Joseph Hernandez

All Publications

• A great disturbance in the force: IL-2 receptor defects disrupt immune homeostasis. Current opinion in pediatrics Hernandez, J. D., Hsieh, E. W. 2022

  Abstract

  PURPOSE OF REVIEW: The current review highlights how inborn errors of immunity (IEI) due to IL-2 receptor (IL-2R) subunit defects may result in children presenting with a wide variety of infectious and inflammatory presentations beyond typical X-linked severe combined immune deficiency (X-SCID) associated with IL-2Rgamma.RECENT FINDINGS: Newborn screening has made diagnosis of typical SCID presenting with severe infections less common. Instead, infants are typically diagnosed in the first days of life when they appear healthy. Although earlier diagnosis has improved clinical outcomes for X-SCID, atypical SCID or other IEI not detected on newborn screening may present with more limited infectious presentations and/or profound immune dysregulation. Early management to prevent/control infections and reduce inflammatory complications is important for optimal outcomes of definitive therapies. Hematopoietic stem cell transplant (HSCT) is curative for IL-2Ralpha, IL-2Rbeta, and IL-2Rgamma defects, but gene therapy may yield comparable results for X-SCID.SUMMARY: Defects in IL-2R subunits present with infectious and inflammatory phenotypes that should raise clinician's concern for IEI. Immunophenotyping may support the suspicion for diagnosis, but ultimately genetic studies will confirm the diagnosis and enable family counseling. Management of infectious and inflammatory complications will determine the success of gene therapy or HSCT.

  View details for DOI 10.1097/MOP.0000000000001181

  View details for PubMedID 36165614

• Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet+ B cells. Nature immunology Csomos, K., Ujhazi, B., Blazso, P., Herrera, J. L., Tipton, C. M., Kawai, T., Gordon, S., Ellison, M., Wu, K., Stowell, M., Haynes, L., Cruz, R., Zakota, B., Nguyen, J., Altrich, M., Geier, C. B., Sharapova, S., Dasso, J. F., Leiding, J. W., Smith, G., Al-Herz, W., de Barros Dorna, M., Fadugba, O., Fronkova, E., Kanderova, V., Svaton, M., Henrickson, S. E., Hernandez, J. D., Kuijpers, T., Kandilarova, S. M., Naumova, E., Milota, T., Sediva, A., Moshous, D., Neven, B., Saco, T., Sargur, R., Savic, S., Sleasman, J., Sunkersett, G., Ward, B. R., Komatsu, M., Pittaluga, S., Kumanovics, A., Butte, M. J., Cancro, M. P., Pillai, S., Meffre, E., Notarangelo, L. D., Walter, J. E. 2022

  Abstract

  The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact of RAG1/RAG2 on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an 'experiment of nature' to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal a RAG-dependent 'domino effect' that impacts stringency of tolerance and B cell fate in the periphery.

  View details for DOI 10.1038/s41590-022-01271-6

  View details for PubMedID 35902638

• Partial RAG Deficiency Favors Expansion of T-bet high CD21 low B Cells with Unique Repertoire and Transcriptome Csomos, K., Ujhazi, B., Blazso, P., Gordon, S., Tipton, C. M., Scharer, C., Dasso, J., Sargur, R., Ward, B., Hernandez, J. D., Butte, M., Notarangelo, L., Cancro, M. P., Walter, J. SPRINGER/PLENUM PUBLISHERS. 2022: S56

  View details for Web of Science ID 000784584900102

• Clean up by aisle 2: roles for IL-2 receptors in host defense and tolerance. Current opinion in immunology Hsieh, E. W., Hernandez, J. D. 2021; 72: 298-308

  Abstract

  Although IL-2 was first recognized as growth factor for T cells, it is now also appreciated to be a key regulator of T cells through its effects on regulatory T cells (Treg). The IL-2 receptor (IL-2R) subunits' different (i) ligand affinities, (ii) dimerization or trimerization relationships with other cytokine subunits, (iii) expression across multiple cell types, and (iv) downstream signaling effects, largely dictate cellular tolerance and antimicrobial processes. Defects in IL-2Rgamma result in profound and almost universally fatal immune deficiency, unless treated with hematopoietic stem cell transplantation (HSCT). Defects in IL-2Ralpha and IL-2Rbeta result in more limited infection susceptibility, particularly to herpesviruses. However, the most prominent clinical symptomatology for IL-2Ralpha and IL-2Rbeta defects include multi-organ autoimmunity and inflammation, consistent with the critical role of IL-2 in establishing and maintaining immune tolerance. Here, we review how we have arrived at our current understanding of the complex roles of IL-2/2R in host defense and tolerance focusing on the insights gained from human clinical immunology.

  View details for DOI 10.1016/j.coi.2021.07.010

  View details for PubMedID 34479098

• Are we diagnosing too late? RAG deficiency in young adults with end organ damage Saco, T., Geier, C., Buchbinder, D., Hernandez, J., Sharapova, S., Cochino, A., Milota, T., Latysheva, E., Westerman-Clark, E., Fadugba, O., Morris, E., Albert, M., Dimitrova, D., Moshous, D., Kanakry, J., Md, S., de Villartay, J., Sargur, R., Notarangelo, L., Walter, J. MOSBY-ELSEVIER. 2021: AB69

  View details for Web of Science ID 000629158000216

• Novel nonsense IKBKG Mutation in an Infant Presenting with Pneumocysti s Jiroveci Pneumonia and Disseminated Mycobacterium Szulgai Infection Lo, R., Rosenthal, A., Shah, A., Chen, S., Eguiguren, L., Siddiqi, A., Hernandez, J., Lewis, D. SPRINGER/PLENUM PUBLISHERS. 2020: S119–S120

  View details for Web of Science ID 000540191100176

• Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE Farmer, J. R., Foldvari, Z., Ujhazi, B., De Ravin, S., Chen, K., Bleesing, J. H., Schuetz, C., Al-Herz, W., Abraham, R. S., Joshi, A. Y., Costa-Carvalho, B. T., Buchbinder, D., Booth, C., Reiff, A., Ferguson, P. J., Aghamohammadi, A., Abolhassani, H., Puck, J. M., Adeli, M., Cancrini, C., Palma, P., Bertaina, A., Locatelli, F., Di Matteo, G., Geha, R. S., Kanariou, M. G., Lycopoulou, L., Tzanoudaki, M., Sleasman, J. W., Parikh, S., Pinero, G., Fischer, B. M., Dbaibo, G., Unal, E., Patiroglu, T., Karakukcu, M., Al-Saad, K., Dilley, M. A., Pai, S., Dutmer, C. M., Gelfand, E. W., Geier, C. B., Eibl, M. M., Wolf, H. M., Henderson, L. A., Hazen, M. M., Bonfim, C., Wolska-Kusnierz, B., Butte, M. J., Hernandez, J. D., Nicholas, S. K., Stepensky, P., Chandrakasan, S., Miano, M., Westermann-Clark, E., Goda, V., Krivan, G., Holland, S. M., Fadugba, O., Henrickson, S. E., Ozen, A., Karakoc-Aydiner, E., Baris, S., Kiykim, A., Bredius, R., Hoeger, B., Boztug, K., Pashchenko, O., Neven, B., Moshous, D., de Villartay, J., Bousfiha, A., Hill, H. R., Notarangelo, L. D., Walter, J. E. 2019; 7 (6): 1970-+

  View details for DOI 10.1016/j.jaip.2019.02.038

  View details for Web of Science ID 000473777600035

• Outcomes and treatment strategies for autoimmunity and hyperinflammation in patients with RAG deficiency. The journal of allergy and clinical immunology. In practice Farmer, J. R., Foldvari, Z., Ujhazi, B., De Ravin, S. S., Chen, K., Bleesing, J. J., Schuetz, C., Al-Herz, W., Abraham, R. S., Joshi, A. Y., Costa-Carvalho, B. T., Buchbinder, D., Booth, C., Reiff, A., Ferguson, P. J., Aghamohammadi, A., Abolhassani, H., Puck, J. M., Adeli, M., Cancrini, C., Palma, P., Bertaina, A., Locatelli, F., Di Matteo, G., Geha, R. S., Kanariou, M. G., Lycopoulou, E., Tzanoudaki, M., Sleasman, J. W., Parikh, S., Pinero, G., Fischer, B. M., Dbaibo, G., Unal, E., Patiroglu, T., Karakukcu, M., Al-Saad, K. K., Dilley, M. A., Pai, S., Dutmer, C. M., Gelfand, E. W., Geier, C. B., Eibl, M. M., Wolf, H. M., Henderson, L. A., Hazen, M. M., Bonfim, C., Wolska-Kusnierz, B., Butte, M. J., Hernandez, J. D., Nicholas, S. K., Stepensky, P., Chandrakasan, S., Miano, M., Westermann-Clark, E., Goda, V., Krivan, G., Holland, S. M., Fadugba, O., Henrickson, S. E., Ozen, A., Karakoc-Aydiner, E., Baris, S., Kiykim, A., Bredius, R., Hoeger, B., Boztug, K., Pashchenko, O., Neven, B., Moshous, D., Villartay, J. d., Bousfiha, A. A., Hill, H. R., Notarangelo, L. D., Walter, J. E. 2019

  Abstract

  BACKGROUND: While autoimmunity and hyperinflammation secondary to recombinase 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. The majority of patients (55.6%) presented with more than one 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 (AIHA), immune thrombocytopenia (ITP) and autoimmune neutropenia (AN), respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in the majority of cases (64.7%, 73.7%, and 71.4% for AIHA, ITP, and AN, 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. Multi-lineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.

  View details for PubMedID 30877075

• Defective B Cell Fitness Impairs Mutation Away from Self and Sustains Red Blood Cell Reactivity in Hypomorphic RAG Deficiency Csomos, K., Ujhazi, B., Wu, K., Cruz, R., Stowell, M., Keszei, M., Al-Herz, W., Hernandez, J. D., Savic, S., Sargur, R., Mihailova, S., Sharapova, S. O., Butte, M., Walter, J. SPRINGER/PLENUM PUBLISHERS. 2019: S127

  View details for Web of Science ID 000463709600209

• Anti-cytokine Antibodies Emerge After Viral Infections and Persist in Patients in Partial RAG Deficiency Dawson, I., Ujhazi, B., Csomos, K., Abraham, R. S., Sleasman, J., Kuijpers, T., Neven, B., Leiding, J., Mihailova, S., Holland, S. M., Song, C., Goda, V., Krivan, G., Savic, S., Sargur, R., Henderson, L., Al-Herz, W., Dorna, M., Hernandez, J. D., Butte, M., Walter, J. SPRINGER/PLENUM PUBLISHERS. 2019: S116–S117

  View details for Web of Science ID 000463709600192

• Development of multiple features of antigen-induced asthma pathology in a new strain of mast cell deficient BALB/c-KitW-sh/W-sh mice. Laboratory investigation; a journal of technical methods and pathology Hernandez, J. D., Yu, M. n., Sibilano, R. n., Tsai, M. n., Galli, S. J. 2019

  Abstract

  Mast cell-deficient mice are widely used to identify and quantify contributions of mast cells to diverse biological responses in vivo, including allergic inflammation. However, despite the fact that scores of genes have been identified as modifiers of allergic inflammation, most mast cell-deficient models have been available only on a single genetic background. We transferred the KitW-sh allele onto the BALB/c background to generate BALB/c mast cell-deficient mice (BALB/c-KitW-sh/W-sh). BALB/c-KitW-sh/W-sh mice have dramatically reduced mast cell numbers (0-2% of wild type) in all tissues examined, as well as subtle hematologic differences from the corresponding wild type mice, including splenomegaly with evidence of increased splenic hematopoiesis. We examined in BALB/c-KitW-sh/W-sh mice models of allergic inflammation that are substantially diminished in C57BL/6-KitW-sh/W-sh mast cell-deficient mice. In a model of acute allergic inflammation, i.e., IgE-dependent passive cutaneous anaphylaxis, both ear swelling and leukocyte infiltration were largely or entirely absent in BALB/c-KitW-sh/W-sh mice. In contrast, in two different models of allergic airway inflammation, airway hyperresponsiveness, lung inflammation, and airway remodeling developed robustly in mast cell-deficient BALB/c-KitW-sh/W-sh mice. These results support the conclusion that the importance of mast cell contributions in various models of allergic inflammation may be at least partially determined by genetic background.

  View details for DOI 10.1038/s41374-019-0354-2

  View details for PubMedID 31857699

• Reply. The journal of allergy and clinical immunology. In practice Postolova, A., Hernandez, J. D. 2018; 6 (6): 2178

  View details for PubMedID 30390915

• Allergic Diseases and Immune-Mediated Food Disorders in Pediatric Acute-Onset Neuropsychiatric Syndrome. Pediatric allergy, immunology, and pulmonology Rosa, J. S., Hernandez, J. D., Sherr, J. A., Smith, B. M., Brown, K. D., Farhadian, B., Mahony, T., McGhee, S. A., Lewis, D. B., Thienemann, M., Frankovich, J. D. 2018; 31 (3): 158-165

  Abstract

  Background: The prevalence and impact of allergic and immune-mediated food disorders in pediatric acute-onset neuropsychiatric syndrome (PANS) are mostly unknown. Objective: We sought to explore the prevalence of atopic dermatitis (AD), asthma, allergic rhinitis (AR), IgE-mediated food allergies (FAs), and other immune-mediated food disorders requiring food avoidance in patients with PANS. In addition, to further understand the extent of food restriction in this population, we investigated the empiric use of dietary measures to improve PANS symptoms. Methods: Pediatric patients in a PANS Clinic and Research Program were given surveys regarding their caregiver burdens, allergic and food-related medical history, and whether food elimination resulted in perception of improvement of PANS symptoms. A review of health records was conducted to confirm that all responses in the survey were concordant with documentation of each patient's medical chart. Results: Sixty-nine (ages 4-20 years) of 80 subjects who fulfilled PANS criteria completed the surveys. Thirteen (18.8%) had AD, 11 (15.9%) asthma, 33 (47.8%) AR, 11 (15.9%) FA, 1 (1.4%) eosinophilic gastrointestinal disorders, 1 (1.4%) food protein-induced enterocolitis syndrome, 3 (4.3%) milk protein-induced proctocolitis syndrome, and 3 (4.3%) celiac disease. Thirty subjects (43.5%) avoided foods due to PANS; elimination of gluten and dairy was most common and was associated with perceived improvement of PANS symptoms (by parents). This perceived improvement was not confirmed with objective data. Conclusions: The prevalence of allergic and immune-mediated food disorders in PANS is similar to the general population as reported in the literature, with the exception of AR that appears to be more prevalent in our PANS cohort. More research will be required to establish whether diet or allergies influence PANS symptoms.

  View details for DOI 10.1089/ped.2018.0888

  View details for PubMedID 30283713

  View details for PubMedCentralID PMC6154445

• Allergic Diseases and Immune-Mediated Food Disorders in Pediatric Acute-Onset Neuropsychiatric Syndrome PEDIATRIC ALLERGY IMMUNOLOGY AND PULMONOLOGY Rosa, J. S., Hernandez, J. D., Sherr, J. A., Smith, B. M., Brown, K. D., Farhadian, B., Mahony, T., McGhee, S. A., Lewis, D. B., Thienemann, M., Frankovich, J. D. 2018; 31 (3): 158–65

  View details for DOI 10.1089/ped.2018.0888

  View details for Web of Science ID 000445067100006

• Anaphylaxis to invasive chlorhexidine administration despite tolerance of topical chlorhexidine use JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE Postolova, A., Bradley, J. T., Parris, D., Sherr, J., McGhee, S. A., Hernandez, J. D. 2018; 6 (3): 1067-+

  View details for PubMedID 29226805

• Alternations in repertoire of T and B cell subsets in patients with partial recombination activating gene (RAG) deficiency with autoimmunity and history of viral infections Csomos, K., Ujhazi, B., Butte, M. J., Hernandez, J., Geha, R., Al-Herz, W., Notarangelo, L. D., Meffre, E., Walter, J. E. SPRINGER/PLENUM PUBLISHERS. 2018: 420–21

  View details for Web of Science ID 000431311600200

• Naive B cells are prone to develop into polyreactive autoantibody secreting cells from adult RAG2-deficient patient with combined immunodeficiency Stowell, M. T., Walter, J. E., Pennix, T. C., Ujhazi, B., Mueller, G., Butte, M., Hoyte, E. G., Hernandez, J. D., Meffre, E. F., Csomos, K. MOSBY-ELSEVIER. 2018: AB22

  View details for Web of Science ID 000429306700069

• The pathophysiology of anaphylaxis. The Journal of allergy and clinical immunology Reber, L. L., Hernandez, J. D., Galli, S. J. 2017; 140 (2): 335–48

  Abstract

  Anaphylaxis is a severe systemic hypersensitivity reaction that is rapid in onset; characterized by life-threatening airway, breathing, and/or circulatory problems; and usually associated with skin and mucosal changes. Because it can be triggered in some persons by minute amounts of antigen (eg, certain foods or single insect stings), anaphylaxis can be considered the most aberrant example of an imbalance between the cost and benefit of an immune response. This review will describe current understanding of the immunopathogenesis and pathophysiology of anaphylaxis, focusing on the roles of IgE and IgG antibodies, immune effector cells, and mediators thought to contribute to examples of the disorder. Evidence from studies of anaphylaxis in human subjects will be discussed, as well as insights gained from analyses of animal models, including mice genetically deficient in the antibodies, antibody receptors, effector cells, or mediators implicated in anaphylaxis and mice that have been "humanized" for some of these elements. We also review possible host factors that might influence the occurrence or severity of anaphylaxis. Finally, we will speculate about anaphylaxis from an evolutionary perspective and argue that, in the context of severe envenomation by arthropods or reptiles, anaphylaxis might even provide a survival advantage.

  View details for PubMedID 28780941

• Clinical Management of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS): Part II – Use of Immunomodulatory Therapies Journal of Child and Adolescent Psychopharmacology Frankovich, J., Swedo, S., Murphy, T., Dale, R. C., Agalliu, D., Williams, K., Daines, M., Hornig, M., Chugani, H., Sanger, T., Muscal, E., Pasternack, M., Cooperstock, M., Gans, H., Zhang, Y., Cunningham, M., Bernstein, G., Bromberg, R., Willett, T., Brown, K., Farhadian, B., Chang, K., Geller, D., Hernandez, J., Sherr, J., et al 2017; 27 (7): 574-593

  View details for DOI 10.1089/cap.2016.0148

• Pediatric Acute-Onset Neuropsychiatric Syndrome Response to Oral Corticosteroid Bursts: An Observational Study of Patients in an Academic Community-Based PANS Clinic. Journal of child and adolescent psychopharmacology Brown, K. n., Farmer, C. n., Farhadian, B. n., Hernandez, J. n., Thienemann, M. n., Frankovich, J. n. 2017; 27 (7): 629–39

  Abstract

  Sudden-onset severe obsessive-compulsive symptoms and/or severely restrictive food intake with at least two coinciding, similarly debilitating neuropsychiatric symptoms define Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). When associated with Group A Streptococcus, the syndrome is labeled Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS). An abnormal immune response to infection and subsequent neuroinflammation is postulated to play an etiologic role. Most patients have a relapsing-remitting course. Treatment outcome data for youth with PANS and PANDAS are limited.One hundred seventy-eight consecutive patients were seen in the Stanford PANS clinic between September 1, 2012 and January 15, 2016, of whom 98 met PANS or PANDAS criteria, had a single episode of PANS or relapsing/remitting course, and collectively experienced 403 flares. Eighty-five flares were treated with 102 total courses of oral corticosteroids of either short (4-5 days) or long (5 days-8 weeks) duration. Response to treatment was assessed within 14 days of initiating a short burst of corticosteroids and at the end of a long burst based on clinician documentation and patient questionnaires. Data were analyzed by using multilevel random-effects models.Patients experienced shorter flares when treated with oral corticosteroids (6.4 ± 5.0 weeks vs. 11.4 ± 8.6 weeks) than when not treated (p < 0.001), even after controlling for presumed confounding variables, including age at flare, weeks since onset of PANS illness, sex, antibiotic treatment, prophylactic antibiotics, previous immunomodulatory treatment, maintenance anti-inflammatory therapy, psychiatric medications, and cognitive behavioral therapy (p < 0.01). When corticosteroids were given for the initial PANS episode, flares tended to be shorter (10.3 ± 5.7 weeks) than when not treated (16.5 ± 9.6 weeks) (p = 0.06). This difference was statistically significant after controlling for the relevant confounding variables listed earlier (p < 0.01). Earlier use of corticosteroids was associated with shorter flare durations (p < 0.001). Longer courses of corticosteroids were associated with a more enduring impact on the duration of neuropsychiatric symptom improvement (p = 0.014).Corticosteroids may be a helpful treatment intervention in patients with new-onset and relapsing/remitting PANS and PANDAS, hastening symptom improvement or resolution. When corticosteroids are given earlier in a disease flare, symptoms improve more quickly and patients achieve clinical remission sooner. Longer courses of corticosteroids may result in more durable remissions. A double-blind placebo-controlled clinical trial of corticosteroids in PANS is warranted to formally assess treatment efficacy.

  View details for PubMedID 28714753

• A TNFRSF14-Fc epsilon RI-mast cell pathway contributes to development of multiple features of asthma pathology in mice NATURE COMMUNICATIONS Sibilano, R., Gaudenzio, N., DeGorter, M. K., Reber, L. L., Hernandez, J. D., Starkl, P. M., Zurek, O. W., Tsai, M., Zahner, S., Montgomery, S. B., Roers, A., Kronenberg, M., Yu, M., Galli, S. J. 2016; 7

  Abstract

  Asthma has multiple features, including airway hyperreactivity, inflammation and remodelling. The TNF superfamily member TNFSF14 (LIGHT), via interactions with the receptor TNFRSF14 (HVEM), can support TH2 cell generation and longevity and promote airway remodelling in mouse models of asthma, but the mechanisms by which TNFSF14 functions in this setting are incompletely understood. Here we find that mouse and human mast cells (MCs) express TNFRSF14 and that TNFSF14:TNFRSF14 interactions can enhance IgE-mediated MC signalling and mediator production. In mouse models of asthma, TNFRSF14 blockade with a neutralizing antibody administered after antigen sensitization, or genetic deletion of Tnfrsf14, diminishes plasma levels of antigen-specific IgG1 and IgE antibodies, airway hyperreactivity, airway inflammation and airway remodelling. Finally, by analysing two types of genetically MC-deficient mice after engrafting MCs that either do or do not express TNFRSF14, we show that TNFRSF14 expression on MCs significantly contributes to the development of multiple features of asthma pathology.

  View details for DOI 10.1038/ncomms13696

  View details for Web of Science ID 000389853400001

  View details for PubMedID 27982078

  View details for PubMedCentralID PMC5171877

• Novel tools for primary immunodeficiency diagnosis: making a case for deep profiling. Current opinion in allergy and clinical immunology Hsieh, E. W., Hernandez, J. D. 2016; 16 (6): 549-556

  Abstract

  This review gives an overview of the systems-immunology single-cell proteomic and transcriptomic approaches that can be applied to study primary immunodeficiency. It also introduces recent advances in multiparameter tissue imaging, which allows extensive immune phenotyping in disease-affected tissue.Mass cytometry is a variation of flow cytometry that uses rare earth metal isotopes instead of fluorophores as tags bound to antibodies, allowing simultaneous measurement of over 40 parameters per single-cell. Mass cytomety enables comprehensive single-cell immunophenotyping and functional assessments, capturing the complexity of the immune system, and the molecularly heterogeneous consequences of primary immunodeficiency defects. Protein epitopes and transcripts can be simultaneously detected allowing immunophenotype and gene expression evaluation in mixed cell populations. Multiplexed epitope imaging has the potential to provide extensive phenotypic characterization at the subcellular level, in the context of 3D tissue microenvironment.Mass cytometry and multiplexed epitope imaging can complement genetic methods in diagnosis and study of the pathogenesis of primary immunodeficiencies. The ability to understand the effect of a specific defect across multiple immune cell types and pathways, and in affected tissues, may provide new insight into tissue-specific disease pathogenesis and evaluate effects of therapeutic interventions.

  View details for PubMedID 27749361

• Different activation signals induce distinct mast cell degranulation strategies JOURNAL OF CLINICAL INVESTIGATION Gaudenzio, N., Sibilano, R., Marichal, T., Starkl, P., Reber, L. L., Cenac, N., McNeil, B. D., Dong, X., Hernandez, J. D., Sagi-Eisenberg, R., Hammel, I., Roers, A., Valitutti, S., Tsai, M., Espinosa, E., Galli, S. J. 2016; 126 (10): 3981-3998

  Abstract

  Mast cells (MCs) influence intercellular communication during inflammation by secreting cytoplasmic granules that contain diverse mediators. Here, we have demonstrated that MCs decode different activation stimuli into spatially and temporally distinct patterns of granule secretion. Certain signals, including substance P, the complement anaphylatoxins C3a and C5a, and endothelin 1, induced human MCs rapidly to secrete small and relatively spherical granule structures, a pattern consistent with the secretion of individual granules. Conversely, activating MCs with anti-IgE increased the time partition between signaling and secretion, which was associated with a period of sustained elevation of intracellular calcium and formation of larger and more heterogeneously shaped granule structures that underwent prolonged exteriorization. Pharmacological inhibition of IKK-β during IgE-dependent stimulation strongly reduced the time partition between signaling and secretion, inhibited SNAP23/STX4 complex formation, and switched the degranulation pattern into one that resembled degranulation induced by substance P. IgE-dependent and substance P-dependent activation in vivo also induced different patterns of mouse MC degranulation that were associated with distinct local and systemic pathophysiological responses. These findings show that cytoplasmic granule secretion from MCs that occurs in response to different activating stimuli can exhibit distinct dynamics and features that are associated with distinct patterns of MC-dependent inflammation.

  View details for DOI 10.1172/JCI85538

  View details for Web of Science ID 000384703300034

  View details for PubMedID 27643442

  View details for PubMedCentralID PMC5096814

• Molecular and cellular mechanisms of food allergy and food tolerance. journal of allergy and clinical immunology Chinthrajah, R. S., Hernandez, J. D., Boyd, S. D., Galli, S. J., Nadeau, K. C. 2016; 137 (4): 984-997

  Abstract

  Ingestion of innocuous antigens, including food proteins, normally results in local and systemic immune nonresponsiveness in a process termed oral tolerance. Oral tolerance to food proteins is likely to be intimately linked to mechanisms that are responsible for gastrointestinal tolerance to large numbers of commensal microbes. Here we review our current understanding of the immune mechanisms responsible for oral tolerance and how perturbations in these mechanisms might promote the loss of oral tolerance and development of food allergies. Roles for the commensal microbiome in promoting oral tolerance and the association of intestinal dysbiosis with food allergy are discussed. Growing evidence supports cutaneous sensitization to food antigens as one possible mechanism leading to the failure to develop or loss of oral tolerance. A goal of immunotherapy for food allergies is to induce sustained desensitization or even true long-term oral tolerance to food allergens through mechanisms that might in part overlap with those associated with the development of natural oral tolerance.

  View details for DOI 10.1016/j.jaci.2016.02.004

  View details for PubMedID 27059726

• Single-cell systems-level analysis of human Toll-like receptor activation defines a chemokine signature in patients with systemic lupus erythematosus JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY O'Gorman, W. E., Hsieh, E. W., Savig, E. S., Gherardini, P. F., Hernandez, J. D., Hansmann, L., Balboni, I. M., Utz, P. J., Bendall, S. C., Fantl, W. J., Lewis, D. B., Nolan, G. P., Davis, M. M. 2015; 136 (5): 1326-1336

  Abstract

  Activation of Toll-like receptors (TLRs) induces inflammatory responses involved in immunity to pathogens and autoimmune pathogenesis, such as in patients with systemic lupus erythematosus (SLE). Although TLRs are differentially expressed across the immune system, a comprehensive analysis of how multiple immune cell subsets respond in a system-wide manner has not been described.We sought to characterize TLR activation across multiple immune cell subsets and subjects, with the goal of establishing a reference framework against which to compare pathologic processes.Peripheral whole-blood samples were stimulated with TLR ligands and analyzed by means of mass cytometry simultaneously for surface marker expression, activation states of intracellular signaling proteins, and cytokine production. We developed a novel data visualization tool to provide an integrated view of TLR signaling networks with single-cell resolution. We studied 17 healthy volunteer donors and 8 patients with newly diagnosed and untreated SLE.Our data revealed the diversity of TLR-induced responses within cell types, with TLR ligand specificity. Subsets of natural killer cells and T cells selectively induced nuclear factor κ light chain enhancer of activated B cells in response to TLR2 ligands. CD14(hi) monocytes exhibited the most polyfunctional cytokine expression patterns, with more than 80 distinct cytokine combinations. Monocytic TLR-induced cytokine patterns were shared among a group of healthy donors, with minimal intraindividual and interindividual variability. Furthermore, autoimmune disease altered baseline cytokine production; newly diagnosed untreated SLE patients shared a distinct monocytic chemokine signature, despite clinical heterogeneity.Mass cytometry defined a systems-level reference framework for human TLR activation, which can be applied to study perturbations in patients with inflammatory diseases, such as SLE.

  View details for DOI 10.1016/j.jaci.2015.04.008

  View details for Web of Science ID 000364787200023

  View details for PubMedID 26037552

• Multivalent interactions between lectins and supramolecular complexes: Galectin-1 and self-assembled pseudopolyrotaxanes CHEMISTRY & BIOLOGY Belitsky, J. M., Nelson, A., Hernandez, J. D., Baum, L. G., Stoddart, J. F. 2007; 14 (10): 1140-1151

  Abstract

  Supramolecular chemistry has been employed to develop flexible and adaptable multivalent neoglycoconjugates for binding galectin-1 (Gal-1). Gal-1, a dimeric lectin with two galactoside-binding sites, regulates cancer progression and immune responses. Self-assembled pseudopolyrotaxanes consisting of lactoside-displaying cyclodextrin (LCD) "beads" threaded onto polyviologen "strings" display mobile ligands as a result of cyclodextrin rotation about, and limited translation along, the polymer chain. The pseudopolyrotaxanes rapidly and efficiently precipitate Gal-1 and provide valency-corrected enhancements of up to 30-fold compared to native lactose and 20-fold over free LCD in a T-cell agglutination assay. A supramolecular statistical effect was observed, wherein the efficacy of Gal-1 inhibition correlates with the number of ligands connected to each other solely through mechanical and noncovalent interactions. Such flexible and adaptable self-assembled pseudopolyrotaxanes show promise for the study of multivalent interactions and targeting of therapeutically relevant lectins.

  View details for DOI 10.1016/j.chembiol.2007.09.007

  View details for Web of Science ID 000250602200007

  View details for PubMedID 17961826

  View details for PubMedCentralID PMC2072908

• Differential glycosylation of T(H)1, T(H)2 and T-H-17 effector cells selectively regulates susceptibility to cell death NATURE IMMUNOLOGY Toscano, M. A., Bianco, G. A., Ilarregui, J. M., Croci, D. O., Correale, J., Hernandez, J. D., Zwirner, N. W., Poirier, F., Riley, E. M., Baum, L. G., Rabinovich, G. A. 2007; 8 (8): 825-834

  Abstract

  Regulated glycosylation controls T cell processes, including activation, differentiation and homing by creating or masking ligands for endogenous lectins. Here we show that stimuli promoting T helper type 1 (TH1), TH2 or interleukin 17-producing T helper (TH-17) differentiation can differentially regulate the glycosylation pattern of T helper cells and modulate their susceptibility to galectin-1, a glycan-binding protein with anti-inflammatory activity. Although TH1- and TH-17-differentiated cells expressed the repertoire of cell surface glycans critical for galectin-1-induced cell death, TH2 cells were protected from galectin-1 through differential sialylation of cell surface glycoproteins. Consistent with those findings, galectin-1-deficient mice developed greater TH1 and TH-17 responses and enhanced susceptibility to autoimmune neuroinflammation. Our findings identify a molecular link among differential glycosylation of T helper cells, susceptibility to cell death and termination of the inflammatory response.

  View details for DOI 10.1038/ni1489

  View details for Web of Science ID 000248169400010

  View details for PubMedID 17589510

• T-cell activation results in microheterogeneous changes in glycosylation of CD45 INTERNATIONAL IMMUNOLOGY Hernandez, J. D., Klein, J., Van Dyken, S. J., Marth, J. D., Baum, L. G. 2007; 19 (7): 847-856

  Abstract

  During T-cell development and activation, dramatic changes occur in glycan structures that decorate cell-surface glycoproteins. These changes have been considered to be general cellular events that affect many glycans on many glycoproteins. For example, loss of sialic acid from core 1 O-glycans on T-cell surface glycoproteins CD45, CD43 and CD8, detected with peanut agglutinin (PNA), is a hallmark of immature thymocytes and activated peripheral T cells. Loss of cell-surface sialic acid during T-cell activation has been proposed to enhance TCR reactivity with antigen. However, CD4 T-cell activation also results in increased binding of the CZ-1 antibody that recognizes a sialic acid-containing epitope on CD45RB. This indicates that increased sialylation of the CZ-1 epitope occurs during CD4 T cell activation, and that loss of cell surface sialic acid during T-cell activation is a selective event rather than affecting all cell surface glycans. As specific glycans on specific glycoprotein backbones control critical events in T-cell maturation and survival, understanding mechanisms of selective glycoprotein glycosylation is important for regulating T-cell development and function. We define the sialylated O-glycan epitope recognized by CZ-1, and find that, paradoxically, CZ-1 and PNA binding are simultaneously increased on activated CD4(+) T cells, demonstrating site-specific changes in CD45 sialylation. Moreover, we identify ST3Gal I as the sialyltransferase responsible for creating the CZ-1 epitope. Thus, changes in glycan structure during T-cell activation are microheterogeneous and unique to individual glycans on specific glycoproteins, implying that these glycans have precise functions in T-cell biology.

  View details for DOI 10.1093/intimm/dxm053

  View details for Web of Science ID 000249127900004

  View details for PubMedID 17606981

• Galectin-1 binds different CD43 glycoforms to cluster CD43 and regulate T cell death JOURNAL OF IMMUNOLOGY Hernandez, J. D., Nguyen, J. T., He, J., Wang, W., Ardman, B., Green, J. M., Fukuda, M., Baum, L. G. 2006; 177 (8): 5328-5336

  Abstract

  Galectin-1 kills immature thymocytes and activated peripheral T cells by binding to glycans on T cell glycoproteins including CD7, CD45, and CD43. Although roles for CD7 and CD45 in regulating galectin-1-induced death have been described, the requirement for CD43 remains unknown. We describe a novel role for CD43 in galectin-1-induced death, and the effects of O-glycan modification on galectin-1 binding to CD43. Loss of CD43 expression reduced galectin-1 death of murine thymocytes and human T lymphoblastoid cells, indicating that CD43 is required for maximal T cell susceptibility to galectin-1. CD43, which is heavily O-glycosylated, contributes a significant fraction of galectin-1 binding sites on T cells, as T cells lacking CD43 bound approximately 50% less galectin-1 than T cells expressing CD43. Although core 2 modification of O-glycans on other glycoprotein receptors is critical for galectin-1-induced cross-linking and T cell death, galectin-1 bound to CD43 fusion proteins modified with either unbranched core 1 or branched core 2 O-glycans and expression of core 2 O-glycans did not enhance galectin-1 binding to CD43 on T cells. Moreover, galectin-1 binding clustered CD43 modified with either core 1 or core 2 O-glycans on the T cell surface. Thus, CD43 bearing either core 1 or core 2 O-glycans can positively regulate T cell susceptibility to galectin-1, identifying a novel function for CD43 in controlling cell death. In addition, these studies demonstrate that different T cell glycoproteins on the same cell have distinct requirements for glycan modifications that allow recognition and cross-linking by galectin-1.

  View details for Web of Science ID 000241093100045

  View details for PubMedID 17015718

• CD45 signals outside of lipid rafts to promote ERK activation, synaptic raft clustering, and IL-2 production JOURNAL OF IMMUNOLOGY Zhang, M., Moran, M., Round, J., Low, T. A., Patel, V. P., Tomassian, T., Hernandez, J. D., Miceli, M. C. 2005; 174 (3): 1479-1490

  Abstract

  CD45 is dynamically repositioned within lipid rafts and the immune synapse during T cell activation, although the molecular consequences of CD45 repositioning remain unclear. In this study we examine the role of CD45 membrane compartmentalization in regulating murine T cell activation. We find that raft-localized CD45 antagonizes IL-2 production by opposing processive TCR signals, whereas raft-excluded CD45 promotes ERK-dependent polarized synaptic lipid raft clustering and IL-2 production. We propose that these dual CD45 activities ensure that only robust TCR signals proceed, whereas signals meeting threshold requirements are potentiated. Our findings highlight membrane compartmentalization as a key regulator of CD45 function and elucidate a novel signal transduction pathway by which raft-excluded CD45 positively regulates T cell activation.

  View details for Web of Science ID 000226571300043

  View details for PubMedID 15661907

• Galectin-1 induces nuclear translocation of endonuclease G in caspase- and cytochrome c-independent T cell death CELL DEATH AND DIFFERENTIATION Hahn, H. P., Pang, M., He, J., Hernandez, J. D., Yang, R. Y., Li, L. Y., Wang, X., Liu, F. T., Baum, L. G. 2004; 11 (12): 1277-1286

  Abstract

  Galectin-1, a mammalian lectin expressed in many tissues, induces death of diverse cell types, including lymphocytes and tumor cells. The galectin-1 T cell death pathway is novel and distinct from other death pathways, including those initiated by Fas and corticosteroids. We have found that galectin-1 binding to human T cell lines triggered rapid translocation of endonuclease G from mitochondria to nuclei. However, endonuclease G nuclear translocation occurred without cytochrome c release from mitochondria, without nuclear translocation of apoptosis-inducing factor, and prior to loss of mitochondrial membrane potential. Galectin-1 treatment did not result in caspase activation, nor was death blocked by caspase inhibitors. However, galectin-1 cell death was inhibited by intracellular expression of galectin-3, and galectin-3 expression inhibited the eventual loss of mitochondrial membrane potential. Galectin-1-induced cell death proceeds via a caspase-independent pathway that involves a unique pattern of mitochondrial events, and different galectin family members can coordinately regulate susceptibility to cell death.

  View details for DOI 10.1038/sj.cdd.4401485

  View details for Web of Science ID 000225109800005

  View details for PubMedID 15297883

  View details for PubMedCentralID PMC1201488

• Ah, sweet mystery of death! Galectins and control of cell fate GLYCOBIOLOGY Hernandez, J. D., Baum, L. G. 2002; 12 (10): 127R-136R

  Abstract

  Control of cell death is critical in eukaryotic development, immune system homeostasis, and control of tumorigenesis. The galectin family of lectins is implicated in all of these processes. Other families of molecules function as death receptors or death effectors, but galectins are uniquely capable of acting both extracellularly and intracellularly to control cell death. Extracellularly, galectins cross-link glycan ligands to transduce signals that lead directly to death or that influence other signals regulating cell fate. Intracellular expression of galectins can modulate other signals controlling cell viability. Individual galectins can act on multiple cell types, and multiple galectins can act on the same cell. Understanding how galectins regulate cell viability and function will broaden our knowledge of the roles of galectins in basic biological processes and facilitate development of therapeutic applications for galectins in autoimmunity, transplant-related disease, and cancer.

  View details for Web of Science ID 000178448200001

  View details for PubMedID 12244068

• Structure and organization of the RBMY genes on the human Y chromosome: Transposition and amplification of an ancestral autosomal hnRNPG gene GENOMICS Chai, N. N., Zhou, H. Y., Hernandez, J., Najmabadi, H., Bhasin, S., Yen, P. H. 1998; 49 (2): 283-289

  Abstract

  The RBMY (RNA-binding motif, Y chromosome) gene family encodes a germ-cell-specific nuclear protein implicated in spermatogenesis. It consists of approximately 30 genes and pseudogenes, found on both arms of the Y chromosome. RBMY shares high homology with an autosomal hnRNPG gene that contains an RNA-binding motif and one of the four SRGY repeats found in RBMY. One proposal is that RBMY represents an ancestral hnRNPG gene, transposed to the Y chromosome and then amplified. We characterized seven RBMY genes in interval 6 of the Y chromosome long arm. Four have the normal structure with 12 exons spanning 15 kb, whereas one lacks the first 3 exons, therefore representing a pseudogene. The remaining two genes belong to a different subfamily, resembling the autosomal hnRNPG gene with only one SRGY repeat. We also found that most RBMY genes in interval 6 are arranged in tandem. The structure and organization of the Y-linked RBMY genes support the transposition-amplification hypothesis.

  View details for Web of Science ID 000073656400014

  View details for PubMedID 9598316