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1.
Am J Hum Genet ; 108(2): 346-356, 2021 02 04.
Article in English | MEDLINE | ID: mdl-33513338

ABSTRACT

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.


Subject(s)
Matrix Attachment Region Binding Proteins/genetics , Mutation , Neurodevelopmental Disorders/genetics , Chromatin/metabolism , Female , Genetic Association Studies , Haploinsufficiency , Humans , Male , Matrix Attachment Region Binding Proteins/chemistry , Matrix Attachment Region Binding Proteins/metabolism , Models, Molecular , Mutation, Missense , Protein Binding , Protein Domains , Transcription, Genetic
2.
Eur J Immunol ; 53(4): e2250036, 2023 04.
Article in English | MEDLINE | ID: mdl-36608264

ABSTRACT

Recurrent respiratory papillomatosis (RRP), a rare chronic disease caused primarily by human papillomavirus types 6 and 11, consists of repeated growth of premalignant papillomas in the airway. RRP is characterized by multiple abnormalities in innate and adaptive immunity. Natural killer (NK) cells play important roles in immune surveillance and are part of the innate immune responses that help prevent tumor growth. We identified that papillomas lack classical class I MHC and retain nonclassical class I MHC expression. Moreover, in this study, we have identified and characterized the mechanism that blocks NK cell targeting of papilloma cells. Here, we show for the first time that the PGE2 secreted by papilloma cells directly inhibits NK cells activation/degranulation principally through the PGE2 receptor EP2, and to a lesser extent through EP4 signaling. Thus, papilloma cells have a potent mechanism to block NK cell function that likely supports papilloma cell growth.


Subject(s)
Papilloma , Papillomavirus Infections , Respiratory Tract Infections , Humans , Dinoprostone/metabolism , Killer Cells, Natural
3.
Semin Cancer Biol ; 87: 170-183, 2022 12.
Article in English | MEDLINE | ID: mdl-36402301

ABSTRACT

Human papillomaviruses (HPVs) cause cancers of the uterine cervix, oropharynx, anus, and vulvovaginal tract. Low-risk HPVs, such as HPV6 and 11, can also cause benign mucosal lesions including genital warts, and in patients with recurrent respiratory papillomatosis, lesions in the larynx, and on occasion, in the lungs. However, both high and less tumorigenic HPVs share a striking commonality in manipulating both innate and adaptive immune responses in HPV- infected keratinocytes, the natural host for HPV infection. In addition, immune/inflammatory cell infiltration into the tumor microenvironment influences cancer growth and prognosis, and this process is tightly regulated by different chemokines. Chemokines are small proteins and exert their biological effects by binding with G protein-coupled chemokine receptors (GPCRs) that are found on the surfaces of select target cells. Chemokines are not only involved in the establishment of a pro-tumorigenic microenvironment and organ-directed metastases but also involved in disease progression through enhancing tumor cell growth and proliferation. Therefore, having a solid grasp on chemokines and immune checkpoint modulators can help in the treatment of these cancers. In this review, we discuss the recent advances on the expression patterns and regulation of the main chemokines found in HPV-induced cancers, and their effects on both immune and non-immune cells in these lesions. Importantly, we also present the current knowledge of therapeutic interventions on the expression of specific chemokine and their receptors that have been shown to influence the development and progression of HPV-induced cancers.


Subject(s)
Neoplasms , Papillomavirus Infections , Female , Humans , Papillomavirus Infections/complications , Chemokines , Neoplasms/etiology , Tumor Microenvironment , Carcinogenesis
4.
Ann Allergy Asthma Immunol ; 128(2): 161-168.e1, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34699968

ABSTRACT

BACKGROUND: Allergic and nonallergic adverse reactions have been reported with global coronavirus disease 2019 (COVID-19) vaccination. It was previously hypothesized that polyethylene glycol (PEG) may be responsible for anaphylactic reactions to messenger RNA (mRNA) COVID-19 vaccines. OBJECTIVE: To report the workflow established at our institution, types, and frequency of adverse reactions to mRNA COVID-19 vaccines in patients presenting for allergy evaluation. METHODS: A COVID-19 vaccine adverse reaction registry was established. We used PEG prick skin testing, followed by PEG challenges in selected cases, to ensure PEG tolerance and encourage completion of COVID-19 vaccination series. RESULTS: A total of 113 patients were included. Most vaccine reactions (86.7%) occurred in women. Anaphylaxis occurred only in women, all of which had a history of allergic disease and two-thirds had asthma. Anaphylaxis rate was 40.6 cases per million. None of the anaphylactic cases developed hypotension, required intubation, or required hospital admission. Systemic allergic symptoms, not fulfilling anaphylaxis criteria, were significantly more common in Pfizer-BioNTech than Moderna-vaccinated patients (P = .02). We observed a higher incidence of dermatologic nonurticarial reactions in men (P = .004). Among first-dose reactors, 86.7% received and tolerated the second dose. We observed a high rate of false-positive intradermal skin test results and frequent subjective symptoms with oral PEG challenge. CONCLUSION: Intradermal PEG testing has limited utility in evaluating anaphylaxis to mRNA vaccines. Most severe postvaccination allergic symptoms are not caused by hypersensitivity to PEG. Most people with reaction to the initial mRNA vaccine can be safely revaccinated. Patients with anaphylaxis to COVID-19 vaccines benefit from physician-observed vaccination.


Subject(s)
Anaphylaxis , COVID-19 Vaccines/adverse effects , COVID-19 , Vaccination Hesitancy , Anaphylaxis/etiology , COVID-19/prevention & control , Female , Humans , Male , Polyethylene Glycols/adverse effects , Skin Tests , Vaccines, Synthetic/adverse effects , mRNA Vaccines/adverse effects
5.
Proc Natl Acad Sci U S A ; 116(38): 19055-19063, 2019 09 17.
Article in English | MEDLINE | ID: mdl-31484767

ABSTRACT

Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1ß secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1ß at baseline. Finally, both patients displayed elevated levels of inflammasome-induced cytokines in the serum. Six NLRP1 GOF mutations have previously been described to underlie 3 allelic Mendelian diseases with differing phenotypes and modes of inheritance. Our results demonstrate that an autosomal recessive, syndromic form of JRRP can be associated with an NLRP1 GOF mutation.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Apoptosis Regulatory Proteins/genetics , Gain of Function Mutation , Homozygote , Papillomavirus Infections/genetics , Papillomavirus Infections/pathology , Respiratory Tract Infections/genetics , Respiratory Tract Infections/pathology , Child, Preschool , Cytokines/metabolism , Female , Humans , Infant , Inflammasomes , Keratinocytes/cytology , Keratinocytes/immunology , Keratinocytes/metabolism , Male , NLR Proteins , Pedigree , Siblings , Syndrome
6.
J Clin Immunol ; 41(1): 66-75, 2021 01.
Article in English | MEDLINE | ID: mdl-33025378

ABSTRACT

PURPOSE: To evaluate the safety and tolerability of IgPro20 manual push (also known as rapid push) infusions at flow rates of 0.5-2.0 mL/min. METHODS: Patients with primary immunodeficiency (PID) with previous experience administering IgPro20 (Hizentra®, CSL Behring, King of Prussia, PA, USA) were enrolled in the Hizentra® Label Optimization (HILO) study (NCT03033745) and assigned to Pump-assisted Volume Cohort, Pump-assisted Flow Rate Cohort, or Manual Push Flow Rate Cohort; this report describes the latter. Patients administered IgPro20 via manual push at 0.5, 1.0, and 2.0 mL/min/site for 4 weeks each. Responder rates (percentage of patients who completed a predefined minimum number of infusions), safety outcomes, and serum immunoglobulin G (IgG) trough levels were evaluated. RESULTS: Sixteen patients were treated; 2 patients (12.5%) discontinued at the 1.0-mL/min level (unrelated to treatment). Responder rates were 100%, 100%, and 87.5% at 0.5-, 1.0-, and 2.0-mL/min flow rates, respectively. Mean weekly infusion duration decreased from 103-108 to 23-28 min at the 0.5- and 2.0-mL/min flow rates, respectively. Rates of treatment-related treatment-emergent adverse events (TEAEs) per infusion were 0.023, 0.082, and 0.025 for the 0.5-, 1.0-, and 2.0-mL/min flow rates, respectively. Most TEAEs were mild local reactions and tolerability (infusions without severe local reactions/total infusions) was 100% across flow rate levels. Serum IgG levels (mean [SD]) were similar at study start (9.36 [2.53] g/L) and end (9.58 [2.12] g/L). CONCLUSIONS: Subcutaneous IgPro20 manual push infusions at flow rates up to 2.0 mL/min were well tolerated and reduced infusion time in treatment-experienced patients with PID. TRIAL REGISTRATION: NCT03033745.


Subject(s)
Immunoglobulin G/administration & dosage , Primary Immunodeficiency Diseases/drug therapy , Adolescent , Adult , Aged , Disease Management , Drug Monitoring , Female , Humans , Immunoglobulin G/adverse effects , Infusion Pumps , Infusions, Subcutaneous , Injections, Subcutaneous , Male , Middle Aged , Patient Compliance , Primary Immunodeficiency Diseases/diagnosis , Primary Immunodeficiency Diseases/etiology , Treatment Outcome , Young Adult
7.
J Clin Immunol ; 41(2): 458-469, 2021 02.
Article in English | MEDLINE | ID: mdl-33409867

ABSTRACT

PURPOSE: To evaluate the safety and tolerability of subcutaneous IgPro20 (Hizentra®, CSL Behring, King of Prussia, PA, USA) administered at high infusion parameters (> 25 mL and > 25 mL/h per injection site) in patients with primary immunodeficiency. METHODS: The Hizentra® Label Optimization (HILO) study was an open-label, parallel-arm, non-randomized study (NCT03033745) of IgPro20 using a forced upward titration design for infusion parameters. Patients experienced with pump-assisted IgPro20 infusions received weekly IgPro20 infusions at a stable dose in the Pump-Assisted Volume Cohort (N = 15; 25-50 mL per injection site) and in the Pump-Assisted Flow Rate Cohort (N = 18; 25-100 mL/h per injection site). Responder rates (percentage of patients who successfully completed ≥ 75% of planned infusions), safety outcomes, and serum immunoglobulin G (IgG) trough levels were evaluated. RESULTS: Responder rates were 86.7% (13/15, 25 mL) and 73.3% (11/15, 40 and 50 mL) in the Volume Cohort, and 77.8% (14/18, 25 and 50 mL/h), 66.7% (12/18, 75 mL/h), and 61.1% (11/18, 100 mL/h) in the Flow Rate Cohort. Infusion compliance was ≥ 90% in all patients in the Volume Cohort and in 83.3% of patients in the Flow Rate Cohort. The number of injection sites (Volume Cohort) and the infusion duration (Flow Rate Cohort) decreased with increasing infusion parameters. The rate of treatment-emergent adverse events per infusion was low (0.138 [Volume Cohort] and 0.216 [Flow Rate Cohort]). Serum IgG levels remained stable during the study. CONCLUSION: Pump-assisted IgPro20 infusions are feasible at 50 mL and 100 mL/h per injection site in treatment-experienced patients, which may result in fewer injection sites and shorter infusion times. TRIAL REGISTRATION: NCT03033745 ; registered January 27, 2017.


Subject(s)
Immunoglobulin G/administration & dosage , Immunoglobulin G/adverse effects , Immunologic Deficiency Syndromes/immunology , Immunologic Deficiency Syndromes/therapy , Primary Immunodeficiency Diseases/immunology , Primary Immunodeficiency Diseases/therapy , Adult , Aged , Cohort Studies , Female , Humans , Immunoglobulin G/immunology , Immunoglobulins, Intravenous/adverse effects , Infusion Pumps/adverse effects , Infusions, Subcutaneous/adverse effects , Male , Middle Aged , Young Adult
8.
J Clin Immunol ; 41(3): 610-620, 2021 04.
Article in English | MEDLINE | ID: mdl-33411154

ABSTRACT

PURPOSE: Newborn screening (NBS) quantifies T cell receptor excision circles (TREC) and identifies infants with T cell lymphopenia (TCL). This study elucidates the demographics, laboratory characteristics, genetics, and clinical outcomes following live viral vaccine administration of term infants with transient or persistent idiopathic TCL. METHODS: A single-center retrospective analysis was performed from September 2010 through June 2018. Laboratory variables were compared with Mann-Whitney tests. Correlations between initial TREC levels and T cell counts were determined by Spearman tests. RESULTS: Twenty-two transient and 21 persistent TCL infants were identified. Males comprised 68% of the transient and 52% of the persistent TCL cohorts. Whites comprised 23% of the transient and 29% of the persistent cohorts. Median initial TREC levels did not differ (66 vs. 60 TRECs/µL of blood, P = 0.58). The transient cohort had higher median initial CD3+ (2135 vs. 1169 cells/µL, P < 0.001), CD4+ (1460 vs. 866 cells/µL, P < 0.001), and CD8+ (538 vs. 277 cells/µL, P < 0.001) counts. The median age of resolution for the transient cohort was 38 days. Genetic testing revealed 2 genes of interest which warrant further study and several variants of uncertain significance in immunology-related genes in the persistent cohort. 19 transient and 14 persistent subjects received the initial rotavirus and/or MMRV immunization. No adverse reactions to live viral vaccines were reported in either cohort. CONCLUSION: Transient and persistent TCL infants differ by demographic, laboratory, and clinical characteristics. Select transient and persistent TCL patients may safely receive live attenuated viral vaccines, but larger confirmatory studies are needed.


Subject(s)
Lymphopenia/epidemiology , T-Lymphocytes , CD4 Lymphocyte Count , Disease Susceptibility , Female , Humans , Infant, Newborn , Lymphocyte Count , Lymphopenia/diagnosis , Lymphopenia/etiology , Male , Neonatal Screening , New York/epidemiology , Public Health Surveillance , Retrospective Studies , Vaccination , Viral Vaccines/administration & dosage , Viral Vaccines/immunology
9.
Mol Med ; 24(1): 23, 2018 05 16.
Article in English | MEDLINE | ID: mdl-30134802

ABSTRACT

BACKGROUND: Stratified human keratinocytes (SHKs) are an essential part of mucosal innate immune response that modulates adaptive immunity to microbes encountered in the environment. The importance of these SHKs in mucosal integrity and development has been well characterized, however their regulatory immunologic role at different mucosal sites, has not. In this study we compared the immune gene expression of SHKs from five different anatomical sites before and after HPV16 transfection using microarray analyses. METHODS: Individual pools of human keratinocytes from foreskin, cervix, vagina, gingiva, and tonsils (HFKs, HCKs, HVKs, HGKs and HTLKs) were prepared. Organotypic (raft) cultures were established for both normal and HPV16 immortalized HFKs, HCKs, HVKs, HGKs and HTLKs lines which stably maintained episomal HPV16 DNA. Microarray analysis was carried out using the HumanHT-12 V4 gene chip (Illumina). Immune gene expression profiles were obtained by global gene chip (GeneSifter) and Ingenuity pathway analysis (IPA) for each individual site, with or without HPV16 transfection. RESULTS: We examined site specific innate immune response gene expression in SHKs from all five different anatomical sites before and after HPV16 transfection. We observed marked differences in SHK immune gene repertoires within and between mucosal tracts before HPV 16 infection. In addition, we observed additional changes in SHKs immune gene repertoire patterns when these SHKs were productively transfected with HPV16. Some immune response genes were similarly expressed by SHKs from different sites. However, there was also variable expression of non-immune response genes, such as keratin genes, by the different SHKs. CONCLUSIONS: Our results suggest that keratinocytes from different anatomical sites are likely hard wired in their innate immune responses, and that these immune responses are unique depending on the anatomical site from which the SHKs were derived. These observations may help explain why select HPV types predominate at different mucosal sites, cause persistent infection at these sites, and on occasion, lead to HPV induced malignant and benign tumor development.


Subject(s)
Human papillomavirus 16/genetics , Keratinocytes/immunology , Transcriptome/immunology , Cervix Uteri , Female , Foreskin , Gingiva , Humans , Immunity, Innate , Male , Microarray Analysis , Palatine Tonsil , Papillomavirus Infections/genetics , Papillomavirus Infections/immunology , Signal Transduction , Transfection , Vagina
14.
J Clin Immunol ; 33 Suppl 2: S90-4, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23271459

ABSTRACT

The treatment of primary immunodeficiency disease (PIDD) patients with immunoglobulin obtained from healthy controls, given intravenously, is a relatively recent event, having first been given in 1981. Intravenous immunoglobulin (IVIG) replacement in PIDD has been shown to prevent serious/recurrent infections because higher IgG levels can be obtained through IV administration, as opposed to the intramuscular route. Significant variation in IgG levels in controls is dependent on age and sex, which provides the rationale for the concept that there is a "biological IgG trough/level", hereafter called biological IgG level, in PIDD, as there is in healthy controls. Each PIDD patient has a biological IgG level that can be altered by comorbid conditions that evoke IgG loss or changes in metabolism/catabolism. The pharmacokinetic comparison of IVIG vs. SCIG demonstrates the various benefits of each in treating PIDD. Acutely ill PIDD patients should only receive IVIG. "Rush" SCIG treatment can also be used to attain the biological IgG level, but for less emergent care of PIDD. Finally, future opportunities exist to enhance IgG replacement in PIDD, including microbe-specific IgG and IgG subclass-specific enriched preparations.


Subject(s)
Immunoglobulins, Intravenous/therapeutic use , Immunologic Deficiency Syndromes/therapy , Immunotherapy/methods , Humans , Immunoglobulins, Intravenous/pharmacokinetics , Immunologic Deficiency Syndromes/immunology , Infection Control , Infections/etiology , Precision Medicine , Treatment Outcome
15.
J Clin Immunol ; 33 Suppl 2: S99-103, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23242829

ABSTRACT

Many factors need to be considered when choosing the mode of delivery of immunoglobulin (IgG) replacement therapy for a given patient with primary immunodeficiency disease (PIDD). Despite some general guidance as provided in the previous discussions, a number of ongoing questions remain. This article attempts to provide some answers and clarification for clinical situations in which the choice of intravenous IgG (IVIG) or subcutaneous IgG (SCIG) may be ambiguous.


Subject(s)
Decision Making, Computer-Assisted , Immunoglobulins, Intravenous/administration & dosage , Immunologic Deficiency Syndromes/therapy , Practice Patterns, Physicians'/standards , Drug Administration Routes , Guideline Adherence/ethics , Humans , Immunologic Deficiency Syndromes/epidemiology , Immunologic Deficiency Syndromes/immunology , Patient Rights/ethics , Practice Guidelines as Topic/standards , Practice Patterns, Physicians'/ethics
16.
Ann Allergy Asthma Immunol ; 111(6 Suppl): S10-3, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24267400

ABSTRACT

OBJECTIVE: To illustrate the need for individualized immunoglobulin therapy in patients with primary immunodeficiency diseases (PIDDs) and review current evidence on how best to identify the biological serum IgG level in patients with antibody-deficient PIDD. DATA SOURCES: Two case studies from the author's clinical practice are discussed. PubMed and Ovid MEDLINE databases were searched for articles pertaining to serum immunoglobulin levels in patients with PIDD and the relation of trough IgG levels to infection incidence and outcomes. STUDY SELECTIONS: Articles and case studies were selected for their relevance to the individualization of IgG therapy for patients with PIDD. The case studies support the position that each patient has a specific "biological" serum IgG level associated with decreasing or preventing recurrent infection. RESULTS: Patients with antibody-deficient PIDD are routinely treated with lifelong immunoglobulin replacement. Although a starting dose has been suggested, the dose of IgG that maintains serum IgG levels that protect against severe or recurrent infection has not been determined. It is likely the serum IgG level required to prevent infection in these patients varies as it does in normal individuals. This biological serum IgG level must be identified for each patient by plotting documented infections vs serum IgG levels over time. CONCLUSION: Clinical experience and recent evidence suggest that optimal treatment of patients with PIDD involves individualizing IgG treatment to identify the optimal IgG serum levels that are required for each patient to become free of recurrent infection or pneumonia instead of trying to achieve a single optimal serum IgG level for all patients.


Subject(s)
Immunization, Passive , Immunologic Deficiency Syndromes/therapy , Jacobsen Distal 11q Deletion Syndrome/therapy , Humans , Immunoglobulin G/therapeutic use , Pneumonia/prevention & control , Precision Medicine
17.
J Immunol ; 186(3): 1870-9, 2011 Feb 01.
Article in English | MEDLINE | ID: mdl-21199898

ABSTRACT

Autoimmune inner ear disease is an enigmatic disorder characterized by recurring episodes of sudden or progressive sensorineural hearing loss. Hearing loss can be improved by timely corticosteroid administration, but only half of those treated respond, and for many responders, that response is lost over time. The mechanisms that control corticosteroid responsiveness in this disorder are largely uncharacterized. We have previously identified that the induction by dexamethasone of IL-1R type II (IL-1R2) expression in PBMC predicts corticosteroid responsiveness in this disorder. In this study, we asked whether IL-1ß was overexpressed, and whether clinical corticosteroid responders differentially regulated IL-1ß expression or release in response to dexamethasone, as compared with nonresponders. IL-1ß has been reported to induce matrix metalloproteinase-9 (MMP-9) expression. Given that metalloproteinases can cleave IL-1R2, we also asked whether MMP-9 expression was altered in this disorder. In this study, we demonstrate that corticosteroid nonresponders have elevated plasma levels of IL-1ß and MMP-9 as compared with clinically responsive patients (p = 0.0008 and p = 0.037, respectively). Increasing MMP-9 expression correlated with increasing IL-1ß concentration, suggesting that IL-1ß expression regulates MMP-9 expression. As expected, monocytes were the predominant producers of IL-1ß. In vitro exposure of PBMC to dexamethasone from clinical corticosteroid responders suppressed IL-1ß release. PBMC of corticosteroid nonresponders have substantially higher release of IL-1ß into the conditioned media, and when exposed to dexamethasone, failed to repress IL-1ß release (p = 0.05). Treatment of PBMC from clinical corticosteroid nonresponders with anakinra resulted in repression of IL-1ß release, suggesting that IL-1ß blockade may be a viable therapy for these patients.


Subject(s)
Autoimmune Diseases/immunology , Gene Expression Regulation/drug effects , Gene Expression Regulation/immunology , Glucocorticoids/therapeutic use , Interleukin-1beta/biosynthesis , Administration, Oral , Adult , Autoimmune Diseases/drug therapy , Autoimmune Diseases/genetics , Cells, Cultured , Cochlear Implantation , Dexamethasone/pharmacology , Female , Hearing Loss, Sensorineural/drug therapy , Hearing Loss, Sensorineural/immunology , Hearing Loss, Sensorineural/metabolism , Humans , Immunosuppressive Agents/therapeutic use , Interleukin-1beta/blood , Interleukin-1beta/genetics , Male , Matrix Metalloproteinase 9/biosynthesis , Matrix Metalloproteinase 9/blood , Matrix Metalloproteinase Inhibitors , Prednisone/therapeutic use , Prospective Studies
18.
J Immunol ; 186(11): 6633-40, 2011 Jun 01.
Article in English | MEDLINE | ID: mdl-21531896

ABSTRACT

Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus type 6 (HPV-6) or HPV-11. Specific HLA-DR haplotypes DRB1*01:02 and DRB1*03:01 are associated with the development of RRP, disease severity, and Th2-like responses to HPV early proteins. Th1-like responses to HPV proteins have been shown to be protective in animal models. Therefore, we investigated the hypothesis that RRP patients have dysfunctional Th1-like, HPV-specific T cell responses. Using MHC class II tetramers, we identified immunogenic peptides within HPV-11 early proteins. Two distinct peptides (E6(113-132) and E2(1-20)) contained DRB1*01:02- or DRB1*03:01-restricted epitopes, respectively. An additional peptide (E2(281-300)) contained an epitope presented by both alleles. Peptide binding, tetramer, and proliferation assays identified minimal epitopes within these peptides. These epitopes elicited E2/E6-specific CD4(+) T cell responses in RRP patients and healthy control subjects, allowing the isolation of HPV-specific T cell lines using tetramers. The cytokine profiles and STAT signaling of these tetramer-positive T cells were measured to compare the polarization and responsiveness of HPV-specific T cells from patients with RRP and healthy subjects. HPV-specific IFN-γ secretion was substantially lower in T cells from RRP patients. HPV-specific IL-13 secretion was seen at modest levels in T cells from RRP patients and was absent in T cells from healthy control subjects. HPV-specific T cells from RRP patients exhibited reduced STAT-5 phosphorylation and reduced IL-2 secretion, suggesting anergy. Levels of STAT-5 phosphorylation and IFN-γ secretion could be improved through addition of IL-2 to HPV-specific T cell lines from RRP patients. Therapeutic vaccination or interventions aimed at restoring Th1-like cytokine responses to HPV proteins and reversing anergy could improve clinical outcomes for RRP patients.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Cytokines/immunology , Human papillomavirus 11/immunology , STAT5 Transcription Factor/immunology , Amino Acid Sequence , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/metabolism , Cell Line , Cells, Cultured , Cytokines/metabolism , Epitopes, T-Lymphocyte/immunology , Flow Cytometry , HLA-DR Antigens/immunology , HLA-DR alpha-Chains , HLA-DRB1 Chains , Host-Pathogen Interactions/immunology , Human papillomavirus 11/physiology , Interferon-gamma/immunology , Interferon-gamma/metabolism , Interleukin-13/immunology , Interleukin-13/metabolism , Interleukin-2/immunology , Interleukin-2/metabolism , Interleukin-2/pharmacology , Molecular Sequence Data , Oncogene Proteins, Viral/chemistry , Oncogene Proteins, Viral/immunology , Papillomavirus Infections/immunology , Papillomavirus Infections/metabolism , Papillomavirus Infections/virology , Peptides/immunology , Phosphorylation/immunology , Respiratory Tract Infections/immunology , Respiratory Tract Infections/metabolism , Respiratory Tract Infections/virology , STAT5 Transcription Factor/metabolism , Signal Transduction/drug effects , Signal Transduction/immunology , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/metabolism , Viral Proteins/chemistry , Viral Proteins/immunology
19.
Mol Med ; 18: 1338-45, 2012 Dec 06.
Article in English | MEDLINE | ID: mdl-23019074

ABSTRACT

Recurrent respiratory papillomatosis (RRP), characterized by the recurrent growth of benign tumors of the respiratory tract, is caused by infection with human papillomavirus (HPV), predominantly types 6 and 11. Surgical removal of these lesions can be required as frequently as every 3 to 4 wks to maintain a patent airway. There is no approved medical treatment for this disease. In this study, we have characterized the T(H)2-like chemokine profile (CCL17, CCL18, CCL20, CCL22) in patients with RRP and asked whether it was modulated in patients who had achieved significant clinical improvement. CCL17, CCL18 and CCL22 messenger RNAs (mRNAs) were increased in papillomas compared with clinically normal laryngeal epithelium of the RRP patients. Overall, CCL20 mRNA expression was not increased, but there was intense, selective CCL20 protein expression in the basal layer of the papillomas. Patients with RRP expressed more CCL17 (p = 0.003), CCL18 (p = 0.0003), and CCL22 (p = 0.007) in their plasma than controls. Plasma CCL18 decreased over time in three patients enrolled in a pilot clinical trial of celecoxib, and the decrease occurred in conjunction with clinical improvement. There was a significant correlation between sustained clinical remission in additional patients with RRP and reduced levels of CCL17 (p = 0.01), CCL22 (p = 0.002) and CCL18 (p = 0.05). Thus, the change in expression of these three plasma T(H)2-like chemokines may, with future studies, prove to serve as a useful biomarker for predicting disease prognosis.


Subject(s)
Chemokines/metabolism , Papillomavirus Infections/immunology , Papillomavirus Infections/pathology , Respiratory Tract Infections/immunology , Respiratory Tract Infections/pathology , Severity of Illness Index , Th2 Cells/immunology , Case-Control Studies , Celecoxib , Chemokines/blood , Chemokines/genetics , Humans , Larynx/drug effects , Larynx/metabolism , Larynx/pathology , Papilloma/drug therapy , Papilloma/genetics , Papilloma/pathology , Papillomavirus Infections/blood , Papillomavirus Infections/drug therapy , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Remission Induction , Respiratory Tract Infections/blood , Respiratory Tract Infections/drug therapy , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Th2 Cells/drug effects
20.
Ann Allergy Asthma Immunol ; 108(6): 454-459.e7, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22626600

ABSTRACT

BACKGROUND: Allergists around the world have different practice styles when administering subcutaneous aeroallergen immunotherapy (IT) in peak pollen seasons, especially when changing doses or frequency of IT. The Immunotherapy practice parameters do not specifically address this issue. OBJECTIVE: Given the paucity of good data about adjustment of allergen immunotherapy during the pollen seasons, we examined whether a significant difference is present in the way allergists administer immunotherapy during allergy seasons. METHODS: To quantify the practice styles of allergists who are members of the American Academy of Allergy, Asthma and Immunology (AAAAI), a self-reported electronic survey was disseminated in September 2010 with the help of the AAAAI Needs Assessment Committee. The responses were tallied and analyzed according to demographic information. RESULTS: A total of 1,201 allergists in the AAAAI responded to the survey. Most responders practice in an urban or suburban nonacademic practice in the United States and have been in practice for more than 10 years. The size of their practice was variable. Those in practice for more than 10 years were more likely to adjust the dose and frequency of immunotherapy in pollen seasons. CONCLUSION: This survey highlights the differences in the practice styles of AAAAI member allergists, and these differences may be associated with their demographic characteristics. Given the wide variability in how allergists adjust dose and frequency of immunotherapy during pollen seasons, establishing guidelines regarding this routine dilemma might help standardize the delivery of treatment to patients.


Subject(s)
Allergens/immunology , Asthma/therapy , Desensitization, Immunologic/methods , Practice Patterns, Physicians'/standards , Rhinitis, Allergic, Seasonal/therapy , Asthma/immunology , Canada , Data Collection , Drug Administration Schedule , Europe , Female , Humans , Pollen/immunology , Practice Guidelines as Topic , Rhinitis, Allergic, Seasonal/immunology , Surveys and Questionnaires , United States
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