Bio

Clinical Focus


  • Allergy and Immunology
  • CVID
  • Primary immunodeficiency in adults and children
  • Food allergy

Academic Appointments


Administrative Appointments


  • Post Doctoral Fellow in Genetics, Herzenberg Laboratory, Stanford School Of Medicine (2008 - 2012)
  • Resident in Internal Medicine, Highland Alameda County Hospital, Oakland, CA (2012 - 2015)
  • Clinical Fellow in Allergy and Immunology, Icahn School of Medicine, Mount Sinai Hospital, New York (2015 - 2017)

Honors & Awards


  • Dean Fellowship, Stanford University, School of Medicine (2008)
  • Child Health Research Program Fellowship, Packard Foundation, Stanford Medical Center (2008)
  • McCormick Award, Stanford University School of Medicine (2009-2010)
  • SPARK/SPECTRUM Award (under the mentorship of Dr. Kari Nadeau), Stanford School of Medicine (2010)
  • Elizabeth Nash Memorial Fellowship, Cystic Fibrosis Research Inc. (2011-2012)
  • AAAAI Interest Section Fellow in Training Award, AAAAI (2012)
  • Award for poster presentation in the Research category, ACP regional Meeting (2013)
  • Observer at the PID Summer School, CIS, PID summer school (2017)
  • AAAAI/Elliot and Roslyn Jaffe Third-Year Fellowship Food Allergy Research Award, Icahn School of Medicine at Mount Sinai, New York (2017)

Boards, Advisory Committees, Professional Organizations


  • Member, EGID (2018 - Present)
  • Member, ACAAI (2014 - Present)
  • Member, CIS (2014 - Present)
  • Member, AAAAI (2014 - Present)

Professional Education


  • Fellowship:Icahn School of Medicine at Mount Sinai Allergy and Immunology Fellowship (2017) NY
  • Residency:Alameda Health System Highland Hospital GME (2015) CA
  • PhD Training:Marseille School of Medicine (2011) France
  • Board Certification: Allergy and Immunology, American Board of Allergy and Immunology (2017)
  • Board Certification: Internal Medicine, American Board of Internal Medicine (2015)
  • Fellowship:Stanford University (2012) CA
  • Fellowship:Stanford University Allergy and Immunology Fellowship (2012) CA
  • Medical Education:Marseille School of Medicine (2008) France
  • PhD, Marseille School of Medicine, French Ph.D. with best Honors, Infectious Disease, Marseille University (2011)
  • MD, Marseille School of Medicine, France, State Diploma of Internal Medicine and Diploma of Specialized Studies in Adult Pulmonary Medicine (2011)

Patents


  • Yael Gernez, Tirouvanziam R, Nadeau KN, and Herzenberg LA. "United States Patent ASB-004 Methods and assays for detecting and quantifying pure subpopulation of white blood cells in immune system disorders", Stanford University Office of Technology Transfer, Stanford, CA, Jul 1, 2011

Publications

All Publications


  • Severe autoinflammation in four patients with C-terminal variants in CDC42 successfully treated with IL-1beta inhibition. The Journal of allergy and clinical immunology Gernez, Y., de Jesus, A. A., Alsaleem, H., Macaubas, C., Roy, A., Lovell, D., Jagadeesh, K. A., Alehashemi, S., Erdman, L., Grimley, M., Talarico, S., Bacchetta, R., Lewis, D. B., Canna, S. W., Laxer, R. M., Mellins, E. D., Goldbach-Mansky, R., Weinacht, K. G. 2019

    Abstract

    Four patients with novel variants in the C-terminal domain of CDC42, severe autoinflammation, constitutive elevation of serum interleukin 18, and predisposition to macrophage activation syndrome respond to treatment with interleukin-1beta signaling inhibition.

    View details for DOI 10.1016/j.jaci.2019.06.017

    View details for PubMedID 31271789

  • A Case of Disseminated Pneumocystis Jiroveci in a Non-Human Immunodeficiency Virus Infected Patient Siddiqi, A. E., Sacha, J., Saenz, R., Liu, A., Kunder, C., Uzel, G., Martin, B., Lewis, D. B., Gernez-Goldhammer, Y. SPRINGER/PLENUM PUBLISHERS. 2019: S73?S74
  • Autoimmune Lymphoproliferative Syndrome with Histopathologic Features of Castleman Disease Lo, R., Gratzinger, D., Keiser, E., Chang, K., Gernez-Goldhammer, Y. SPRINGER/PLENUM PUBLISHERS. 2019: S103?S104
  • Novel CDC42 Mutation Causes Severe Autoinflammatory Syndrome Responsive to IL-1 Inhibition Gernez, Y., Kirbey, M., Balagas, J. M., Macaubas, C. I., Canna, S., Lewis, D. B., Mellins, E., Bacchetta, R., Weinacht, K. G. SPRINGER/PLENUM PUBLISHERS. 2019: S69
  • Epigenetic Immune Cell Quantification for Diagnosis and Monitoring of Patients with Primary Immune Deficiencies and Immune Regulatory Disorders Schulze, J., Werner, J., Schildknecht, K., Lakshmanan, U., Gruetzkau, A., Chu, J., Gernez, Y., Speckmann, C., Weinacht, K. G., Bertaina, A., Baron, U., Borte, S., Olek, S., Bacchetta, R. SPRINGER/PLENUM PUBLISHERS. 2019: S30
  • Resistin is elevated in cystic fibrosis sputum and correlates negatively with lung function JOURNAL OF CYSTIC FIBROSIS Forrest, O. A., Chopyk, D. M., Gernez, Y., Brown, M. R., Conrad, C. K., Moss, R. B., Tangpricha, V., Peng, L., Tirouvanziam, R. 2019; 18 (1): 64?70
  • Vedolizumab for autoimmune enteropathy in primary immunodeficiency: a case series of outcomes Sifers, T., Maglione, P., Baker, M., Tsuang, A., Gernez, Y., Pham, M. N., Feuille, E., Hirten, R., Colombel, J., Cunningham-Rundles, C. SPRINGER/PLENUM PUBLISHERS. 2018: 431
  • Variability in diagnosis and management of acquired cold-induced urticaria. The journal of allergy and clinical immunology. In practice Gernez, Y., Sicherer, S. H., Wang, J. 2018

    View details for DOI 10.1016/j.jaip.2017.12.030

    View details for PubMedID 29530343

  • Humoral immunodeficiencies: conferred risk of infections and benefits of immunoglobulin replacement therapy. Transfusion Gernez, Y., Baker, M. G., Maglione, P. J. 2018; 58 Suppl 3: 3056?64

    Abstract

    Primary immunodeficiency (PID) diseases result from genetic defects of the immune system that increase a patient's susceptibility to infections. The types of infections that occur in patients with PID diseases are dictated largely by the nature of the immunodeficiency, which can be defined by dysfunction of cellular or humoral defenses. An increasing number of PID diseases, including those with both cellular and humoral defects, have antibody deficiency as a major feature, and as a result can benefit from immunoglobulin replacement therapy. In fact, the most common PID diseases worldwide are antibody deficiencies and include common variable immunodeficiency, congenital agammaglobulinemia, hyper-IgM syndrome, specific antibody deficiency, and Good syndrome. Although immunoglobulin replacement therapy is the cornerstone of treatment for the majority of these conditions, a thorough understanding of the specific infections for which these patients are at increased risk can hasten diagnosis and guide additional therapies. Moreover, the infection trends in some patients with PID disease who have profound defects of cellular immunity, such as autosomal-dominant hyper-IgE syndrome (Job/Buckley syndrome) or dedicator of cytokinesis 8 (DOCK8) deficiency, suggest that select patients might benefit from immunoglobulin replacement therapy even if their immunodeficiency is not limited to antibody defects. In this review, we provide an overview of the predisposition to infections seen in PID disease that may benefit from immunoglobulin replacement therapy.

    View details for DOI 10.1111/trf.15020

    View details for PubMedID 30536429

  • Resistin is elevated in cystic fibrosis sputum and correlates negatively with lung function. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society Forrest, O. A., Chopyk, D. M., Gernez, Y., Brown, M. R., Conrad, C. K., Moss, R. B., Tangpricha, V., Peng, L., Tirouvanziam, R. 2018

    Abstract

    Resistin is an immunometabolic mediator that is elevated in several inflammatory disorders. A ligand for Toll-like receptor 4, resistin modulates the recruitment and activation of myeloid cells, notably neutrophils. Neutrophils are major drivers of cystic fibrosis (CF) lung disease, in part due to the release of human neutrophil elastase- and myeloperoxidase-rich primary granules, leading to tissue damage. Here we assessed the relationship of resistin to CF lung disease.Resistin levels were measured in plasma and sputum from three retrospective CF cohorts spanning a wide range of disease. We also assessed the ability of neutrophils to secrete resistin upon activation in vitro. Finally, we constructed a multivariate model assessing the relationship between resistin levels and lung function.Plasma resistin levels were only marginally higher in CF than in healthy control subjects. By contrast, sputum resistin levels were very high in CF, reaching 50-100 fold higher levels than in plasma. Among CF patients, higher plasma resistin levels were associated with allergic bronchopulmonary aspergillosis, and higher sputum resistin levels were associated with CF-related diabetes. Mechanistically, in vitro release of neutrophil primary granules was concomitant with resistin secretion. Overall, sputum resistin levels were negatively correlated with CF lung function, independently of other variables (age, sex, and genotype).Our data establish relationships between resistin levels in the plasma and sputum of CF patients that correlate with disease status, and identify resistin as a novel mechanistic link between neutrophilic inflammation and lung disease in CF.

    View details for PubMedID 29937317

  • Immunotherapy for Food Allergy: Are We There Yet? journal of allergy and clinical immunology. In practice Gernez, Y., Nowak-Wegrzyn, A. 2017; 5 (2): 250-272

    Abstract

    Current clinical research focuses on food allergen-specific immunotherapy through oral (OIT), sublingual (SLIT), or epicutaneous (EPIT) routes. Immunotherapy relies on the delivery of gradually increasing doses of specific allergens to induce desensitization (defined as temporary antigen hyporesponsiveness that depends on regular food ingestion) and, ultimately, tolerance (defined as the ability to ingest food without symptoms despite prolonged periods of avoidance or irregular intake). Although the majority of the patients treated with OIT achieve desensitization, only a minority achieves tolerance. OIT involves higher maintenance doses of food protein (300 mg-4g) compared with SLIT (2.5-7.5 mg) and EPIT (250-500 mcg). OIT efficacy is higher compared with SLIT, but OIT is associated with higher rate of systemic adverse events compared with SLIT and EPIT. OIT is also associated with a minor risk of eosinophilic esophagitis. Combined treatment of OIT and anti-IgE monoclonal antibody has improved safety but not efficacy compared with OIT alone. Early initiation of peanut OIT in peanut-allergic infants and young children may afford superior efficacy and safety. In this review, we discuss the allergen-specific strategies currently explored for the treatment of food allergy, including immunotherapy with native and heat-modified food proteins. Additional research employs strategies to improve the safety and efficacy of allergen immunotherapy through modifications of allergen structure and addition of immunomodulatory adjuvants.

    View details for DOI 10.1016/j.jaip.2016.12.004

    View details for PubMedID 28283151

  • Autosomal Dominant Hyper-IgE Syndrome in the USIDNET Registry. The journal of allergy and clinical immunology. In practice Gernez, Y., Freeman, A. F., Holland, S. M., Garabedian, E., Patel, N. C., Puck, J. M., Sullivan, K. E., Akhter, J., Secord, E., Chen, K., Buckley, R., Haddad, E., Ochs, H. D., Fuleihan, R., Routes, J., Muskat, M., Lugar, P., Mancini, J., Cunningham-Rundles, C. 2017

    Abstract

    Autosomal dominant hyper-IgE syndrome (AD-HIES) is a rare condition.Data from the USIDNET Registry provide a resource to examine the characteristics of patients with rare immune deficiency diseases.A query was submitted to the USIDNET requesting deidentified data for patients with physician-diagnosed AD-HIES through July 2016.Data on 85 patients diagnosed with AD-HIES (50 males; 35 females) born between 1950 and 2013, collected by 14 physicians from 25 states and Quebec, were entered into the USIDNET Registry by July 2016. Cumulative follow-up was 2157 years. Of these patients, 45.9% had a family history of HIES. The complications reported included skin abscesses (74.4%), eczema (57.7%), retained primary teeth (41.4%), fractures (39%), scoliosis (34.1%), and cancer (7%). Reported allergic diseases included food (37.8%), environmental (18%), and drugs (42.7%). The mean serum IgE level was 8383.7 kU/mL and was inversely correlated to the patient's age. A total of 49.4% had eosinophilia; 56% were known to be on trimethoprim-sulfamethoxazole, 26.6% on antifungal coverage, and 30.6% on immunoglobulin replacement therapy. Pneumonias were more commonly attributed to Staphylococcus aureus (55.3%) or Aspergillus fumigatus (22.4%); 19.5% had a history of lung abscess; these were most often associated with Pseudomonas aeruginosa (P Fisher's exact test = .029) or A. fumigatus (P Fisher's exact test = .016). Lung abscesses were significantly associated with drug reactions (P ?2 = .01; odds ratio: 4.03 [1.2-12.97]), depression (P Fisher's exact test = .036), and lower Karnofsky index scores (P Mann-Whitney = .007).Data from the USIDNET Registry summarize the currently reported clinical characteristics of a large cohort of subjects with AD-HIES.

    View details for DOI 10.1016/j.jaip.2017.06.041

    View details for PubMedID 28939137

  • Clinical and biological response to rituximab treatment in 3 patients with acquired C1-inhibitor deficiency. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology Busse, P. J., Gernez, Y. 2017; 119 (4): 380?82

    View details for DOI 10.1016/j.anai.2017.07.032

    View details for PubMedID 28866304

  • Hemoptysis in a Patient with Elevated Immunoglobulin E JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE Gernez, Y., Tsuang, A., Smith, T. D., Shahjehan, K., Hui, Y., Maglione, P. J., Cunningham-Rundles, C. 2016; 4 (6): 1054-1058

    Abstract

    Recurrent pneumonia with cavitation leading to pneumatoceles, secondary fungal infections, and hemoptysis are major causes of mortality and morbidity in patients with hyper-IgE syndrome. Prevention and aggressive treatment of pneumonia in these patients are essential to prevent further lung damage, but treatment may be delayed because the classic signs/symptoms of infection such as fever, chills, or rigors may be lacking. Early imaging to identify infection is essential for diagnosis and treatment. The mainstay of therapy is continuous, full-dose daily trimethoprim-sulfamethoxazole and commonly fungal coverage. Because hyper-IgE syndrome is a progressive disease, patients' condition may worsen despite compliance with prophylactic therapy.

    View details for DOI 10.1016/j.jaip.2016.08.003

    View details for Web of Science ID 000389613300003

    View details for PubMedID 27693026

    View details for PubMedCentralID PMC5322743

  • Modulatory Effects of Aspergillus Colonization and Abpa on Blood and Sputum Granulocytes in CF Gernez, Y., Waters, J., Dunn, C. E., Davies, Z., Everson, C., Tirouvanziam, R., Herzenberg, L., Moss, R. B. MOSBY-ELSEVIER. 2016: AB29
  • The basophil surface marker CD203c identifies Aspergillus species sensitization in patients with cystic fibrosis JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Mirkovic, B., Lavelle, G. M., Azim, A. A., Helma, K., Gargoum, F. S., Molloy, K., Gernez, Y., Dunne, K., Renwick, J., Murphy, P., Moss, R. B., Greene, C. M., Gunaratnam, C., Chotirmall, S. H., McElvaney, N. G. 2016; 137 (2): 436-?

    Abstract

    Colonization by Aspergillus fumigatus in patients with cystic fibrosis (CF) can cause A fumigatus sensitization and/or allergic bronchopulmonary aspergillosis (ABPA), which affects pulmonary function and clinical outcomes. Recent studies show that specific allergens upregulate the surface-expressed basophil marker CD203c in sensitized subjects, a response that can be readily measured by using flow cytometry.We sought to identify A fumigatus sensitization in patients with CF by using the basophil activation test (BAT).Patients with CF attending Beaumont Hospital were screened for study inclusion. BAT was used to identify A fumigatus sensitization. Serologic (total and A fumigatus-specific IgE), pulmonary function, and body mass index measurements were performed.The BAT discriminates A fumigatus-sensitized from nonsensitized patients with CF. Persistent isolation of A fumigatus in sputum is a significant risk factor for A fumigatus sensitization. Levels of the A fumigatus-stimulated basophil activation marker CD203c inversely correlated with pulmonary function and body mass index in A fumigatus-sensitized but not nonsensitized patients with CF. Total and A fumigatus-specific IgE, but not IgG, levels are increased in A fumigatus-sensitized patients with CF and ABPA when compared with those in A fumigatus-sensitized and nonsensitized patients with CF without ABPA. Itraconazole treatment did not affect A fumigatus sensitization.Combining the BAT with routine serologic testing allows classification of patients with CF into 3 groups: nonsensitized, A fumigatus-sensitized, and ABPA. Accurate and prompt identification of A fumigatus-associated clinical status might allow early and targeted therapeutic intervention, potentially improving clinical outcomes.

    View details for DOI 10.1016/j.jaci.2015.07.045

    View details for Web of Science ID 000369235500012

  • Basophil activation test determination of CD63 combined with CD203c is not superior to CD203c alone in identifying allergic bronchopulmonary aspergillosis in cystic fibrosis. The Journal of allergy and clinical immunology Gernez, Y., Waters, J., Tirouvanziam, R., Herzenberg, L., Moss, R. 2016; 138 (4): 1195?96

    View details for PubMedID 27215492

  • Basophil activation test determination of CD63 combined with CD203c is not superior to CD203c alone in identifying ABPA in cystic fibrosis Journal of Allergy and Clinical Immunology Gernez, Y., Waters, J., Tirouvanziam, R., Herzenberg, L. A., Moss, R. B. 2016: 1195?96
  • Blood basophil activation is a reliable biomarker of allergic bronchopulmonary aspergillosis in cystic fibrosis EUROPEAN RESPIRATORY JOURNAL Gernez, Y., Walters, J., Mirkovic, B., Lavelle, G. M., Colleen, D. E., Davies, Z. A., Everson, C., Tirouvanziam, R., Silver, E., Wallenstein, S., Chotirmall, S. H., McElvaney, N. G., Herzenberg, L. A., Moss, R. B. 2016; 47 (1): 177-185

    Abstract

    The diagnosis of cystic fibrosis (CF) patients with allergic bronchopulmonary aspergillosis (ABPA) is clinically challenging, due to the absence of an objective biological test. Since blood basophils play a major role in allergic responses, we hypothesised that changes in their surface activation pattern discriminate between CF patients with and without ABPA.We conducted a prospective longitudinal study (Stanford cohort) comparing basophil activation test CD203c levels by flow cytometry before and after activation with Aspergillus fumigatus allergen extract or recombinant Asp f1 in 20 CF patients with ABPA (CF-ABPA) and in two comparison groups: CF patients with A. fumigatus colonisation (AC) but without ABPA (CF-AC; n=13) and CF patients without either AC or ABPA (CF; n=12). Patients were tested every 6?months and when ill with pulmonary exacerbation. We also conducted cross-sectional validation in a separate patient set (Dublin cohort).Basophil CD203c surface expression reliably discriminated CF-ABPA from CF-AC and CF over time. Ex vivo stimulation with A. fumigatus extract or recombinant Asp f1 produced similar results within the Stanford (p<0.0001) and the Dublin cohorts. CF-ABPA patients were likelier to have elevated specific IgE to A. fumigatus and were less frequently co-infected with Staphylococcus aureus.Basophil CD203c upregulation is a suitable diagnostic and stable monitoring biomarker of ABPA in CF.

    View details for DOI 10.1183/13993003.01068-2015

    View details for Web of Science ID 000367443900023

  • Earth Mover's Distance (EMD): A True Metric for Comparing Biomarker Expression Levels in Cell Populations. PloS one Orlova, D. Y., Zimmerman, N., Meehan, S., Meehan, C., Waters, J., Ghosn, E. E., Filatenkov, A., Kolyagin, G. A., Gernez, Y., Tsuda, S., Moore, W., Moss, R. B., Herzenberg, L. A., Walther, G. 2016; 11 (3)

    Abstract

    Changes in the frequencies of cell subsets that (co)express characteristic biomarkers, or levels of the biomarkers on the subsets, are widely used as indices of drug response, disease prognosis, stem cell reconstitution, etc. However, although the currently available computational "gating" tools accurately reveal subset frequencies and marker expression levels, they fail to enable statistically reliable judgements as to whether these frequencies and expression levels differ significantly between/among subject groups. Here we introduce flow cytometry data analysis pipeline which includes the Earth Mover's Distance (EMD) metric as solution to this problem. Well known as an informative quantitative measure of differences between distributions, we present three exemplary studies showing that EMD 1) reveals clinically-relevant shifts in two markers on blood basophils responding to an offending allergen; 2) shows that ablative tumor radiation induces significant changes in the murine colon cancer tumor microenvironment; and, 3) ranks immunological differences in mouse peritoneal cavity cells harvested from three genetically distinct mouse strains.

    View details for DOI 10.1371/journal.pone.0151859

    View details for PubMedID 27008164

  • Blood basophil activation is a reliable biomarker of allergic bronchopulmonary aspergillosis in cystic fibrosis. The European respiratory journal Gernez, Y., Walters, J., Mirkovi?, B., Lavelle, G. M., Colleen, D. E., Davies, Z. A., Everson, C., Tirouvanziam, R., Silver, E., Wallenstein, S., Chotirmall, S. H., McElvaney, N. G., Herzenberg, L. A., Moss, R. B. 2015

    Abstract

    The diagnosis of cystic fibrosis (CF) patients with allergic bronchopulmonary aspergillosis (ABPA) is clinically challenging, due to the absence of an objective biological test. Since blood basophils play a major role in allergic responses, we hypothesised that changes in their surface activation pattern discriminate between CF patients with and without ABPA.We conducted a prospective longitudinal study (Stanford cohort) comparing basophil activation test CD203c levels by flow cytometry before and after activation with Aspergillus fumigatus allergen extract or recombinant Asp f1 in 20 CF patients with ABPA (CF-ABPA) and in two comparison groups: CF patients with A. fumigatus colonisation (AC) but without ABPA (CF-AC; n=13) and CF patients without either AC or ABPA (CF; n=12). Patients were tested every 6?months and when ill with pulmonary exacerbation. We also conducted cross-sectional validation in a separate patient set (Dublin cohort).Basophil CD203c surface expression reliably discriminated CF-ABPA from CF-AC and CF over time. Ex vivo stimulation with A. fumigatus extract or recombinant Asp f1 produced similar results within the Stanford (p<0.0001) and the Dublin cohorts. CF-ABPA patients were likelier to have elevated specific IgE to A. fumigatus and were less frequently co-infected with Staphylococcus aureus.Basophil CD203c upregulation is a suitable diagnostic and stable monitoring biomarker of ABPA in CF.

    View details for PubMedID 26585435

  • The basophil surface marker CD203c identifies Aspergillus species sensitization in patients with cystic fibrosis. The Journal of allergy and clinical immunology Mirkovi?, B., Lavelle, G. M., Azim, A. A., Helma, K., Gargoum, F. S., Molloy, K., Gernez, Y., Dunne, K., Renwick, J., Murphy, P., Moss, R. B., Greene, C. M., Gunaratnam, C., Chotirmall, S. H., McElvaney, N. G. 2015

    Abstract

    Colonization by Aspergillus fumigatus in patients with cystic fibrosis (CF) can cause A fumigatus sensitization and/or allergic bronchopulmonary aspergillosis (ABPA), which affects pulmonary function and clinical outcomes. Recent studies show that specific allergens upregulate the surface-expressed basophil marker CD203c in sensitized subjects, a response that can be readily measured by using flow cytometry.We sought to identify A fumigatus sensitization in patients with CF by using the basophil activation test (BAT).Patients with CF attending Beaumont Hospital were screened for study inclusion. BAT was used to identify A fumigatus sensitization. Serologic (total and A fumigatus-specific IgE), pulmonary function, and body mass index measurements were performed.The BAT discriminates A fumigatus-sensitized from nonsensitized patients with CF. Persistent isolation of A fumigatus in sputum is a significant risk factor for A fumigatus sensitization. Levels of the A fumigatus-stimulated basophil activation marker CD203c inversely correlated with pulmonary function and body mass index in A fumigatus-sensitized but not nonsensitized patients with CF. Total and A fumigatus-specific IgE, but not IgG, levels are increased in A fumigatus-sensitized patients with CF and ABPA when compared with those in A fumigatus-sensitized and nonsensitized patients with CF without ABPA. Itraconazole treatment did not affect A fumigatus sensitization.Combining the BAT with routine serologic testing allows classification of patients with CF into 3 groups: nonsensitized, A fumigatus-sensitized, and ABPA. Accurate and prompt identification of A fumigatus-associated clinical status might allow early and targeted therapeutic intervention, potentially improving clinical outcomes.

    View details for PubMedID 26388311

  • Basophil Activation Is a Reliable Biomarker Of Allergic Bronchopulmonary Aspergillosis (ABPA) In CF: One Year Results Of a Longitudinal Cohort Study Gernez, Y., Waters, J., Dunn, C., Davies, Z., Tirouvanziam, R., Everson, C., Tamaresis, J., Herzenberg, L., Moss, R. B. MOSBY-ELSEVIER. 2014: AB58
  • Blood basophils from cystic fibrosis patients with allergic bronchopulmonary aspergillosis are primed and hyper-responsive to stimulation by aspergillus allergens JOURNAL OF CYSTIC FIBROSIS Gernez, Y., Dunn, C. E., Everson, C., Mitsunaga, E., Gudiputi, L., Krasinska, K., Davies, Z. A., Herzenberg, L. A., Tirouvanziam, R., Moss, R. B. 2012; 11 (6): 502-510

    Abstract

    Fifteen to sixty percent of cystic fibrosis patients harbor Aspergillus fumigatus (Af) in their airways (CF-AC) and some will develop allergic bronchopulmonary aspergillosis (CF-ABPA). Since basophils play a key role in allergy, we hypothesized that they would display alterations in CF-ABPA patients compared to CF-AC or patients without Af colonization (CF).Using flow cytometry, we measured CD203c, CD63 and CD123 levels on basophils from CF-ABPA (N=11), CF-AC (N=14), and CF (N=12) patients before and after ex vivo stimulation with Af allergens.Baseline CD203c was increased in basophils from CF-ABPA compared to CF-AC and CF patients. Af extract and recombinant Aspf1 stimulated basophils from CF-ABPA patients to markedly upregulate CD203c, along with modest upregulation of CD63 and a CD123 downward trend. Plasma TARC/CCL17 at baseline and post-stimulation cell supernatant histamine levels were similar in the three groups.In CF-ABPA, blood basophils are primed and hyperresponsive to Af allergen stimulation.

    View details for DOI 10.1016/j.jcf.2012.04.008

    View details for Web of Science ID 000312115900004

    View details for PubMedID 22608296

  • Modulation of mTOR Effector Phosphoproteins in Blood Basophils from Allergic Patients JOURNAL OF CLINICAL IMMUNOLOGY Gernez, Y., Tirouvanziam, R., Reshamwala, N., Yu, G., Weldon, B. C., Galli, S. J., Herzenberg, L. A., Nadeau, K. C. 2012; 32 (3): 565-573

    Abstract

    The mammalian target of rapamycin (mTOR) pathway contributes to various immunoinflammatory processes. Yet, its potential involvement in basophil responses in allergy remains unclear. In this pilot study, we quantified two key mTOR effector phosphoproteins, the eukaryotic initiation factor 4E (peIF4E) and S6 ribosomal protein (pS6rp), in blood basophils from nut allergy patients (NA, N?=?16) and healthy controls (HC, N?=?13). Without stimulation in vitro, basophil peIF4E levels were higher in NA than HC subjects (P?=?0.014). Stimulation with nut (offending) but not chicken / rice (non-offending) extract increased basophil peIF4E and pS6rp levels (+32%, P?=?0.018, and +98%, P?=?0.0026, respectively) in NA but not HC subjects, concomitant with increased surface levels of CD203c and CD63, both known to reflect basophil activation. Pre-treatment with the mTOR inhibitor rapamycin decreased pS6rp and CD203c responses in nut extract-stimulated basophils in NA subjects. Thus, basophil responses to offending allergens are associated with modulation of mTOR effector phosphoproteins.

    View details for DOI 10.1007/s10875-012-9651-x

    View details for Web of Science ID 000305982100019

    View details for PubMedID 22350221

  • Immunophenotyping of Peripheral Eosinophils Demonstrates Activation in Eosinophilic Esophagitis JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Tammie Nguyen, T., Gernez, Y., Fuentebella, J., Patel, A., Tirouvanziam, R., Reshamwala, N., Bass, D., Berquist, W. E., Cox, K. L., Kerner, J. A., Nadeau, K. C. 2011; 53 (1): 40-47

    Abstract

    Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder characterized by upper gastrointestinal symptoms and the presence of high numbers of eosinophils in the esophagus. Although eosinophils in the esophagus have been found to be activated in subjects with EoE, detailed studies of intracellular signaling pathways involved in the mechanism of activation of eosinophils in EoE have heretofore been limited. The aim of the study was to assess whether any surface molecules or transcription factors are activated in peripheral eosinophils in subjects with EoE.Eosinophils and CD3+ lymphocytes were identified directly from 50 ?L of whole blood of EoE and control subjects. Using Hi-FACS, levels of surface activation markers, including CD66b, and intracellular phosphoepitopes, including phosphorylated forms of signal transducer and activator of transcription (phospho-STAT) 1 and 6, were measured within each cell subset.Levels of surface CD66b as well as levels of intracellular phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were significantly higher for untreated subjects with EoE vs healthy controls (P < 0.05). Levels of phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were lower in subjects with EoE on therapy versus untreated subjects with EoE (P < 0.05).Levels of phospho-STAT1 and phospho-STAT6, transcription factors involved in inflammatory processes, were both significantly higher in peripheral eosinophils from untreated (ie, newly diagnosed) subjects with EoE versus subjects with EoE on therapy, healthy controls. Blood-based measurements of CD66b and phospho-STAT levels in peripheral eosinophils may be beneficial for identifying EoE.

    View details for DOI 10.1097/MPG.0b013e318212647a

    View details for Web of Science ID 000291925500006

    View details for PubMedID 21694534

  • Basophil CD203c Levels Are Increased at Baseline and Can Be Used to Monitor Omalizumab Treatment in Subjects with Nut Allergy INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY Gernez, Y., Tirouvanziam, R., Yu, G., Ghosn, E. E., Reshamwala, N., Tammie Nguyen, T., Tsai, M., Galli, S. J., Herzenberg, L. A., Herzenberg, L. A., Nadeau, K. C. 2011; 154 (4): 318-327

    Abstract

    Basophils contribute to anaphylaxis and allergies. We examined the utility of assessing basophil-associated surface antigens (CD11b/CD63/CD123/CD203c/CD294) in characterizing and monitoring subjects with nut allergy.We used flow cytometry to analyze basophils at baseline (without any activation) and after ex vivo stimulation of whole blood by addition of nut or other allergens for 2, 10, and 30 min. We also evaluated whether basophil expression of CD11b/CD63/CD123/CD203c/CD294 was altered in subjects treated with anti-IgE monoclonal antibody (omalizumab) to reduce plasma levels of IgE.We demonstrate that basophil CD203c levels are increased at baseline in subjects with nut allergy compared to healthy controls (13 subjects in each group, p < 0.0001). Furthermore, we confirm that significantly increased expression of CD203c occurs on subject basophils when stimulated with the allergen to which the subject is sensitive and can be detected rapidly (10 min of stimulation, n = 11, p < 0.0008). In 5 subjects with severe peanut allergy, basophil CD203c expression following stimulation with peanut allergen was significantly decreased (p < 0.05) after 4 and 8 weeks of omalizumab treatment but returned toward pretreatment levels after treatment cessation.Subjects with nut allergy show an increase of basophil CD203c levels at baseline and following rapid ex vivo stimulation with nut allergen. Both can be reduced by omalizumab therapy. These results highlight the potential of using basophil CD203c levels for baseline diagnosis and therapeutic monitoring in subjects with nut allergy.

    View details for DOI 10.1159/000321824

    View details for Web of Science ID 000288529200007

    View details for PubMedID 20975283

    View details for PubMedCentralID PMC3214954

  • Increased HLA-DR Expression on Tissue Eosinophils in Eosinophilic Esophagitis JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Patel, A. J., Fuentebella, J., Gernez, Y., Nguyen, T., Bass, D., Berquist, W., Cox, K., Sibley, E., Kerner, J., Nadeau, K. 2010; 51 (3): 290-294

    Abstract

    The aim of the study was to investigate whether eosinophils have increased human leukocyte antigen (HLA)-DR expression in subjects with eosinophilic esophagitis (EoE) compared with controls.Patients who were undergoing an upper endoscopy with biopsies for suspected gastroesophageal reflux disease (GERD) or EoE at Lucile Packard Children's Hospital were enrolled. In total, the blood and tissue samples of 10 healthy controls (HC), 11 subjects with GERD, and 10 with EoE were studied. Multiple tissue staining to identify eosinophils (via eosinophil cationic protein-clone EG2) and major histocompatibility complex class II cell surface receptors (via HLA-DR) was performed via immunohistochemistry. The peripheral blood was analyzed using flow cytometry to detect eosinophil HLA-DR expression among these subjects.In the tissue, a greater proportion of eosinophils expressed HLA-DR among the subjects with EoE (mean 0.83 +/- 0.14, n = 9) relative to those with GERD (mean 0.18 +/- 0.19, n = 8, P < 0.01) and HC (mean 0.18 +/- 0.13, n = 6, P < 0.01). In total, 6 participants (4 HC subjects and 2 subjects with GERD) did not have any eosinophils identified on tissue staining and were unable to be included in the present statistical analysis. In the blood, there was no statistically significant difference in eosinophil HLA-DR expression among HC subjects (mean 415 +/- 217, n = 6), subjects with GERD (mean 507 +/- 429, n = 2), and those with EoE (mean 334 +/- 181, n = 6).These data demonstrate that the eosinophils from the esophagus of subjects with EoE have increased HLA-DR expression within this tissue.

    View details for DOI 10.1097/MPG.0b013e3181e083e7

    View details for Web of Science ID 000281453500008

    View details for PubMedID 20639774

  • Activation of critical, host-induced, metabolic and stress pathways marks neutrophil entry into cystic fibrosis lungs PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Makam, M., Diaz, D., Laval, J., Gernez, Y., Conrad, C. K., Dunn, C. E., Davies, Z. A., Moss, R. B., Herzenberg, L. A., Herzenberg, L. A., Tirouvanziam, R. 2009; 106 (14): 5779-5783

    Abstract

    Cystic fibrosis (CF) patients undergo progressive airway destruction caused in part by chronic neutrophilic inflammation. While opportunistic pathogens infecting CF airways can cause inflammation, we hypothesized that host-derived metabolic and stress signals would also play a role in this process. We show that neutrophils that have entered CF airways have increased phosphorylation of the eukaryotic initiation factor 4E and its partner the 4E-binding protein 1; 2 key effectors in the growth factor- and amino acid-regulated mammalian target of rapamycin (mTOR) pathway. Furthermore CF airway neutrophils display increased phosphorylation of the cAMP response element binding protein (CREB), a major transcriptional coactivator in stress signaling cascades. These active intracellular pathways are associated with increased surface expression of critical adaptor molecules, including the growth factor receptor CD114 and the receptor for advanced glycation end-products (RAGE), a CREB inducer and sensor for host-derived damage-associated molecular patterns (DAMPs). Most CF airway fluids lack any detectable soluble RAGE, an inhibitory decoy receptor for DAMPs. Concomitantly, CF airway fluids displayed high and consequently unopposed levels of S100A12; a potent mucosa- and neutrophil-derived DAMP. CF airway neutrophils also show increased surface levels of 2 critical CREB targets, the purine-recycling enzyme CD39 and the multifunctional, mTOR-inducing CXCR4 receptor. This coordinated set of events occurs in all patients, even in the context of minimal airway inflammation and well-preserved lung function. Taken together, our data demonstrate an early and sustained activation of host-responsive metabolic and stress pathways upon neutrophil entry into CF airways, suggesting potential targets for therapeutic modulation.

    View details for DOI 10.1073/pnas.0813410106

    View details for Web of Science ID 000264967500059

    View details for PubMedID 19293384

    View details for PubMedCentralID PMC2667067

  • Enhanced Expression of CD66b on Peripheral Blood Granulocytes in Eosinophilic Esophagitis Nguyen, T., Gernez, Y., Fuentebella, J., Patel, A., Herzenberg, L., Tirouvanziam, R., Nadeau, K. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2009: S120?S121
  • A rare cause of stridor in a 59 year old woman in intensive care REVUE DES MALADIES RESPIRATOIRES Gernez, Y., Breen, D., Peloni, J., Meric, B., Dutau, H. 2008; 25 (7): 871-874

    Abstract

    Stridor in the post extubation period occurs frequently and is most commonly caused by laryngeal oedema. During this period, the trachea can also be obstructed by pseudomembranes.We report the case of a 59 year old woman who required re-intubation, 15 days after extubation because of the acute onset of severe respiratory distress secondary to pseudomembranes in her trachea.It is essential that physicians who care for patients during the post extubation period are aware of this severe and life threatening cause of stridor. Definitive treatment with the rigid bronchoscope allows for rapid recanalisation of the airway.

    View details for DOI 10.1019/200720293

    View details for Web of Science ID 000259903000015

    View details for PubMedID 18946415

  • Profound functional and signaling changes in viable inflammatory neutrophils homing to cystic fibrosis airways PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Tirouvanziam, R., Gernez, Y., Conrad, C. K., Moss, R. B., Schrijver, I., Dunn, C. E., Davies, Z. A., Herzenberg, L. A., Herzenberg, L. A. 2008; 105 (11): 4335-4339

    Abstract

    Blood neutrophils recruited to cystic fibrosis (CF) airways are believed to be rapidly killed by resident bacteria and to passively release elastase and other toxic by-products that promote disease progression. By single-cell analysis, we demonstrate that profound functional and signaling changes readily occur within viable neutrophils recruited to CF airways, compared with their blood counterparts. Airway neutrophils have undergone conventional activation, as shown by decreased intracellular glutathione, increased lipid raft assembly, surface mobilization of CD11b+ and CD66b+ granules, and increased levels of the cytoskeleton-associated phospho-Syk kinase. Unexpectedly, they also mobilize to the surface CD63+ elastase-rich granules, usually confined intracellularly, and lose surface expression of CD16 and CD14, both key receptors in phagocytosis. Furthermore, they express CD80, major histocompatibility complex type II, and the prostaglandin D2 receptor CD294, all normally associated with other lineages, which reflects functional reprogramming. This notion is reinforced by their decreased total phosphotyrosine levels, mirroring a postactivated stage, and increased levels of the phospho-S6 ribosomal protein, a key anabolic switch. Thus, we identified a subset of neutrophils within CF airways with a viable but dysfunctional phenotype. This subset provides a possible therapeutic target and indicates a need to revisit current paradigms of CF airway disease.

    View details for DOI 10.1073/pnas.0712386105

    View details for Web of Science ID 000254263300048

    View details for PubMedID 18334635

    View details for PubMedCentralID PMC2393742

  • Altered phosphorylated signal transducer and activator of transcription profile of CD4(+)CD161(+) T cells in asthma: Modulation by allergic status and oral corticosteroids JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Gernez, Y., Tirouvanziam, R., Nguyen, K. D., Herzenberg, L. A., Krensky, A. M., Nadeau, K. C. 2007; 120 (6): 1441-1448

    Abstract

    Asthma is a complex immunologic disorder linked to altered cytokine signaling.We tested whether asthmatic patients showed any change in cytokine-dependent signal transducer and activator of transcription (STAT) levels, focusing on the central/effector-memory CD4(+)CD161(+) subset, which represents 15% to 25% of circulating T cells.We quantified intracellular levels of active phosphorylated STAT (phospho-STAT) 1, 3, 5, and 6 by means of flow cytometry, without any activation or expansion.Baseline phospho-STAT1 and phospho-STAT6 levels were increased in CD4(+)CD161(+) T cells from asthmatic patients compared with those from healthy control subjects (by 10- and 8-fold, respectively). This asthma-associated alteration was both subset specific because no change was seen in CD4(+)CD161(-)CD25(+) (regulatory T cells) and CD4(+)CD161(-)CD25(-) subsets and isoform specific because phospho-STAT5 and phospho-STAT3 levels were unchanged. Among asthmatic patients, phospho-STAT1 and phospho-STAT6 levels correlated negatively with each other, suggesting antagonistic regulation. Oral corticosteroid (OCS) treatment significantly decreased phospho-STAT6 and IL-4 levels but not phospho-STAT1 levels. Disease parameters showing significant correlations with phospho-STAT1, phospho-STAT6, or both included age at onset, plasma IgE levels, and levels of the T(H)2 cytokines IL-4 and IL-10 and the T(H)1 cytokine IL-2. Overall, combined phospho-STAT1 and phospho-STAT6 measurements showed excellent predictive value for identifying (1) asthmatic patients versus healthy control subjects, (2) allergic versus nonallergic asthmatic patients, and (3) asthmatic patients taking versus those not taking OCSs.Baseline changes in phospho-STAT1 and phospho-STAT6 levels in blood CD4(+)CD161(+) T cells identify asthmatic patients and mirror their allergic status and response to OCSs.These results confirm the pathologic importance of activated STAT1 and STAT6 in asthma and suggest their potential use as clinical biomarkers.

    View details for DOI 10.1016/j.jaci.2007.08.012

    View details for Web of Science ID 000251653800029

    View details for PubMedID 17919711

    View details for PubMedCentralID PMC2679255

  • Phospho-FACS: a powerful tool for exploring intracellular transduction cascades REVUE DES MALADIES RESPIRATOIRES Gernez, Y., Herzenberg, L. A., Herzenberg, L. A., Tirouvanziam, R. 2007; 24 (8): 955-964

    Abstract

    FACS (fluorescence-activated cell sorting), or flow cytometry, was developed in 1971 by Leonard Herzenberg's team at Stanford University. Under continuous development, this technology enables single-cell multiparametric analysis and sorting, based on physical properties of cells and/or their relative expression levels of specific glycoproteic epitopes and metabolites.Recently, the use of fluorescent antibodies specific for phosphorylated epitopes - or "phospho-epitopes" - within proteins of interest has further extended the range of FACS analyses. This new application, dubbed "phospho-FACS", has quickly become a tool of choice for delineating intracellular phosphorylation cascades.In both basic research and clinical research, the application of phospho-FACS to cellular subsets from blood or the periphery, whether frequent or rare, enables the discovery of pathological biomarkers and therapeutic innovation.Thanks to its rapid implementation and its ability to generate single-cell data, the phospho-FACS technique features numerous advantages compared to preexisting analytical methods for intracellular phosphorylation cascades.

    View details for DOI 10.1019/20072001118

    View details for Web of Science ID 000251260100004

    View details for PubMedID 18033184

  • A contributive result of open-lung biopsy improves survival in acute respiratory distress syndrome patients CRITICAL CARE MEDICINE Papazian, L., Doddoli, C., Chetaille, B., Gernez, Y., Thirion, X., Roch, A., Donati, Y., Bonnety, M., Zandotti, C., Thomas, P. 2007; 35 (3): 755-762

    Abstract

    The impact of a contributive result of open-lung biopsy on the outcome of patients with acute respiratory distress syndrome (ARDS) has not been extensively investigated. The aim of this study was therefore to determine the rate of contributive open-lung biopsy and whether it improved the prognosis of ARDS patients.Prospective study conducted during an 8-yr period.A 14-bed medico-surgical intensive care unit and a 12-bed medical intensive care unit from the same hospital.One hundred open-lung biopsies were performed in 100 patients presenting ARDS.Open-lung biopsy was performed after > or = 5 days of evolution of ARDS when there was no improvement in the respiratory status despite negative microbiological samples cultures and potential indication for corticosteroid treatment.Ten patients presented a mechanical complication following open-lung biopsy (two pneumothoraces and eight moderate air leaks). The unique independent factor associated with this complication was the minute ventilation when open-lung biopsy was performed (odds ratio, 1.20; 95% confidence interval, 1.03-1.41; p = .02). Fibrosis was noted in 53 patients but was associated with an infection in 29 of these 53 patients (55%). A contributive result of open-lung biopsy (defined as the addition of a new drug) was noted in 78 patients. Simplified Acute Physiology Score II was the only independent predictive factor of a contributive open-lung biopsy (odds ratio, 0.96; 95% confidence interval, 0.92-0.99; p = .04). Survival was higher in patients with a contributive open-lung biopsy (67%) than in patients in whom open-lung biopsy results did not modify the treatment (14%) (p < .001). The factors predicting survival were a contributive result of open-lung biopsy, female gender, and the Organ System Failures score the day of open-lung biopsy.The present study shows that open-lung biopsy provided a contributive result in 78% of ARDS patients with a negative bronchoalveolar lavage. Survival of ARDS patients improved when open-lung biopsy was contributive.

    View details for DOI 10.1097/01.CCM.0000257325.88144.30

    View details for Web of Science ID 000244470800009

    View details for PubMedID 17255856

  • Hypersensitivity to carboplatin - An effect of generic drugs? REVUE DES MALADIES RESPIRATOIRES Gernez, Y., Barlesi, F., Astoul, R., Magnan, A. 2006; 23 (3): 269-272

    Abstract

    Carboplatin is a chemotherapeutic agent used frequently in thoracic medicine on account of its relatively good tolerance. Nevertheless hypersensitivity reactions have been described.We report the cases of 2 patients, treated for undifferentiated bronchial carcinoma and carcinoma of the breast, presenting with hypersensitivity reactions to carboplatin developing after 6 and 8 courses respectively. The first patient presented with an irritant maculo-papular rash and the second with severe hypotension and bronchospasm. Neither of these reactions was fatal. Both of these reactions occurred when generic carboplatin was substituted for the propriety preparation.Hypersensitivity reactions to carboplatin should be recognised by respiratory physicians on account of their potential seriousness and their occurrence after several courses of treatment. This takes on particular importance at a time when plans for domiciliary treatment of patients are being considered. In addition a national survey of hypersensitivity to carboplatin should be considered by the regional drug safety centres.

    View details for DOI 10.1019/200530242

    View details for Web of Science ID 000238841600010

    View details for PubMedID 16788528

  • Acute respiratory distress syndrome following inhalation of barium sulphate REVUE DES MALADIES RESPIRATOIRES Gernez, Y., Barlesi, F., Doddoli, C., Chetaille, B., Forel, J. M., Astoul, P., Papazian, L. 2005; 22 (3): 477-480

    Abstract

    Barium sulfate (BS) is chosen to explore swallowing disorders because of its reduced osmolality allowing no adverse reaction if aspirated in the bronchial tree.A 66-years old man treated for an advanced stage mesothelioma experienced a BS aspiration during an esophagography. He developed 3 days after an acute respiratory distress syndrome (ARDS) and deceased. The post-mortem examination revealed a diffuse alveolar damage (DAD).Whereas BS aspiration is generally well tolerated, serious adverse event as a DAD would exceptionally occurs. Thus, a close watch over respiratory symptoms has to be kept after BS administration, especially in debilitated and elderly patients.

    View details for DOI 10.1019/200530014

    View details for Web of Science ID 000230752700015

    View details for PubMedID 16227934

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