Publications by authors named "John W Sleasman"

73 Publications

Normal IgH Repertoire Diversity in an Infant with ADA Deficiency After Gene Therapy.

J Clin Immunol 2021 Oct 28;41(7):1597-1606. Epub 2021 Jun 28.

Molecular HIV Host Interaction Section, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.

Purpose: Adenosine deaminase (ADA) deficiency causes severe combined immunodeficiency (SCID) through an accumulation of toxic metabolites within lymphocytes. Recently, ADA deficiency has been successfully treated using lentiviral-transduced autologous CD34+ cells carrying the ADA gene. T and B cell function appears to be fully restored, but in many patients' B cell numbers remain low, and assessments of the immunoglobulin heavy (IgHV) repertoire following gene therapy are lacking.

Methods: We performed deep sequencing of IgHV repertoire in peripheral blood lymphocytes from a child following lentivirus-based gene therapy for ADA deficiency and compared to the IgHV repertoire in healthy infants and adults.

Results: After gene therapy, Ig diversity increased over time as evidenced by V, D, and J gene usage, N-additions, CDR3 length, extent of somatic hypermutation, and Ig class switching. There was the emergence of predominant IgHM, IgHG, and IgHA CDR3 lengths after gene therapy indicating successful oligoclonal expansion in response to antigens. This provides proof of concept for the feasibility and utility of molecular monitoring in following B cell reconstitution following gene therapy for ADA deficiency.

Conclusion: Based on deep sequencing, gene therapy resulted in an IgHV repertoire with molecular diversity similar to healthy infants.
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http://dx.doi.org/10.1007/s10875-021-01034-2DOI Listing
October 2021

Regulation of Intrinsic and Bystander T Follicular Helper Cell Differentiation and Autoimmunity by Tsc1.

Front Immunol 2021 14;12:620437. Epub 2021 Apr 14.

Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, NC, United States.

T Follicular helper (Tfh) cells promote germinal center (GC) B cell responses to develop effective humoral immunity against pathogens. However, dysregulated Tfh cells can also trigger autoantibody production and the development of autoimmune diseases. We report here that Tsc1, a regulator for mTOR signaling, plays differential roles in Tfh cell/GC B cell responses in the steady state and in immune responses to antigen immunization. In the steady state, Tsc1 in T cells intrinsically suppresses spontaneous GC-Tfh cell differentiation and subsequent GC-B cell formation and autoantibody production. In immune responses to antigen immunization, Tsc1 in T cells is required for efficient GC-Tfh cell expansion, GC-B cell induction, and antigen-specific antibody responses, at least in part promoting GC-Tfh cell mitochondrial integrity and survival. Interestingly, in mixed bone marrow chimeric mice reconstituted with both wild-type and T cell-specific Tsc1-deficient bone marrow cells, Tsc1 deficiency leads to enhanced GC-Tfh cell differentiation of wild-type CD4 T cells and increased accumulation of wild-type T regulatory cells and T follicular regulatory cells. Such bystander GC-Tfh cell differentiation suggests a potential mechanism that could trigger self-reactive GC-Tfh cell/GC responses and autoimmunity neighboring GC-Tfh cells.
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http://dx.doi.org/10.3389/fimmu.2021.620437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079652PMC
June 2021

Differential controls of MAIT cell effector polarization by mTORC1/mTORC2 via integrating cytokine and costimulatory signals.

Nat Commun 2021 04 1;12(1):2029. Epub 2021 Apr 1.

Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC, USA.

Mucosal-associated invariant T (MAIT) cells have important functions in immune responses against pathogens and in diseases, but mechanisms controlling MAIT cell development and effector lineage differentiation remain unclear. Here, we report that IL-2/IL-15 receptor β chain and inducible costimulatory (ICOS) not only serve as lineage-specific markers for IFN-γ-producing MAIT1 and IL-17A-producing MAIT17 cells, but are also important for their differentiation, respectively. Both IL-2 and IL-15 induce mTOR activation, T-bet upregulation, and subsequent MAIT cell, especially MAIT1 cell, expansion. By contrast, IL-1β induces more MAIT17 than MAIT1 cells, while IL-23 alone promotes MAIT17 cell proliferation and survival, but synergizes with IL-1β to induce strong MAIT17 cell expansion in an mTOR-dependent manner. Moreover, mTOR is dispensable for early MAIT cell development, yet pivotal for MAIT cell effector differentiation. Our results thus show that mTORC2 integrates signals from ICOS and IL-1βR/IL-23R to exert a crucial role for MAIT17 differentiation, while the IL-2/IL-15R-mTORC1-T-bet axis ensures MAIT1 differentiation.
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http://dx.doi.org/10.1038/s41467-021-22162-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016978PMC
April 2021

Thymic Epithelial Cell-Derived IL-15 and IL-15 Receptor α Chain Foster Local Environment for Type 1 Innate Like T Cell Development.

Front Immunol 2021 1;12:623280. Epub 2021 Mar 1.

Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC, United States.

Expression of tissue-restricted antigens (TRAs) in thymic epithelial cells (TECs) ensures negative selection of highly self-reactive T cells to establish central tolerance. Whether some of these TRAs could exert their canonical biological functions to shape thymic environment to regulate T cell development is unclear. Analyses of publicly available databases have revealed expression of transcripts at various levels of many cytokines and cytokine receptors such as IL-15, IL-15Rα, IL-13, and IL-23a in both human and mouse TECs. Ablation of either IL-15 or IL-15Rα in TECs selectively impairs type 1 innate like T cell, such as NKT1 and γδT1 cell, development in the thymus, indicating that TECs not only serve as an important source of IL-15 but also trans-present IL-15 to ensure type 1 innate like T cell development. Because type 1 innate like T cells are proinflammatory, our data suggest the possibility that TEC may intrinsically control thymic inflammatory innate like T cells to influence thymic environment.
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http://dx.doi.org/10.3389/fimmu.2021.623280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957058PMC
September 2021

Trajectories of Depressive Symptoms, Neurocognitive Function, and Viral Suppression With Antiretroviral Therapy Among Youth With HIV Over 36 months.

J Acquir Immune Defic Syndr 2021 06;87(2):851-859

Department of Psychiatry, University of California San Diego, La Jolla, CA.

Background: Depression and neurocognitive impairment are highly prevalent among persons living with HIV and associated with poorer clinical outcomes; however, longitudinal studies of depression-neurocognition relationships in youth living with HIV (YLWH), and the role of antiretroviral therapy (ART), are lacking. This study tested whether (1) depressive symptomatology, across somatic, cognitive, and affective symptom domains, improved with ART and (2) more severe depressive symptoms at baseline were associated with poorer neurocognitive function and poorer HIV suppression.

Setting: Data were collected from 181 YLWH (18-24 years) who were treatment-naive, a subset of whom (n = 116) initiated ART.

Methods: Participants were categorized into elevated (DS) or nonelevated (non-DS) depressive symptom groups at entry (Beck Depression Inventory-II ≥14) and followed for 36 months. Neurocognition (5-domain battery) and depressive symptoms were repeatedly assessed. Longitudinal models examined depressive symptomatology, neurocognition, and odds of HIV nonsuppression by group.

Results: Greater improvements in depressive symptoms were observed in the DS group over 36 months [beta = -0.14, (-0.24 to -0.03)], particularly within cognitive and affective domains. Verbal learning performance increased in the DS group [beta = 0.13, (0.01 to 0.24)], whereas psychomotor function improved somewhat in the non-DS group [beta = -0.10, (-0.22 to 0.00)]. Adjusted for ART adherence, odds of HIV nonsuppression did not significantly differ by group [odds ratio = 0.22, (0.04 to 1.23)]; however, greater somatic symptoms at study entry were associated with an increased risk of nonsuppression over time [odds ratio = 2.33 (1.07 to 5.68)].

Conclusion: Depressive symptoms were associated with differential neurocognitive trajectories, and somatic depressive symptoms at baseline may predict poorer subsequent HIV suppression. Identifying and treating depressive symptoms at ART initiation may benefit neurocognitive and clinical outcomes in YLWH.
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http://dx.doi.org/10.1097/QAI.0000000000002653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131211PMC
June 2021

Vasculitis as a Major Morbidity Factor in Patients With Partial RAG Deficiency.

Front Immunol 2020 21;11:574738. Epub 2020 Oct 21.

University of South Florida at Johns Hopkins All Children's Hospital, Saint Petersburg, FL, United States.

Vasculitis can be a life-threatening complication associated with high mortality and morbidity among patients with primary immunodeficiencies (PIDs), including variants of severe and combined immunodeficiencies ((S)CID). Our understanding of vasculitis in partial defects in recombination activating gene (RAG) deficiency, a prototype of (S)CIDs, is limited with no published systematic evaluation of diagnostic and therapeutic modalities. In this report, we sought to establish the clinical, laboratory features, and treatment outcome of patients with vasculitis due to partial RAG deficiency. Vasculitis was a major complication in eight (13%) of 62 patients in our cohort with partial RAG deficiency with features of infections and immune dysregulation. Vasculitis occurred early in life, often as first sign of disease (50%) and was complicated by significant end organ damage. Viral infections often preceded the onset of predominately non-granulomatous-small vessel vasculitis. Autoantibodies against cytokines (IFN-α, -ω, and IL-12) were detected in a large fraction of the cases tested (80%), whereas the majority of patients were anti-neutrophil cytoplasmic antibodies (ANCA) negative (>80%). Genetic diagnosis of RAG deficiency was delayed up to 2 years from the onset of vasculitis. Clinical cases with sole skin manifestation responded well to first-line steroid treatment, whereas systemic vasculitis with severe end-organ complications required second-line immunosuppression and/or hematopoietic stem cell transplantation (HSCT) for definitive management. In conclusion, our data suggest that vasculitis in partial RAG deficiency is prevalent among patients with partial RAG deficiency and is associated with high morbidity. Therefore, partial RAG deficiency should be included in the differential diagnosis of patients with early-onset systemic vasculitis. Diagnostic serology may be misleading with ANCA negative findings, and search for conventional autoantibodies should be extended to include those targeting cytokines.
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http://dx.doi.org/10.3389/fimmu.2020.574738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609967PMC
June 2021

Benefits of Prophylactic Short-Course Immune Tolerance Induction in Patients With Infantile Pompe Disease: Demonstration of Long-Term Safety and Efficacy in an Expanded Cohort.

Front Immunol 2020 6;11:1727. Epub 2020 Aug 6.

Division of Medical Genetics, Department of Pediatrics, Duke University Health System, Durham, NC, United States.

Immune tolerance induction (ITI) with a short-course of rituximab, methotrexate, and/or IVIG in the enzyme replacement therapy (ERT)-naïve setting has prolonged survival and improved clinical outcomes in patients with infantile Pompe disease (IPD) lacking endogenous acid-alpha glucosidase (GAA), known as cross-reactive immunologic material (CRIM)-negative. In the context of cancer therapy, rituximab administration results in sustained B-cell depletion in 83% of patients for up to 26-39 weeks with B-cell reconstitution beginning at approximately 26 weeks post-treatment. The impact of rituximab on serum immunoglobulin levels is not well studied, available data suggest that rituximab can cause persistently low immunoglobulin levels and adversely impact vaccine responses. Data on a cohort of IPD patients who received a short-course of ITI with rituximab, methotrexate, and IVIG in the ERT-naïve setting and had ≥6 months of follow-up were retrospectively studied. B-cell quantitation, ANC, AST, ALT, immunization history, and vaccine titers after B-cell reconstitution were reviewed. Data were collected for 34 IPD patients (25 CRIM-negative and 9 CRIM-positive) with a median age at ERT initiation of 3.5 months (0.1-11.0 months). B-cell reconstitution, as measured by normalization of CD19%, was seen in all patients ( = 33) at a median time of 17 weeks range (11-55 weeks) post-rituximab. All maintained normal CD19% with the longest follow-up being 248 weeks post-rituximab. 30/34 (88%) maintained negative/low anti-rhGAA antibody titers, even with complete B-cell reconstitution. Infections during immunosuppression were reported in five CRIM-negative IPD patients, all resolved satisfactorily on antibiotics. There were no serious sequelae or deaths. Of the 31 evaluable patients, 27 were up to date on age-appropriate immunizations. Vaccine titers were available for 12 patients after B-cell reconstitution and adequate humoral response was observed in all except an inadequate response to the Pneumococcal vaccine ( = 2). These data show the benefits of short-course prophylactic ITI in IPD both in terms of safety and efficacy. Data presented here are from the youngest cohort of patients treated with rituximab and expands the evidence of its safety in the pediatric population.
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http://dx.doi.org/10.3389/fimmu.2020.01727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424004PMC
April 2021

Negative control of diacylglycerol kinase ζ-mediated inhibition of T cell receptor signaling by nuclear sequestration in mice.

Eur J Immunol 2020 11 6;50(11):1729-1745. Epub 2020 Jul 6.

Division of Allergy and Immunology, Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, North Carolina.

Diacylglycerol kinases (DGKs) play important roles in restraining diacylglycerol (DAG)-mediated signaling. Within the DGK family, the ζ isoform appears to be the most important isoform in T cells for controlling their development and function. DGKζ has been demonstrated to regulate T cell maturation, activation, anergy, effector/memory differentiation, defense against microbial infection, and antitumor immunity. Given its critical functions, DGKζ function should be tightly regulated to ensure proper signal transduction; however, mechanisms that control DGKζ function are still poorly understood. We report here that DGKζ dynamically translocates from the cytosol into the nuclei in T cells after TCR stimulation. In mice, DGKζ mutant defective in nuclear localization displayed enhanced ability to inhibit TCR-induced DAG-mediated signaling in primary T cells, maturation of conventional αβT and iNKT cells, and activation of peripheral T cells compared with WT DGKζ. Our study reveals for the first time nuclear sequestration of DGKζ as a negative control mechanism to spatially restrain it from terminating DAG mediated signaling in T cells. Our data suggest that manipulation of DGKζ nucleus-cytosol shuttling as a novel strategy to modulate DGKζ activity and immune responses for treatment of autoimmune diseases and cancer.
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http://dx.doi.org/10.1002/eji.201948442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705894PMC
November 2020

Higher soluble CD14 levels are associated with lower visuospatial memory performance in youth with HIV.

AIDS 2019 12;33(15):2363-2374

aDivision of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Duke University School of Medicine, Durham bUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina cUniversity of California San Diego, La Jolla, California dChildren's Diagnostic & Treatment Center, Fort Lauderdale, Florida eHunter College, CUNY, New York, New York fUniversity of Houston, Houston, Texas gNIH, Bethesda, Maryland, USA.

Objective: HIV-associated neurocognitive disorders persist despite early antiretroviral therapy (ART) and optimal viral suppression. We examined the relationship between immunopathogenesis driven by various pathways of immune activation and discrete neurocognitive performance domains in youth with HIV (YWH).

Design: Observational cross-sectional study.

Methods: YWH, ages 20-28 years, enrolled in Adolescent Medicine Trials Network 071/101 were assessed for biomarkers of macrophage, lymphocyte activation, and vascular inflammation using ELISA/multiplex assays. Standardized neurocognitive tests were performed, and demographically adjusted z-scores were combined to form indices of attention, motor, executive function, verbal, and visuospatial memory. Cross-sectional analysis of the relationship between 18 plasma inflammatory biomarkers and each neurocognitive domain was performed. Linear regression models were fit for each combination of log-transformed biomarker value and neurocognitive domain score, and were adjusted for demographics, socioeconomic status, substance use, depression, CD4 T-cell count, HIV viral load, and ART status.

Results: Study included 128 YWH [mean age 23.8 (SD 1.7) years, 86% men, 68% African American]. Verbal and visuospatial memory domains were most significantly impaired in the cohort (z = -1.59 and -1.0, respectively). Higher sCD14 was associated with impaired visuospatial memory, which remained robust after adjusting for other biomarkers, demographics, and HIV-associated covariates. Among biomarkers of vascular inflammation, sICAM-1 was negatively associated with verbal memory and attention, whereas sVCAM-1 was positively associated with executive function and visuospatial memory. Specific neurocognitive domains were not associated with sCD163, LPS, or CCL2 levels.

Conclusion: Impaired visuospatial memory in YWH is associated with immune activation, as reflected by higher sCD14.
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http://dx.doi.org/10.1097/QAD.0000000000002371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905124PMC
December 2019

Immune globulin subcutaneous, human - klhw 20% for primary humoral immunodeficiency: an open-label, Phase III study.

Immunotherapy 2019 11 17;11(16):1371-1386. Epub 2019 Oct 17.

Good Samaritan Medical Center; 1309 N Flagler Dr, West Palm Beach, FL 33401, USA.

This prospective, Phase III study assessed the pharmacokinetics (PK), safety and tolerability of immune globulin subcutaneous, human - klhw 20% solution (IGSC-C 20%) in participants with primary humoral immunodeficiency (PI), compared with immune globulin injection (human), 10% caprylate/chromatography purified (IGIV-C 10%). About 53 participants enrolled. Total 44 received IGIV-C 10% in the run-in phase and then entered the IV phase (with an additional nine who were already receiving IGIV-C 10% and entered the IV phase directly) for steady-state IV PK assessments. Total 49 entered the SC phase (weekly doses of IGSC-C 20% for ∼24 weeks). The PK profiles of IGIV-C 10% and IGSC-C 20% and their safety and tolerability parameters were compared. At a dose adjustment factor of 1.37, IGSC-C 20% provided comparable (noninferior and bioequivalent) overall total immunoglobulin G exposure to IGIV-C 10% over an equal time interval. About 33 participants reported 79 adverse events during run-in + IV phases; 41 participants reported 141 adverse events during the SC phase, with most being local infusion site reactions. The majority of infusion site reactions were mild to moderate in severity. IGSC-C 20% was bioequivalent to IGIV-C 10% and was well tolerated, with a safety profile comparable with IGIV-C 10%, in this study. Trial registration: ClinicalTrials.gov identifier: NCT02604810.
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http://dx.doi.org/10.2217/imt-2019-0159DOI Listing
November 2019

Heterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis.

Am J Hum Genet 2019 09 22;105(3):549-561. Epub 2019 Aug 22.

Division of Allergy and Immunology, Department of Pediatrics, University of Utah, Salt Lake City, UT 84112, USA.

FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4 but lower than normal CD8 cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1 (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth.
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http://dx.doi.org/10.1016/j.ajhg.2019.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731368PMC
September 2019

Tenofovir Has Minimal Effect on Biomarkers of Bone Health in Youth with HIV Receiving Initial Antiretroviral Therapy.

AIDS Res Hum Retroviruses 2019 08 27;35(8):746-754. Epub 2019 Jun 27.

1Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina.

Both HIV infection and tenofovir disoproxil fumarate (TDF) treatment adversely impact bone metabolism and may lead to osteopenia, which has critical implications for youth with HIV (YWH). This study evaluates changes in the biomarkers of bone metabolism and inflammation among YWH receiving initial treatment with TDF- and non-TDF-containing antiretroviral therapies (ARTs). YWH [ = 23, median age 21 years (range 18-24), 87% male, 61% African American] were assessed for inflammatory and bone metabolism biomarkers at enrollment, after 48 weeks of TDF-containing ART, and 96 weeks of ART without TDF with continued viral suppression. Spearman's rank correlation evaluated biomarker associations. Bone alkaline phosphatase, parathyroid hormone, and osteopontin increased after TDF treatment. All fell after TDF was discontinued. Levels of RANKL and osteoprotegerin did not change throughout the study. There was little correlation between biomarkers of bone metabolism and either macrophage or lymphocyte activation at any time point. Our results establish baseline associations between bone metabolism and immune biomarkers for this population, and find that before CD4 T cell decline chronic inflammation does not perturb biomarkers of bone metabolism among YWH. The adverse effects of TDF on bone health may be marginal for YWH at the early stages of disease.
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http://dx.doi.org/10.1089/AID.2018.0270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688113PMC
August 2019

Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency.

J Allergy Clin Immunol Pract 2019 Jul - Aug;7(6):1970-1985.e4. Epub 2019 Mar 12.

Division of Pediatric Blood and Marrow Transplantation, Duke University School of Medicine, Durham, NC.

Background: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series.

Objective: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency.

Methods: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology.

Results: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients.

Conclusions: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.
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http://dx.doi.org/10.1016/j.jaip.2019.02.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612449PMC
September 2020

Funding Pediatric Subspecialty Training: Are T32 Grants the Future?

J Pediatr 2018 11;202:4-7.e1

Division of Pediatric Allergy and Immunology, Department of Pediatrics, Duke University, Durham, NC.

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http://dx.doi.org/10.1016/j.jpeds.2018.08.035DOI Listing
November 2018

Sexually transmitted infections and immune activation among HIV-infected but virally suppressed youth on antiretroviral therapy.

J Clin Virol 2018 05 7;102:7-11. Epub 2018 Feb 7.

Duke University, School of Medicine, Department of Pediatrics, 133 MSRB I, DUMC Box 2644, Durham, NC, 27710, United States.

Background: Human immunodeficiency virus (HIV) infection is associated with chronic immune activation, and concurrent sexually transmitted infections (STIs) may increase immune activation.

Objectives: Because HIV-infected youth are at high risk of STIs and little is known about the impact of STIs on immune activation in HIV-infected youth, we conducted an exploratory study examining the association between STIs and systemic inflammation and immune activation among HIV-infected adolescents.

Study Design: Forty-nine behaviorally infected U.S. youth ages 18-24 years with baseline CD4 T-cells >350 who maintained viral suppression on therapy by week 48 were included. Evaluation for STIs (herpes simplex virus [HSV], Chlamydia trachomatis, syphilis, Neisseria gonorrhoeae) was conducted as standard of care and reported on case report forms. Measures of T-cell subsets, systemic immune activation, and soluble factors were examined at week 48 for differences between participants with an STI diagnosis during the 48 weeks compared to those without an STI.

Results: Forty-three participants (88%) were male; 57% had baseline CD4+ T-cell counts >500 cells/mm. Eighteen youth were reported to have ≥1 STI. At week 48, participants with STIs demonstrated lower CD4 T-cell counts (any STI vs. no STI, p = 0.024; HSV vs. no STI, p = 0.022) and evidence of increased systemic immune activation, including higher CD57 intensity, higher HLA-DR intensity, and lower CD28 percentage, when compared to those without STIs. There were no differences in soluble factors between STI groups.

Conclusions: Results indicate novel activation of CD4 T-cells among HIV-infected youth who have STIs other than HSV, which may contribute to disease progression.
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http://dx.doi.org/10.1016/j.jcv.2018.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889960PMC
May 2018

Soluble CD14, CD163, and CD27 biomarkers distinguish ART-suppressed youth living with HIV from healthy controls.

J Leukoc Biol 2018 04 29;103(4):671-680. Epub 2018 Jan 29.

Department of Pediatrics, Division of Allergy, Immunology and Pulmonary Medicine, School of Medicine, Duke University, Durham, North Carolina, USA.

Objective: To define inflammatory pathways in youth living with HIV infection (YLWH), assessments of biomarkers associated with lymphocyte and macrophage activation, vascular injury, or bone metabolism were performed in YLWH in comparison with healthy controls (HC).

Design: Longitudinal multicenter study comparing biomarkers in YLWH suppressed on antiretroviral therapy (ART), those with ongoing viral replication, and HC were compared using single blood samples obtained at end of study.

Methods: Twenty-three plasma proteins were measured by ELISA or multiplex assays. Principal component analysis (PCA) was used to define contributions of individual biomarkers to define outcome groups.

Results: The study cohort included 129 predominantly African American, male participants, 21-25 years old at entry. Nine biomarkers of lymphocyte and macrophage activation and cardiovascular injury differed between HC and YLWH. Significant positive correlations were identified between lymphocyte and macrophage activation biomarkers among HC and YLWH. Correlations distinct to YLWH were predominantly between biomarkers of macrophage and vascular inflammation. PCA of outcome groups showed HC and suppressed YLWH clustering together for lymphocyte activation biomarkers, whereas macrophage activation markers showed all YLWH clustering distinct from HC. Cardiovascular biomarkers were indistinguishable across groups. Averaged variable importance projection to assess single biomarkers that maximally contribute to discriminate among outcome groups identified soluble CD27, CD14, and CD163 as the 3 most important with TNFα and LPS also highly relevant in providing separation.

Conclusions: Soluble inflammatory and lymphocyte biomarkers sufficiently distinguish YLWH from HC. Persistent macrophage activation biomarkers may provide a means to monitor consequences of HIV infection in fully suppressed YLWH.
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http://dx.doi.org/10.1002/JLB.3A0717-294RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528780PMC
April 2018

Association Between Breast Milk Bacterial Communities and Establishment and Development of the Infant Gut Microbiome.

JAMA Pediatr 2017 07;171(7):647-654

Department of Pediatrics, University of California, Los Angeles.

Importance: Establishment of the infant microbiome has lifelong implications on health and immunity. Gut microbiota of breastfed compared with nonbreastfed individuals differ during infancy as well as into adulthood. Breast milk contains a diverse population of bacteria, but little is known about the vertical transfer of bacteria from mother to infant by breastfeeding.

Objective: To determine the association between the maternal breast milk and areolar skin and infant gut bacterial communities.

Design, Setting, And Participants: In a prospective, longitudinal study, bacterial composition was identified with sequencing of the 16S ribosomal RNA gene in breast milk, areolar skin, and infant stool samples of 107 healthy mother-infant pairs. The study was conducted in Los Angeles, California, and St Petersburg, Florida, between January 1, 2010, and February 28, 2015.

Exposures: Amount and duration of daily breastfeeding and timing of solid food introduction.

Main Outcomes And Measures: Bacterial composition in maternal breast milk, areolar skin, and infant stool by sequencing of the 16S ribosomal RNA gene.

Results: In the 107 healthy mother and infant pairs (median age at the time of specimen collection, 40 days; range, 1-331 days), 52 (43.0%) of the infants were male. Bacterial communities were distinct in milk, areolar skin, and stool, differing in both composition and diversity. The infant gut microbial communities were more closely related to an infant's mother's milk and skin compared with a random mother (mean difference in Bray-Curtis distances, 0.012 and 0.014, respectively; P < .001 for both). Source tracking analysis was used to estimate the contribution of the breast milk and areolar skin microbiomes to the infant gut microbiome. During the first 30 days of life, infants who breastfed to obtain 75% or more of their daily milk intake received a mean (SD) of 27.7% (15.2%) of the bacteria from breast milk and 10.3% (6.0%) from areolar skin. Bacterial diversity (Faith phylogenetic diversity, P = .003) and composition changes were associated with the proportion of daily breast milk intake in a dose-dependent manner, even after the introduction of solid foods.

Conclusions And Relevance: The results of this study indicate that bacteria in mother's breast milk seed the infant gut, underscoring the importance of breastfeeding in the development of the infant gut microbiome.
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http://dx.doi.org/10.1001/jamapediatrics.2017.0378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710346PMC
July 2017

Novel pathogenic variants in FOXP3 in fetuses with echogenic bowel and skin desquamation identified by ultrasound.

Am J Med Genet A 2017 May 20;173(5):1219-1225. Epub 2017 Mar 20.

Greenwood Genetic Center, Greenwood, South Carolina.

Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is a rare, X-linked recessive disease that affects regulatory T cells (Tregs) resulting in diarrhea, enteropathy, eczema, and insulin-dependent diabetes mellitus. IPEX syndrome is caused by pathogenic alterations in FOXP3 located at Xp11.23. FOXP3 encodes a transcription factor that interacts with several partners, including NFAT and NF-κB, and is necessary for the proper cellular differentiation of Tregs. Although variable, the vast majority of IPEX syndrome patients have onset of disease during infancy with severe enteropathy. Only five families with prenatal presentation of IPEX syndrome have been reported. Here, we present two additional prenatal onset cases with novel inherited frameshift pathogenic variants in FOXP3 that generate premature stop codons. Ultrasound findings in the first patient identified echogenic bowel, echogenic debris, scalp edema, and hydrops. In the second patient, ultrasound findings included polyhydramnios with echogenic debris, prominent fluid-filled loops of bowel, and echogenic bowel. These cases further broaden the phenotypic spectrum of IPEX syndrome by describing previously unappreciated prenatal ultrasound findings associated with the disease.
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http://dx.doi.org/10.1002/ajmg.a.38144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515470PMC
May 2017

Brief Report: Antibody Responses to Quadrivalent HPV Vaccination in HIV-Infected Young Women as Measured by Total IgG and Competitive Luminex Immunoassay.

J Acquir Immune Defic Syndr 2017 06;75(2):241-245

*Division of Adolescent and Transition Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH; †Westat, Rockville, MD; ‡Pediatric, Adolescent and Maternal AIDS Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD; and §Division of Allergy and Immunology and Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Duke University School of Medicine, Durham, NC.

We compared antibody responses of HIV-infected young women to the human papillomavirus (HPV) 6, 11, 16, and 18 vaccine using total immunoglobulin (Ig) G Luminex immunoassay (LIA) and competitive Luminex immunoassay (cLIA) assays. HPV18 seropositivity after HPV vaccination as measured with IgG LIA remained high (98%) 48 weeks after vaccination, in contrast with seropositivity as measured with cLIA (73%). Seropositivity rates at week 48 as measured by both IgG LIA and cLIA remained high for HPV6, 11, and 16 (93.5%-100%). These results suggest that the lower rate of seropositivity to HPV18 when cLIA vs. IgG LIA is used is a function of the assay and does not imply lower vaccine immunogenicity.
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http://dx.doi.org/10.1097/QAI.0000000000001355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429191PMC
June 2017

HIV-1 Infection Primes Macrophages Through STAT Signaling to Promote Enhanced Inflammation and Viral Replication.

AIDS Res Hum Retroviruses 2017 07 12;33(7):690-702. Epub 2017 Apr 12.

1 Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida , Gainesville, Florida.

Macrophages play important roles in HIV-1 pathogenesis as targets for viral replication and mediators of chronic inflammation. Similar to IFNγ-priming, HIV-1 primes macrophages, resulting in hyperresponsiveness to subsequent toll-like receptor (TLR) stimulation and increased inflammatory cytokine production. However, the specific molecular mechanism of HIV-1 priming and whether cells must be productively infected or if uninfected bystander cells also are primed by HIV-1 remains unclear. To explore these questions, human macrophages were primed by IFNγ or infected with HIV-1 before activation by TLR ligands. Transcriptome profiling by microarray revealed a gene expression profile for IFNγ-primed cells that was further modulated by the addition of lipopolysaccharide (LPS). HIV-1 infection elicited a gene expression profile that correlated strongly with the profile induced by IFNγ (r = .679, p = .003). Similar to IFNγ, HIV-1 enhanced TLR ligand-induced tumor necrosis factor (TNF) protein expression and release. Increased TNF production was limited to productively infected cells. Specific signal transducer and activator of transcription (STAT)1 and STAT3 inhibitors suppressed HIV-1-mediated enhancement of TLR-induced TNF expression as well as HIV-1 replication. These findings indicate that viral replication and inflammation are linked through a common IFNγ-like, STAT-dependent pathway and that HIV-1-induced STAT1 and STAT3 signaling are involved in both inflammation and HIV-1 replication. Systemic innate immune activation is a hallmark of active HIV-1 replication. Our study shows that inflammation may develop as a consequence of HIV-1 triggering STAT-IFN pathways to support viral replication.
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http://dx.doi.org/10.1089/AID.2016.0273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512335PMC
July 2017

The Regulatory B Cell Compartment Expands Transiently During Childhood and Is Contracted in Children With Autoimmunity.

Arthritis Rheumatol 2017 01;69(1):225-238

Duke University Medical Center, Durham, North Carolina.

Objective: Regulatory B cells that inhibit immune responses through interleukin-10 (IL-10) secretion (B10 cells) have been characterized in adult subjects with autoimmune disease. The aim of this study was to characterize B10 cells in individuals across the entire age range of normal human development and changes in their frequency and numbers in children with autoimmunity.

Methods: The phenotype and numbers of B10 cells in blood were examined in healthy individuals and children with autoimmunity, using flow cytometry. B10 cell function was assessed by measuring the effect of B cell-derived IL-10 on interferon-γ (IFNγ) expression by CD4+ T cells. Serum cytokine levels were measured by enzyme-linked immunosorbent assay.

Results: The frequency of B10 cells transiently increased during childhood, when up to 30% of B cells were competent to produce IL-10, compared with the low frequencies in healthy newborns (3-4%) and adults (7-9%). The surface phenotype of B10 cells in children revealed age-dependent variability. B10 cells from children were distinct from proinflammatory cytokine-producing B cells and down-regulated IFNγ production by CD4+ T cells in vitro. Compared with age-matched healthy controls, children with autoimmunity had lower numbers and frequencies of B10 cells (decreased by 39% and 48%, respectively), higher IFNγ levels, and lower IL-21 levels in serum. IFNγ inhibited, whereas IL-21 promoted, B cell IL-10 competence in vitro.

Conclusion: B10 cells, a functionally defined cell subset with a variable surface phenotype reflective of overall B cell development, transiently expand during childhood. B10 cell frequencies and numbers were decreased in children with autoimmunity, which may be explained in part by alterations in serum IFNγ and IL-21 that differentially regulate B10 cell development.
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http://dx.doi.org/10.1002/art.39820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5195882PMC
January 2017

Antiretroviral treatment initiation does not differentially alter neurocognitive functioning over time in youth with behaviorally acquired HIV.

J Neurovirol 2016 Apr 13;22(2):218-30. Epub 2015 Oct 13.

Children's Diagnostic & Treatment Center, Inc., Ft. Lauderdale, FL, USA.

Although youth living with behaviorally acquired HIV (YLWH) are at risk for cognitive impairments, the relationship of impairments to HIV and potential to improve with antiretroviral therapy (ART) are unclear. This prospective observational study was designed to examine the impact of initiation and timing of ART on neurocognitive functioning in YLWH in the Adolescent Medicine Trials Network for HIV/AIDS Interventions. Treatment naïve YLWH age 18-24 completed baseline and four additional assessments of attention/working memory, complex executive, and motor functioning over 3 years. Group 1 co-enrolled in an early ART initiation study and initiated ART at enrollment CD4 >350 (n = 56); group 2 had CD4 >350 and were not initiating ART (n = 66); group 3 initiated ART with CD4 <350 (n = 59) per standard of care treatment guidelines at the time. Treatment was de-intensified to boosted protease inhibitor monotherapy at 48 weeks for those in group 1 with suppressed viral load. Covariates included demographic, behavioral, and medical history variables. Analyses used hierarchical linear modeling. All groups showed improved performance with peak at 96 weeks in all three functional domains. Trajectories of change were not significantly associated with treatment, timing of treatment initiation, or ART de-intensification. Demographic variables and comorbidities were associated with baseline functioning but did not directly interact with change over time. In conclusion, YLWH showed improvement in neurocognitive functioning over time that may be related to practice effects and nonspecific impact of study participation. Neither improvement nor decline in functioning was associated with timing of ART initiation or therapy de-intensification.
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http://dx.doi.org/10.1007/s13365-015-0389-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4781894PMC
April 2016

Increased inflammation but similar physical composition and function in older-aged, HIV-1 infected subjects.

BMC Immunol 2015 Jul 24;16:43. Epub 2015 Jul 24.

Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Box 100275, Gainesville, FL, 32610-0275, USA.

Background: Systemic immune activation (inflammation) and immunosenescence develop in some people with advancing age. This process, known as "inflamm-aging," is associated with physical frailty and sarcopenia. Meanwhile, successful antiretroviral therapy has led to a growing number of older HIV-1-infected individuals who face both age-related and HIV-1-related inflammation, which may synergistically promote physical decline, including frailty and sarcopenia. The purpose of our study was to determine if inflammation during treated HIV-1 infection worsens physical impairment in older individuals.

Methods: We determined the severity of HIV-associated inflammation and physical performance (strength and endurance) in 21 older HIV-infected individuals (54-69 years) receiving suppressive antiretroviral therapy, balanced for confounding variables including age, anthropometrics, and co-morbidities with 10 uninfected control individuals. Biomarkers for microbial translocation (lipopolysaccharide [LPS]), inflammation (soluble CD14 [sCD14], osteopontin, C-reactive protein [CRP], interleukin-6 [IL-6], soluble ICAM-1 [sICAM-1] and soluble VCAM-1 [sVCAM-1]), and coagulopathy (D-dimer) were assayed in plasma. Activation phenotypes of CD4(+)T cells, CD8(+) T cells and monocytes were measured by flow cytometry. Physical performance was measured by 400 m walking speed, a short physical performance battery [SPPB], and lower extremity muscle strength and fatigue.

Results: Overall physical function was similar in the uninfected and HIV-infected groups. Compared to uninfected individuals, the HIV-infected group had elevated levels of sCD14 (P < 0.001), CRP (P < 0.001) and IL-6 (P = 0.003) and an increased frequency of CD4(+) and CD8(+) T cells with an immunosenescent CD57(+) phenotype (P = 0.004 and P = 0.043, respectively). Neither plasma inflammatory biomarkers nor CD57(+) T cells correlated with CD4(+) T cell counts. Furthermore, none of the elevated inflammatory biomarkers in the HIV-infected subjects were associated with any of the physical performance results.

Conclusions: When age-related co-morbidities were carefully balanced between the uninfected and HIV-infected groups, no evidence of inflammation-associated physical impairment was detected. Despite careful balancing for age, BMI, medications and co-morbidities, the HIV-infected group still displayed evidence of significant chronic inflammation, including elevated sCD14, CRP, IL-6 and CD57(+) T cells, although the magnitude of this inflammation was unrelated to physical impairment.
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http://dx.doi.org/10.1186/s12865-015-0106-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513956PMC
July 2015

Δ(9)-Tetrahydrocannabinol (THC) enhances lipopolysaccharide-stimulated tissue factor in human monocytes and monocyte-derived microvesicles.

J Inflamm (Lond) 2015 12;12:39. Epub 2015 Jun 12.

Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, 2033 Mowry Road, Gainesville, FL 32610-3663 USA.

Background: Immunomodulatory effects in humans of Δ(9-)Tetrahydrocannabinol (THC), the psychoactive component of marijuana are controversial. Tissue factor (TF), the activator of the extrinsic coagulation cascade, is increased on circulating activated monocytes and is expressed on microvesicles released from activated monocytes during inflammatory conditions, which perpetuate coagulopathies in a number of diseases. In view of the increased medicinal use of marijuana, effects of THC on human monocytes and monocyte-derived microvesicles activated by lipopolysaccharide (LPS) were investigated.

Findings: Peak levels of TF procoagulant activity developed in monocytes or microvesicles 6 h following LPS treatment and were unaltered by THC. After 24 h of LPS stimulation, TF activity declined in control-treated or untreated cells and microvesicles, but persisted with THC treatment. Peak TF protein occurred within 6 h of LPS treatment independent of THC; by 24 h, TF protein declined to almost undetectable levels without THC, but was about 4-fold greater with THC. Steady-state TF mRNA levels were similar up to 2 h in the presence of LPS with or without THC, while 10-fold greater TF mRNA levels persisted over 3-24 h with THC treatment. Activation of MAPK or NF-κB pathways was unaltered by THC treatment and inflammatory cytokine IL-6 levels were unchanged. In contrast, TNF and IL-8 levels were enhanced by 20-50 %.

Conclusions: THC enhances TF expression in activated monocytes resulting in elevated procoagulant activity. Marijuana use could potentiate coagulopathies in individuals with chronic immune activation such as HIV-1 infection or inflammatory bowel disease.
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http://dx.doi.org/10.1186/s12950-015-0084-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469459PMC
June 2015

Immune Reconstitution but Persistent Activation After 48 Weeks of Antiretroviral Therapy in Youth With Pre-Therapy CD4 >350 in ATN 061.

J Acquir Immune Defic Syndr 2015 May;69(1):52-60

*New York University School of Medicine, New York, NY; †The Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, Bethesda, MD; ‡Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA; §Westat, Rockville, MD; ‖University of Alabama at Birmingham; ¶Johns Hopkins School of Medicine; #University of South Florida School of Medicine, Tampa, FL; **University of Florida Health Science Center, Gainsville, FL; and ††Duke University School of Medicine, Durham, NC.

Background: Measures of immune outcomes in youth who initiate combination antiretroviral therapy (cART) early in HIV infection are limited.

Design: Adolescent Trials Network 061 examined changes over 48 weeks of cART in T-cell subsets and markers of T-cell and macrophage activation in subjects with pre-therapy CD4 > 350 cells/mm. All subjects had optimal viral suppression from weeks 24 through 48.

Methods: Subjects (n = 48) initiated cART with tenofovir/emtricitabine plus ritonavir-boosted atazanavir. Data were collected at baseline and weeks 12, 24, and 48. Trends were compared to uninfected controls.

Results: Significant increases over 48 weeks were noted in all CD4 populations, including total, naive, central memory (CM), and effector memory RO (EM RO) and effector memory RA (EM RA), whereas numbers of CM and EM RO CD8 cells declined significantly. By week 48, CD4 naive cells were similar to controls, whereas CM CD4 cells remained significantly lower and EM RO and EM RA subsets were significantly higher. CD38 and HLA DR expression, both individually and when co-expressed, decreased over 48 weeks of cART on CD8 cells but remained significantly higher than controls at week 48. In contrast, markers of macrophage activation measured by sCD14 and sCD163 in plasma did not change with cART and were significantly higher than controls.

Conclusions: In youth initiating early cART, CD4 cell reconstitution is robust with decreases in CD8 cells. However, CD8 T-cell and macrophage activation persists at higher levels than uninfected controls.
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http://dx.doi.org/10.1097/QAI.0000000000000549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452031PMC
May 2015

Recalcitrant rhinosinusitis, innate immunity, and mannose-binding lectin.

Ann Otol Rhinol Laryngol 2015 Feb 25;124(2):102-6. Epub 2014 Jul 25.

Sinus & Nasal Institute of Florida, St Petersburg, Florida, USA

Background: Mannose-binding lectin (MBL) is a protein produced by the liver that participates in innate immunity by tagging the surface of microbes for opsonization. Mannose-binding lectin deficiency is present in 7% of the population and has been implicated in recurrent respiratory tract infections in children. Mannose-binding lectin deficiency has not been explored in rhinosinusitis but is associated with increased mortality in adult pneumococcal infection. The purpose of this report is to describe a tertiary rhinology patient experience with MBL deficiency and recalcitrant rhinosinusitis.

Methods: This retrospective case series report characterizes predominantly adult patients with low MBL levels from January 2010 to June 2012. Indications for MBL testing, sinus culture data, immunological testing results, and treatments used to control rhinosinusitis are described.

Results: Mannose-binding lectin levels were deficient in 12 of 36 patients (33.3%) tested. IgG subclasses were abnormally low in 5 of 12 patients; IgA was normal in 11 of 12 patients; and IgM was normal in 11 of 12 patients. Staphylococcus aureus, coagulase-negative Staphylococcus species, and Pseudomonas aeruginosa, known to be "tagged" by MBL, were the most common organisms grown on culture. Treatments included culture directed systemic antimicrobial therapy and topical steroids/antibiotics.

Conclusion: Mannose-binding lectin, an important component of the lectin complement pathway and innate immunity, is possibly associated with recalcitrant adult rhinosinusitis. Steroid/antibiotic irrigations appear to benefit patients with recalcitrant rhinosinusitis and possibly those with MBL deficiency. Given that the prevalence of MBL deficiency in this case series is 4 times that seen in the normal population, additional investigations are warranted to further elucidate the role of MBL deficiency in rhinosinusitis.
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http://dx.doi.org/10.1177/0003489414543680DOI Listing
February 2015

Hypereosinophilic syndrome and hemimelia in a patient with chromosome 6p22.3 deletion.

Pediatr Allergy Immunol 2014 Aug 16;25(5):500-3. Epub 2014 Mar 16.

Division of Allergy, Immunology and Rheumatology, University of South Florida, Tampa, FL, USA.

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http://dx.doi.org/10.1111/pai.12213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149865PMC
August 2014

Δ(9)-Tetrahydrocannabinol treatment during human monocyte differentiation reduces macrophage susceptibility to HIV-1 infection.

J Neuroimmune Pharmacol 2014 Jun 23;9(3):369-79. Epub 2014 Feb 23.

Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, 2033 Mowry Road, Campus Box 103633, Gainesville, FL, 32610-3663, USA.

The major psychoactive component of marijuana, Δ(9)-tetrahydrocannabinol (THC), also acts to suppress inflammatory responses. Receptors for THC, CB1, CB2, and GPR55, are differentially expressed on multiple cell types including monocytes and macrophages, which are important modulators of inflammation in vivo and target cells for HIV-1 infection. Use of recreational and medicinal marijuana is increasing, but the consequences of marijuana exposure on HIV-1 infection are unclear. Ex vivo studies were designed to investigate effects on HIV-1 infection in macrophages exposed to THC during or following differentiation. THC treatment of primary human monocytes during differentiation reduced HIV-1 infection of subsequent macrophages by replication competent or single cycle CCR5 using viruses. In contrast, treatment of macrophages with THC immediately prior to or continuously following HIV-1 exposure failed to alter infection. Specific receptor agonists indicated that the THC effect during monocyte differentiation was mediated primarily through CB2. THC reduced the number of p24 positive cells with little to no effect on virus production per infected cell, while quantitation of intracellular viral gag pinpointed the THC effect to an early event in the viral life cycle. Cells treated during differentiation with THC displayed reduced expression of CD14, CD16, and CD163 and donor dependent increases in mRNA expression of selected viral restriction factors, suggesting a fundamental alteration in phenotype. Ultimately, the mechanism of THC suppression of HIV-1 infection was traced to a reduction in cell surface HIV receptor (CD4, CCR5 and CXCR4) expression that diminished entry efficiency.
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http://dx.doi.org/10.1007/s11481-014-9527-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019698PMC
June 2014

Concordance between self-reported substance use and toxicology among HIV-infected and uninfected at risk youth.

Drug Alcohol Depend 2014 Jan 19;134:376-382. Epub 2013 Nov 19.

Department of Pediatrics, Division of Allergy, Immunology, and Rheumatology, University of South Florida, St. Petersburg, 33701 FL, USA.

Background: Substance use by youth living with HIV (YLWH) is a concern, given potential interactions with virus-associated immune suppression and adverse effects on risk behaviors, neurocognition, and adherence. Self-report substance use measures provide efficient cost-effective assessments. Analyses describe self-reported substance use among YLWH and examine agreement with toxicology assays.

Methods: Seventy-eight youth age 18-24 years (87% male, 71% African-American) with behaviorally acquired HIV-1 infection and 55 uninfected youth completed the Alcohol, Smoking, and Substance Involvement Screening Test to assess drug use frequency, including tobacco, marijuana, cocaine, and alcohol, over the prior three months. Elisa-based toxicology assays were used to detect 27 substances in plasma. Chi-square tests compared substance use between YLWH and uninfected youth; Kappa statistics compared agreement between self-report and toxicology.

Results: YLWH reported marijuana (49%), tobacco (56%), and alcohol (87%) use, with 20%, 28% and 3% reporting daily use of each substance, respectively; other substance use was uncommon. Uninfected youth reported less tobacco use but otherwise similar substance use. All youth who reported daily use of marijuana or tobacco had positive plasma toxicology results, while concordance decreased with less frequent self-reported use. Among youth reporting no substance use, few tested positive (4% YLWH, 2% uninfected youth for cannabis; 8%YLWH for tobacco).

Conclusions: Youth report high rates of marijuana, tobacco, and alcohol use. Concordance between self-report and toxicology for marijuana and tobacco use, particularly for daily users, supports self-report as a valid indicator of substance use in research studies of youth with or without HIV-1 infection.
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http://dx.doi.org/10.1016/j.drugalcdep.2013.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006963PMC
January 2014
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