):19. Epub 2021 Mar 5.

Division of Rheumatology and Immunology, Department of Medicine, Duke University, Durham, NC, 27710, USA.

Purpose Of Review: Ochronosis and alkaptonuria are manifestations of the same condition-a rare autosomal recessive disorder resulting from a constitutional lack of homogentisate 1,2-dioxygenase (HGD) with the consequent accumulation of homogentisic acid (HGA). In ochronosis, HGA undergoes autoxidation as well as enzymatic oxidation to form an ochronotic pigment that accumulates in cartilage and connective tissues. In the beginning, there is homogentisic aciduria and pigmentation of cartilages and other connective tissues. In later years, generalized osteoarthritis of the spine and large joints, termed ochronotic arthropathy, develops.

Recent Findings: The diagnosis is confirmed by quantitative measurement of HGA in urine and mutation analysis of the HGD gene. One of the differential diagnoses for the skin findings is exogenous ochronosis, a limited hyperpigmentation of skin caused by some chemicals. As for the lumbar spine findings, there can be radiographic similarities with ankylosing spondylitis (AS) including reduced intervertebral disc spaces and loss of lumbar lordosis; however, ochronosis will spare the sacroiliac joint, and the lumbar spine will show dense, wafer-like disk calcification with a vacuum disc phenomenon and broad syndesmophytes. Here, we present a case of a patient with probable ochronosis that was treated many years as ankylosing spondylitis without response, and we provide a review of the current literature on ochronosis pathogenesis, diagnosis, and treatment.
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http://dx.doi.org/10.1007/s11882-021-01002-1DOI Listing
March 2021

Hydroxychloroquine and COVID-19: a Rheumatologist's Take on the Lessons Learned.

Curr Allergy Asthma Rep 2021 01 21;21(1). Epub 2021 Jan 21.

Duke University Medical Center, Box 2978, Durham, NC, 27710, USA.

Purpose Of Review: Told from the viewpoint of rheumatologists, this review tells the story of hydroxychloroquine and its swift ascent to become a household name as a therapeutic strategy against the novel SARS-CoV-2 virus. This review describes the history, mechanisms, pharmacokinetics, therapeutic applications, and safety profile of hydroxychloroquine as an immunomodulatory and antiviral agent. It also summarizes the major studies that launched and assessed the use of hydroxychloroquine against COVID-19 infection.

Recent Findings: More recent literature calls into question the long-held dogma that endolysosomal alkalinization is the primary mode of action of hydroxychloroquine. Ongoing uncertainty about the multiple potential mechanisms contributing to the therapeutic effect of hydroxychloroquine in rheumatic and viral disease led to a natural avenue for exploration in the treatment of COVID-19. Taken as a whole, the literature does not support utilizing hydroxychloroquine to treat or prevent infection from the SARS-CoV-2 virus. This is, at least in part, due to the wide variability in hydroxychloroquine pharmacokinetics between patients and difficulty achieving adequate target tissue concentrations of hydroxychloroquine without encountering unacceptable toxicities. Hydroxychloroquine continues to be a routinely prescribed, well-tolerated, effective, and low-cost treatment for rheumatic disease. Its therapeutic versatility has led to frequent repurposing for other conditions, most recently as an investigative treatment against the SARS-CoV-2 virus. Despite overall negative findings, the intense study of hydroxychloroquine against COVID-19 infection has enhanced our overall understanding of how hydroxychloroquine operates in autoimmune disease and beyond.
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http://dx.doi.org/10.1007/s11882-020-00983-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818062PMC
January 2021

Mesenchymal stromal cells reprogram monocytes and macrophages with processing bodies.

Stem Cells 2021 Jan 9;39(1):115-128. Epub 2020 Nov 9.

Marcus Center for Cellular Cures, Duke University, Durham, North Carolina, USA.

Mesenchymal stromal cells (MSCs) are widely used in clinical trials because of their ability to modulate inflammation. The success of MSCs has been variable over 25 years, most likely due to an incomplete understanding of their mechanism. After MSCs are injected, they traffic to the lungs and other tissues where they are rapidly cleared. Despite being cleared, MSCs suppress the inflammatory response in the long term. Using human cord tissue-derived MSCs (hCT-MSCs), we demonstrated that hCT-MSCs directly interact and reprogram monocytes and macrophages. After engaging hCT-MSCs, monocytes and macrophages engulfed cytoplasmic components of live hCT-MSCs, then downregulated gene programs for antigen presentation and costimulation, and functionally suppressed the activation of helper T cells. We determined that low-density lipoprotein receptor-related proteins on monocytes and macrophages mediated the engulfment of hCT-MSCs. Since a large amount of cellular information can be packaged in cytoplasmic RNA processing bodies (p-bodies), we generated p-body deficient hCT-MSCs and confirmed that they failed to reprogram monocytes and macrophages in vitro and in vivo. hCT-MSCs suppressed an inflammatory response caused by a nasal lipopolysaccharide challenge. Although both control and p-body deficient hCT-MSCs were engulfed by infiltrating lung monocytes and macrophages, p-body deficient hCT-MSCs failed to suppress inflammation and downregulate MHC-II. Overall, we identified a novel mechanism by which hCT-MSCs indirectly suppressed a T-cell response by directly interacting and reprogramming monocytes and macrophages via p-bodies. The results of this study suggest a novel mechanism for how MSCs can reprogram the inflammatory response and have long-term effects to suppress inflammation.
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http://dx.doi.org/10.1002/stem.3292DOI Listing
January 2021

Is the HScore useful in COVID-19?

Lancet 2020 05 5;395(10236):e83. Epub 2020 May 5.

Duke University School of Medicine, Department of Medicine, Division of Rheumatology and Immunology, Durham NC 27710, USA.

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http://dx.doi.org/10.1016/S0140-6736(20)31057-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200125PMC
May 2020

Diagnostic interpretation of genetic studies in patients with primary immunodeficiency diseases: A working group report of the Primary Immunodeficiency Diseases Committee of the American Academy of Allergy, Asthma & Immunology.

J Allergy Clin Immunol 2020 01 27;145(1):46-69. Epub 2019 Sep 27.

Departments of Pediatrics and Medicine, University of South Florida, St Petersburg, Fla; Division of Pediatric Allergy/Immunology, Johns Hopkins-All Children's Hospital, St Petersburg, Fla; Division of Pediatric Allergy Immunology, Massachusetts General Hospital, Boston, Mass.

Genetic testing has become an integral component of the diagnostic evaluation of patients with suspected primary immunodeficiency diseases. Results of genetic testing can have a profound effect on clinical management decisions. Therefore clinical providers must demonstrate proficiency in interpreting genetic data. Because of the need for increased knowledge regarding this practice, the American Academy of Allergy, Asthma & Immunology Primary Immunodeficiency Diseases Committee established a work group that reviewed and summarized information concerning appropriate methods, tools, and resources for evaluating variants identified by genetic testing. Strengths and limitations of tests frequently ordered by clinicians were examined. Summary statements and tables were then developed to guide the interpretation process. Finally, the need for research and collaboration was emphasized. Greater understanding of these important concepts will improve the diagnosis and management of patients with suspected primary immunodeficiency diseases.
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http://dx.doi.org/10.1016/j.jaci.2019.09.009DOI Listing
January 2020

On Command Drug Delivery via Cell-Conveyed Phototherapeutics.

Small 2019 09 28;15(37):e1901442. Epub 2019 Jul 28.

Department of Chemistry, University of North Carolina, Chapel Hill, NC, 27599, USA.

Herein, the use of red blood cells (RBCs) as carriers of cytoplasmically interned phototherapeutic agents is described. Photolysis promotes drug release from the RBC carrier thereby providing the means to target specific diseased sites. This strategy is realized with a vitamin B12-taxane conjugate (B12-TAX), in which the drug is linked to the vitamin via a photolabile CoC bond. The conjugate is introduced into mouse RBCs (mRBCs) via a pore-forming/pore-resealing procedure and is cytoplasmically retained due to the membrane impermeability of B12. Photolysis separates the taxane from the B12 cytoplasmic anchor, enabling the drug to exit the RBC carrier. A covalently appended Cy5 antenna sensitizes the conjugate (Cy5-B12-TAX) to far red light, thereby circumventing the intense light absorbing properties of hemoglobin (350-600 nm). Microscopy and imaging flow cytometry reveal that Cy5-B12-TAX-loaded mRBCs act as drug carriers. Furthermore, intravital imaging of mice furnish a real time assessment of circulating phototherapeutic-loaded mRBCs as well as evidence of the targeted photorelease of the taxane upon photolysis. Histopathology confirms that drug release occurs in a well resolved spatiotemporal fashion. Finally, acoustic angiography is employed to assess the consequences of taxane release at the tumor site in Nu/Nu-tumor-bearing mice.
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http://dx.doi.org/10.1002/smll.201901442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739139PMC
September 2019

Chemerin-activated functions of CMKLR1 are regulated by G protein-coupled receptor kinase 6 (GRK6) and β-arrestin 2 in inflammatory macrophages.

Mol Immunol 2019 02 18;106:12-21. Epub 2018 Dec 18.

Thurston Arthritis Research Center and the Department of Medicine, Division of Rheumatology, Allergy, and Immunology, University of North Carolina, Chapel Hill, NC 27599, United States; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, United States. Electronic address:

Chemerin receptor (CMKLR1) is a G protein-coupled receptor (GPCR) implicated in macrophage-mediated inflammation and in several forms of human arthritis. Analogous to other GPCR, CMKLR1 is likely regulated by G protein-coupled receptor kinase (GRK) phosphorylation of intracellular domains in an activation-dependent manner, which leads to recruitment and termination of intracellular signaling via desensitization and internalization of the receptor. The ubiquitously expressed GRK family members include GRK2, GRK3, GRK5, and GRK6, but it is unknown which GRK regulates CMKLR1 cellular and signaling functions. Our data show that activation of CMKLR1 by chemerin in primary macrophages leads to signaling and functional outcomes that are regulated by GRK6 and β-arrestin 2. We show that arrestin recruitment to CMKLR1 following chemerin stimulation is enhanced with co-expression of GRK6. Further, internalization of endogenous CMKLR1, following the addition of chemerin, is decreased in inflammatory macrophages from GRK6- and β-arrestin 2-deficient mice. These GRK6- and β-arrestin 2-deficient macrophages display increased migration toward chemerin and altered AKT and Extracellular-signal Related Kinase (ERK) signaling. Our findings show that chemerin-activated CMKLR1 regulation in inflammatory macrophages is largely GRK6 and β-arrestin mediated, which may impact innate immunity and have therapeutic implications in rheumatic disease.
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http://dx.doi.org/10.1016/j.molimm.2018.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584946PMC
February 2019

A functional genomics predictive network model identifies regulators of inflammatory bowel disease.

Nat Genet 2017 Oct 11;49(10):1437-1449. Epub 2017 Sep 11.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

A major challenge in inflammatory bowel disease (IBD) is the integration of diverse IBD data sets to construct predictive models of IBD. We present a predictive model of the immune component of IBD that informs causal relationships among loci previously linked to IBD through genome-wide association studies (GWAS) using functional and regulatory annotations that relate to the cells, tissues, and pathophysiology of IBD. Our model consists of individual networks constructed using molecular data generated from intestinal samples isolated from three populations of patients with IBD at different stages of disease. We performed key driver analysis to identify genes predicted to modulate network regulatory states associated with IBD, prioritizing and prospectively validating 12 of the top key drivers experimentally. This validated key driver set not only introduces new regulators of processes central to IBD but also provides the integrated circuits of genetic, molecular, and clinical traits that can be directly queried to interrogate and refine the regulatory framework defining IBD.
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http://dx.doi.org/10.1038/ng.3947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660607PMC
October 2017

Immune Gamma Globulin Therapeutic Indications in Immune Deficiency and Autoimmunity.

Curr Allergy Asthma Rep 2016 07;16(8):55

Department of Medicine, Division of Rheumatology, Allergy, and Immunology and the Thurston Arthritis Research Center, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA.

Immune gamma globulin (IgG) has a long history in the treatment of both primary immune deficiency and autoimmune disorders. Disease indications continue to expand and new-generation products increase the versatility of delivery. This review encompasses a historical perspective as well as current and future implications of human immune globulin for the treatment of immune-mediated illness.
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http://dx.doi.org/10.1007/s11882-016-0632-7DOI Listing
July 2016

Single Cell Chemical Cytometry of Akt Activity in Rheumatoid Arthritis and Normal Fibroblast-like Synoviocytes in Response to Tumor Necrosis Factor α.

Anal Chem 2016 08 20;88(15):7786-92. Epub 2016 Jul 20.

Department of Chemistry, University of North Carolina , Chapel Hill, North Carolina 27599, United States.

The etiology of rheumatoid arthritis (RA) is poorly understood, and 30% of patients are unresponsive to established treatments targeting tumor necrosis factor α (TNFα). Akt kinase is implicated in TNFα signaling and may act as a barometer of patient responses to biologic therapies. Fluorescent peptide sensors and chemical cytometry were employed to directly measure Akt activity as well as proteolytic activity in individual fibroblast-like synoviocytes (FLS) from RA and normal subjects. The specificity of the peptide reporter was evaluated and shown to be a valid measure of Akt activity in single cells. The effect of TNFα treatment on Akt activity was highly heterogeneous between normal and RA subjects, which was not observable in bulk analyses. In 2 RA subjects, a bimodal distribution of Akt activity was observed, primarily due to a subpopulation (21.7%: RA Subject 5; 23.8%: RA Subject 6) of cells in which >60% of the reporter was phosphorylated. These subjects also possessed statistically elevated proteolytic cleavage of the reporter relative to normal subjects, suggesting heterogeneity in Akt and protease activity that may play a role in the RA-affected joint. We expect that chemical cytometry studies pairing peptide reporters with capillary electrophoresis will provide valuable data regarding aberrant kinase activity from small samples of clinical interest.
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http://dx.doi.org/10.1021/acs.analchem.6b01801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040665PMC
August 2016

Apoptotic Debris Accumulates on Hematopoietic Cells and Promotes Disease in Murine and Human Systemic Lupus Erythematosus.

J Immunol 2016 05 8;196(10):4030-9. Epub 2016 Apr 8.

Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599;

Apoptotic debris, autoantibody, and IgG-immune complexes (ICs) have long been implicated in the inflammation associated with systemic lupus erythematosus (SLE); however, it remains unclear whether they initiate immune-mediated events that promote disease. In this study, we show that PBMCs from SLE patients experiencing active disease, and hematopoietic cells from lupus-prone MRL/lpr and NZM2410 mice accumulate markedly elevated levels of surface-bound nuclear self-antigens. On dendritic cells (DCs) and macrophages (MFs), the self-antigens are part of IgG-ICs that promote FcγRI-mediated signal transduction. Accumulation of IgG-ICs is evident on ex vivo myeloid cells from MRL/lpr mice by 10 wk of age and steadily increases prior to lupus nephritis. IgG and FcγRI play a critical role in disease pathology. Passive transfer of pathogenic IgG into IgG-deficient MRL/lpr mice promotes the accumulation of IgG-ICs prior to significant B cell expansion, BAFF secretion, and lupus nephritis. In contrast, diminishing the burden IgG-ICs in MRL/lpr mice through deficiency in FcγRI markedly improves these lupus pathologies. Taken together, our findings reveal a previously unappreciated role for the cell surface accumulation of IgG-ICs in human and murine lupus.
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http://dx.doi.org/10.4049/jimmunol.1500418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868781PMC
May 2016

G Protein Coupled Receptor Kinase 3 Regulates Breast Cancer Migration, Invasion, and Metastasis.

PLoS One 2016 6;11(4):e0152856. Epub 2016 Apr 6.

Thurston Arthritis Research Center and the Department of Medicine, Division of Rheumatology, Allergy, and Immunology, University of North Carolina, Chapel Hill, NC 27599, United States of America.

Triple negative breast cancer (TNBC) is a heterogeneous disease that has a poor prognosis and limited treatment options. Chemokine receptor interactions are important modulators of breast cancer metastasis; however, it is now recognized that quantitative surface expression of one important chemokine receptor, CXCR4, may not directly correlate with metastasis and that its functional activity in breast cancer may better inform tumor pathogenicity. G protein coupled receptor kinase 3 (GRK3) is a negative regulator of CXCR4 activity, and we show that GRK expression correlates with tumorigenicity, molecular subtype, and metastatic potential in human tumor microarray analysis. Using established human breast cancer cell lines and an immunocompetent in vivo mouse model, we further demonstrate that alterations in GRK3 expression levels in tumor cells directly affect migration and invasion in vitro and the establishment of distant metastasis in vivo. The effects of GRK3 modulation appear to be specific to chemokine-mediated migration behaviors without influencing tumor cell proliferation or survival. These data demonstrate that GRK3 dysregulation may play an important part in TNBC metastasis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152856PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822790PMC
August 2016

Improved outcomes on subcutaneous IgG in patients with humoral immunodeficiency and co-morbid bowel disease.

Clin Case Rep Rev 2015 Jul;1(7):151-152

University of North Carolina School of Medicine, Division of Rheumatology, Allergy & Immunology, Thurston Arthritis Research Center and Lineberger Comprehensive Cancer Center, 3300 Manning Drive, CB #7280, Chapel Hill, NC 27599.

Immunoglobulin replacement can be life-saving for certain individuals with immunodeficiencies. Subcutaneous IgG (SCIG) is an increasingly used method of replacement over intravenous IgG (IVIG), with potential advantages including fewer systemic side effects, no need for IV access, patient-reported improved quality of life, and decreased cost. However, while patients with certain associated co-morbidities, such as protein-losing enteropathy, may demonstrate more stable IgG levels when on SCIG compared to IVIG, the clinical significance of these experiences is not well described. Using retrospective chart review, we examined three cases in which SCIG and IVIG was administered to patients with either common variable immunodeficiency (CVID) or secondary humoral immunodeficiency and protein-losing gastrointestinal co-morbid disease. Both outpatient and inpatient records were reviewed for data regarding treatment with IVIG versus SCIG, reported frequency and severity of infections, hospitalizations, and IgG levels. All three patients demonstrated improvement in infection rate, stability of IgG levels, and co-morbid disease when on SCIG as compared to IVIG. These findings suggest that the pharmacokinetics of SCIG may translate into more consistent serum IgG levels, contributing to clinical improvement in immunodeficient patients with protein-losing comorbidities when compared to IVIG. Limitations to this study are small patient numbers, retrospective design, and potential therapeutic bias. Further characterization of the effects of co-morbid conditions on immunoglobulin replacement is critical to providing improved and informed patient care.
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http://dx.doi.org/10.15761/CCRR.1000149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4813804PMC
July 2015

Clinically focused exome sequencing identifies an homozygous mutation that confers DOCK8 deficiency.

Pediatr Allergy Immunol 2016 Feb 12;27(1):96-8. Epub 2015 Oct 12.

Mclendon Clinical Laboratory, UNC Hospitals, Chapel Hill, NC, USA.

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http://dx.doi.org/10.1111/pai.12451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724217PMC
February 2016

Roles of chemokines CCL2 and CCL5 in the pharmacokinetics of PEGylated liposomal doxorubicin in vivo and in patients with recurrent epithelial ovarian cancer.

Nanomedicine 2015 Oct 17;11(7):1797-807. Epub 2015 Jun 17.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Carolina Center of Cancer Nanotechnology Excellence, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address:

Unlabelled: Nanoparticles (NPs) are cleared by monocytes and macrophages. Chemokines CCL2 and CCL5 are key mediators for recruitment of these immune cells into tumors and tissues. The purpose of this study was to investigate effects of CCL2 and CCL5 on the pharmacokinetics (PKs) of NPs. Mice deficient in CCL2 or CCL5 demonstrated altered clearance and tissue distribution of polyethylene glycol tagged liposomal doxorubicin (PLD) compared to control mice. The PK studies using mice bearing SKOV3 ovarian cancer xenografts revealed that the presence of tumor cells and higher expression of chemokines were significantly associated with greater clearance of PLD compared to non-tumor bearing mice. Plasma exposure of encapsulated liposomal doxorubicin positively correlated with the total exposure of plasma CCL2 and CCL5 in patients with recurrent epithelial ovarian cancer treated with PLD. These data emphasize that the interplay between PLD and chemokines may have an important role in optimizing PLD therapy.

From The Clinical Editor: The use of nanoparticles as drug delivery carriers is gaining widespread acceptance in the clinical setting. However, the underlying pharmacokinetics of these novel drugs has not really been elucidated. In this interesting article, the authors carried out experiments using mice deficient in CCL2 or CCL5 to study the clearance of liposomal system. They showed the important role the immune system played and would enable better designs of future drug delivery systems.
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http://dx.doi.org/10.1016/j.nano.2015.05.007DOI Listing
October 2015

Nanoscience advances in rheumatology and immunology.

Authors:
Teresa K Tarrant

Curr Rheumatol Rev 2014 ;10(1):1-2

Department of Medicine Division of Rheumatology Allergy and Immunology University of North Carolina at Chapel Hill NC, USA.

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http://dx.doi.org/10.2174/157339711001140924101042DOI Listing
June 2015

Effects of tumor microenvironment heterogeneity on nanoparticle disposition and efficacy in breast cancer tumor models.

Clin Cancer Res 2014 Dec 17;20(23):6083-95. Epub 2014 Sep 17.

Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, Chapel Hill, North Carolina. Carolina Center of Cancer Nanotechnology Excellence, UNC at Chapel Hill, Chapel Hill, North Carolina. Center for Pharmacogenomics and Individualized Therapy, UNC at Chapel Hill, Chapel Hill, North Carolina.

Purpose: Tumor cells are surrounded by a complex microenvironment. The purpose of our study was to evaluate the role of heterogeneity of the tumor microenvironment in the variability of nanoparticle (NP) delivery and efficacy.

Experimental Designs: C3(1)-T-Antigen genetically engineered mouse model (C3-TAg) and T11/TP53(Null) orthotopic syngeneic murine transplant model (T11) representing human breast tumor subtypes basal-like and claudin-low, respectively, were evaluated. For the pharmacokinetic studies, non-liposomal doxorubicin (NL-doxo) or polyethylene glycol tagged (PEGylated) liposomal doxorubicin (PLD) was administered at 6 mg/kg i.v. x1. Area under the concentration versus time curve (AUC) of doxorubicin was calculated. Macrophages, collagen, and the amount of vasculature were assessed by IHC. Chemokines and cytokines were measured by multiplex immunochemistry. NL-doxo or PLD was administered at 6 mg/kg i.v. weekly x6 in efficacy studies. Analyses of intermediary tumor response and overall survival were performed.

Results: Plasma AUC of NL-doxo and PLD encapsulated and released doxorubicin was similar between two models. However, tumor sum total AUC of PLD was 2-fold greater in C3-TAg compared with T11 (P < 0.05). T11 tumors showed significantly higher expression of CC chemokine ligand (CCL) 2 and VEGF-a, greater vascular quantity, and decreased expression of VEGF-c compared with C3-TAg (P < 0.05). PLD was more efficacious compared with NL-doxo in both models.

Conclusion: The tumor microenvironment and/or tumor cell features of breast cancer affected NP tumor delivery and efficacy, but not the small-molecule drug. Our findings reveal the role of the tumor microenvironment in variability of NP delivery and therapeutic outcomes.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-0493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4565518PMC
December 2014

G protein signaling modulator-3: a leukocyte regulator of inflammation in health and disease.

Am J Clin Exp Immunol 2014 15;3(2):97-106. Epub 2014 Aug 15.

Thurston Arthritis Research Center and The Department of Medicine, Division of Rheumatology, Allergy, and Immunology, University of North Carolina Chapel Hill, NC 27599, USA ; Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill, NC 27599, USA.

G protein signaling modulator-3 (GPSM3), also known as G18 or AGS4, is a member of a family of proteins containing one or more copies of a small regulatory motif known as the GoLoco (or GPR) motif. GPSM3 interacts directly with Gα and Gβ subunits of heterotrimeric G proteins to regulate downstream intracellular signals initiated by G protein coupled receptors (GPCRs) that are activated via binding to their cognate ligands. GPSM3 has a selective tissue distribution and is highly expressed in immune system cells; genome-wide association studies (GWAS) have recently revealed that single nucleotide polymorphisms (SNPs) in GPSM3 are associated with chronic inflammatory diseases. This review highlights the current knowledge of GPSM3 function in normal and pathologic immune-mediated conditions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138133PMC
August 2014

Autoimmune lymphoproliferative syndrome: an update and review of the literature.

Curr Allergy Asthma Rep 2014 Sep;14(9):462

Division of Rheumatology, Allergy, and Immunology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA,

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by immune dysregulation due to a defect in lymphocyte apoptosis. The clinical manifestations may be noted in multiple family members and include lymphadenopathy, splenomegaly, increased risk of lymphoma, and autoimmune disease, which typically involves hematopoietic cell lines manifesting as multilineage cytopenias. Since the disease was first characterized in the early 1990s, there have been many advances in the diagnosis and management of this syndrome. The inherited genetic defect of many ALPS patients has involved (FAS) pathway signaling proteins, but there remain those patients who carry undefined genetic defects. Despite ALPS having historically been considered a primary immune defect presenting in early childhood, adult onset presentation is increasingly becoming recognized and more so in genetically undefined patients and those with somatic FAS mutations. Thus, future research may identify novel pathways and/or regulatory proteins important in lymphocyte activation and apoptosis.
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http://dx.doi.org/10.1007/s11882-014-0462-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148697PMC
September 2014

Targeting the molecular and cellular interactions of the bone marrow niche in immunologic disease.

Curr Allergy Asthma Rep 2014 Feb;14(2):402

Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, 27599, USA,

Recent investigations have expanded our knowledge of the regulatory bone marrow (BM) niche, which is critical in maintaining and directing hematopoietic stem cell (HSC) self-renewal and differentiation. Osteoblasts, mesenchymal stem cells (MSCs), and CXCL12-abundant reticular (CAR) cells are niche components in close association with HSCs and have been more clearly defined in immune cell function and homeostasis. Importantly, cellular inhabitants of the BM niche signal through G protein-coupled surface receptors (GPCRs) for various appropriate immune functions. In this article, recent literature on BM niche inhabitants (HSCs, osteoblasts, MSCs, CAR cells) and their GPCR mechanistic interactions are reviewed for better understanding of the BM cells involved in immune development, immunologic disease, and current immune reconstitution therapies.
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http://dx.doi.org/10.1007/s11882-013-0402-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932436PMC
February 2014

G protein-coupled receptor kinase-3-deficient mice exhibit WHIM syndrome features and attenuated inflammatory responses.

J Leukoc Biol 2013 Dec 9;94(6):1243-51. Epub 2013 Aug 9.

1.CB #7280, 3300 Manning Dr., Chapel Hill, NC 27599, USA.

Chemokine receptor interactions coordinate leukocyte migration in inflammation. Chemokine receptors are GPCRs that when activated, are phosphorylated by GRKs to turn off G protein-mediated signaling yet recruit additional signaling machinery. Recently, GRK3 was identified as a negative regulator of CXCL12/CXCR4 signaling that is defective in human WHIM syndrome. Here, we report that GRK3-/- mice exhibit numerous features of human WHIM, such as impaired CXCL12-mediated desensitization, enhanced CXCR4 signaling to ERK activation, altered granulocyte migration, and a mild myelokathexis. Moreover, GRK3-/- protects mice from two acute models of inflammatory arthritis (K/BxN serum transfer and CAIA). In these granulocyte-dependent disease models, protection of GRK3-/- mice is mediated by retention of cells in the marrow, fewer circulating granulocytes in the peripheral blood, and reduced granulocytes in the joints during active inflammation. In contrast to WHIM, GRK3-/- mice have minimal hypogammaglobulinemia and a peripheral leukocytosis with increased lymphocytes and absent neutropenia. Thus, we conclude that the loss of GRK3-mediated regulation of CXCL12/CXCR4 signaling contributes to some, but not all, of the complete WHIM phenotype and that GRK3 inhibition may be beneficial in the treatment of inflammatory arthritis.
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http://dx.doi.org/10.1189/jlb.0213097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828605PMC
December 2013

Autoimmunity in immunodeficiency.

Curr Allergy Asthma Rep 2013 Aug;13(4):361-70

Division of Allergy and Immunology, Dept of Pediatrics, University of North Carolina Hospitals, Chapel Hill, NC 27599, USA.

Primary immunodeficiencies (PID) comprise a diverse group of clinical disorders with varied genetic defects. Paradoxically, a substantial proportion of PID patients develop autoimmune phenomena in addition to having increased susceptibility to infections from their impaired immunity. Although much of our understanding comes from data gathered through experimental models, there are several well-characterized PID that have improved our knowledge of the pathways that drive autoimmunity. The goals of this review will be to discuss these immunodeficiencies and to review the literature with respect to the proposed mechanisms for autoimmunity within each put forth to date.
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http://dx.doi.org/10.1007/s11882-013-0350-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729619PMC
August 2013

G-protein signaling modulator-3, a gene linked to autoimmune diseases, regulates monocyte function and its deficiency protects from inflammatory arthritis.

Mol Immunol 2013 Jun 29;54(2):193-8. Epub 2012 Dec 29.

Department of Pharmacology, UNC School of Medicine, Chapel Hill, NC 27599-7365, USA.

Polymorphism at the GPSM3 gene locus is inversely associated with four systemic autoimmune diseases, including rheumatoid arthritis and ankylosing spondylitis. G-protein signaling modulator-3 (GPSM3) expression is most pronounced in myeloid cells, in which it targets heterotrimeric G-protein Gαi subunits of chemokine receptors, critical to immune function. To begin to explore the regulatory role of GPSM3 in monocytes, human THP-1 and primary mouse myeloid cells were cultured under stimulus conditions; GPSM3 was found by immunoblotting to be expressed at highest levels in the mature monocyte. To evaluate the effects of GPSM3 deficiency on a myeloid-dependent autoimmune disease, collagen antibody-induced arthritis (CAIA) was induced in Gpsm3-/- and control mice, which were then analyzed for clinical score, paw swelling, intra-articular proinflammatory markers, and histopathology. Mice lacking GPSM3 were protected from CAIA, and expression of monocyte-representative pro-inflammatory chemokine receptors and cytokines in paws of Gpsm3-/- mice were decreased. Flow cytometry, apoptosis, and transwell chemotaxis experiments were conducted to further characterize the effect of GPSM3 deficiency on survival and chemokine responsiveness of monocytes. GPSM3-deficient myeloid cells had reduced migration ex vivo to CCL2, CX3CL1, and chemerin and enhanced apoptosis in vitro. Our results suggest that GPSM3 is an important regulator of monocyte function involving mechanisms of differentiation, survival, and chemotaxis, and deficiency in GPSM3 expression is protective in acute inflammatory arthritis.
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http://dx.doi.org/10.1016/j.molimm.2012.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563835PMC
June 2013

Cellular targeting in autoimmunity.

Curr Allergy Asthma Rep 2012 Dec;12(6):495-510

Division of Rheumatology, Allergy, and Immunology and the Thurston Arthritis Research Center, University of North Carolina School of Medicine, Chapel Hill, NC 27517, USA.

Many biologic agents that were first approved for the treatment of malignancies are now being actively investigated and used in a variety of autoimmune diseases such as rheumatoid arthritis (RA), antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, systemic lupus erythematosus (SLE), and Sjogren's syndrome. The relatively recent advance of selective immune targeting has significantly changed the management of autoimmune disorders and in part can be attributed to the progress made in understanding effector cell function and their signaling pathways. In this review, we will discuss the recent FDA-approved biologic therapies that directly target immune cells as well as the most promising investigational drugs affecting immune cell function and signaling for the treatment of autoimmune disease.
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http://dx.doi.org/10.1007/s11882-012-0307-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493824PMC
December 2012

Decreased Th17 and antigen-specific humoral responses in CX₃ CR1-deficient mice in the collagen-induced arthritis model.

Arthritis Rheum 2012 May;64(5):1379-87

Department of Medicine, University of North Carolina at Chapel Hill, CB 7280, 3300 Manning Drive, Chapel Hill, NC 27599, USA.

Objective: CX(3) CR1 is a chemokine receptor that uniquely binds to its ligand fractalkine (CX(3) CL1) and has been shown to be important in inflammatory arthritis responses, largely due to its effects on cellular migration. This study was undertaken to test the hypothesis that genetic deficiency of CX(3) CR1 is protective in the chronic inflammatory arthritis model collagen-induced arthritis (CIA). Because CX(3) CR1 is expressed on T cells and antigen-presenting cells, we also examined adaptive immune functions in this model.

Methods: Autoantibody formation, clinical, histologic, T cell proliferative, and cytokine responses were evaluated in wild-type and CX(3) CR1-deficient DBA/1J mice after immunization with heterologous type II collagen (CII).

Results: CX(3) CR1(-/-) mice had an ∼30% reduction in arthritis severity compared to wild-type mice, as determined by 2 independent measures, paw swelling (P < 0.01) and clinical disease score (P < 0.0001). Additionally, compared to wild-type mice, CX(3) CR1(-/-) mice had an ∼50% decrease in anti-CII autoantibody formation (P < 0.05), decreased Th17 intraarticular cytokine expression (P < 0.01 for interleukin-17 [IL-17] and P < 0.001 for IL-23), and decreased total numbers of Th17 cells in inflamed joints (P < 0.05).

Conclusion: Our findings indicate that CX(3) CR1 deficiency is protective in inflammatory arthritis and may have effects that extend beyond migration that involve adaptive immune responses in autoimmune disease.
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http://dx.doi.org/10.1002/art.34320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3238788PMC
May 2012

Second generation automated anti-CCP test better predicts the clinical diagnosis of rheumatoid arthritis.

J Clin Immunol 2012 Feb 10;32(1):131-7. Epub 2011 Nov 10.

McLendon Clinical Laboratories, University of North Carolina Hospitals, Chapel Hill, NC, USA.

Rheumatoid arthritis (RA) is one of the most common systemic autoimmune diseases. The presence of antibodies to cyclic citrullinated peptide (CCP) is better at discriminating RA patients and is also associated with significantly more disease activity compared to serum rheumatoid factor. In this study, we assessed two new automated second generation tests to detect the presence of anti-CCP antibodies in 226 serum samples submitted to the Clinical Immunology Laboratory for anti-CCP antibody testing. We compared CCP antibody results on these samples obtained using the ImmunoCAP 250 (Phadia) and the Architect i2000SR (Abbott Laboratories) instruments to our currently used CCP IgG third generation manual ELISA (Inova Diagnostics). One hundred and fifty-four samples were negative while 52 were positive by all three tests. Eighteen samples were negative by the automated tests but weakly/moderately positive by manual ELISA yielding an overall concordance of 79%. When we compared the discordant test results to patient diagnosis, we observed a better correlation with clinical RA diagnosis for the new automated tests compared to the manual ELISA. These two new anti-CCP antibody tests have the benefit of automation and may have better positive predictive value for the diagnosis of RA than our current manual ELISA.
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http://dx.doi.org/10.1007/s10875-011-9610-yDOI Listing
February 2012

Enhanced Th17-cell responses render CCR2-deficient mice more susceptible for autoimmune arthritis.

PLoS One 2011 4;6(10):e25833. Epub 2011 Oct 4.

Department of Medicine, Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

CCR2 is considered a proinflammatory mediator in many inflammatory diseases such as rheumatoid arthritis. However, mice lacking CCR2 develop exacerbated collagen-induced arthritis. To explore the underlying mechanism, we investigated whether autoimmune-associated Th17 cells were involved in the pathogenesis of the severe phenotype of autoimmune arthritis. We found that Th17 cells were expanded approximately 3-fold in the draining lymph nodes of immunized CCR2(-/-) mice compared to WT controls (p = 0.017), whereas the number of Th1 cells and regulatory T cells are similar between these two groups of mice. Consistently, levels of the Th17 cell cytokine IL-17A and Th17 cell-associated cytokines, IL-6 and IL-1β were approximately 2-6-fold elevated in the serum and 22-28-fold increased in the arthritic joints in CCR2(-/-) mice compared to WT mice (p = 0.04, 0.0004, and 0.01 for IL-17, IL-6, and IL-1β, respectively, in the serum and p = 0.009, 0.02, and 0.02 in the joints). Furthermore, type II collagen-specific antibodies were significantly increased, which was accompanied by B cell and neutrophil expansion in CCR2(-/-) mice. Finally, treatment with an anti-IL-17A antibody modestly reduced the disease severity in CCR2(-/-) mice. Therefore, we conclude that while we detect markedly enhanced Th17-cell responses in collagen-induced arthritis in CCR2-deficient mice and IL-17A blockade does have an ameliorating effect, factors additional to Th17 cells and IL-17A also contribute to the severe autoimmune arthritis seen in CCR2 deficiency. CCR2 may have a protective role in the pathogenesis of autoimmune arthritis. Our data that monocytes were missing from the spleen while remained abundant in the bone marrow and joints of immunized CCR2(-/-) mice suggest that there is a potential link between CCR2-expressing monocytes and Th17 cells during autoimmunity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0025833PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186765PMC
February 2012

Sclerosing mesenteritis successfully treated with a TNF antagonist.

BMJ Case Rep 2010 Dec 20;2010. Epub 2010 Dec 20.

Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.

A 29-year-old female presented with intermittent nausea, vomiting, fevers, abdominal pain and fatigue. CT scans of the abdomen revealed inflammatory changes within the mesentery and small bowel. Histopathology of the mesentery and omentum showed chronic inflammation and fibrosis, supporting a diagnosis of sclerosing mesenteritis. Over the past 2 years, the patient suffered debilitating paroxysmal abdominal pain despite treatment with prednisone, azathioprine, sulfasalazine and narcotics. Additionally, she developed sacroiliitis diagnosed clinically and on radiographs. Intravenous infliximab (5 mg/kg intravenous) was initiated and continued every 6 weeks for 3 years. The patient has since had a dramatic improvement in her back and abdominal symptoms and has tapered off of prednisone, azathioprine and narcotics. Erythrocyte sedimentation rate, anaemia, leukocytosis and radiographic findings improved after initiation with infliximab. In conclusion, the authors report successfully treating sclerosing mesenteritis with sacroiliitis by the addition of infliximab. This may implicate a role for tumour necrosis factor α in disease pathogenesis.
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http://dx.doi.org/10.1136/bcr.07.2010.3145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3029423PMC
December 2010