All Publications

  • Single cell multi-omic analysis identifies key genes differentially expressed in innate lymphoid cells from COVID-19 patients. Frontiers in immunology Kaushik, A., Chang, I., Han, X., He, Z., Komlosi, Z. I., Ji, X., Cao, S., Akdis, C. A., Boyd, S., Pulendran, B., Maecker, H. T., Davis, M. M., Chinthrajah, R. S., DeKruyff, R. H., Nadeau, K. C. 2024; 15: 1374828


    Introduction: Innate lymphoid cells (ILCs) are enriched at mucosal surfaces where they respond rapidly to environmental stimuli and contribute to both tissue inflammation and healing.Methods: To gain insight into the role of ILCs in the pathology and recovery from COVID-19 infection, we employed a multi-omics approach consisting of Abseq and targeted mRNA sequencing to respectively probe the surface marker expression, transcriptional profile and heterogeneity of ILCs in peripheral blood of patients with COVID-19 compared with healthy controls.Results: We found that the frequency of ILC1 and ILC2 cells was significantly increased in COVID-19 patients. Moreover, all ILC subsets displayed a significantly higher frequency of CD69-expressing cells, indicating a heightened state of activation. ILC2s from COVID-19 patients had the highest number of significantly differentially expressed (DE) genes. The most notable genes DE in COVID-19 vs healthy participants included a) genes associated with responses to virus infections and b) genes that support ILC self-proliferation, activation and homeostasis. In addition, differential gene regulatory network analysis revealed ILC-specific regulons and their interactions driving the differential gene expression in each ILC.Discussion: Overall, this study provides mechanistic insights into the characteristics of ILC subsets activated during COVID-19 infection.

    View details for DOI 10.3389/fimmu.2024.1374828

    View details for PubMedID 39026668

  • CD8+ T cell differentiation status correlates with the feasibility of sustained unresponsiveness following oral immunotherapy. Nature communications Kaushik, A., Dunham, D., Han, X., Do, E., Andorf, S., Gupta, S., Fernandes, A., Kost, L. E., Sindher, S. B., Yu, W., Tsai, M., Tibshirani, R., Boyd, S. D., Desai, M., Maecker, H. T., Galli, S. J., Chinthrajah, R. S., DeKruyff, R. H., Manohar, M., Nadeau, K. C. 2022; 13 (1): 6646


    While food allergy oral immunotherapy (OIT) can provide safe and effective desensitization (DS), the immune mechanisms underlying development of sustained unresponsiveness (SU) following a period of avoidance are largely unknown. Here, we compare high dimensional phenotypes of innate and adaptive immune cell subsets of participants in a previously reported, phase 2 randomized, controlled, peanut OIT trial who achieved SU vs. DS (no vs. with allergic reactions upon food challenge after a withdrawal period; n=21 vs. 30 respectively among total 120 intent-to-treat participants). Lower frequencies of naive CD8+ T cells and terminally differentiated CD57+CD8+ T cell subsets at baseline (pre-OIT) are associated with SU. Frequency of naive CD8+ T cells shows a significant positive correlation with peanut-specific and Ara h 2-specific IgE levels at baseline. Higher frequencies of IL-4+ and IFNgamma+ CD4+ T cells post-OIT are negatively correlated with SU. Our findings provide evidence that an immune signature consisting of certain CD8+ T cell subset frequencies is potentially predictive of SU following OIT.

    View details for DOI 10.1038/s41467-022-34222-8

    View details for PubMedID 36333296

  • Increases in ambient air pollutants during pregnancy are linked to increases in methylation of IL4, IL10, and IFNgamma. Clinical epigenetics Aguilera, J., Han, X., Cao, S., Balmes, J., Lurmann, F., Tyner, T., Lutzker, L., Noth, E., Hammond, S. K., Sampath, V., Burt, T., Utz, P. J., Khatri, P., Aghaeepour, N., Maecker, H., Prunicki, M., Nadeau, K. 2022; 14 (1): 40


    BACKGROUND: Ambient air pollutant (AAP) exposure is associated with adverse pregnancy outcomes, such as preeclampsia, preterm labor, and low birth weight. Previous studies have shown methylation of immune genes associate with exposure to air pollutants in pregnant women, but the cell-mediated response in the context of typical pregnancy cell alterations has not been investigated. Pregnancy causes attenuation in cell-mediated immunity with alterations in the Th1/Th2/Th17/Treg environment, contributing to maternal susceptibility. We recruited women (n=186) who were 20weeks pregnant from Fresno, CA, an area with chronically elevated AAP levels. Associations of average pollution concentration estimates for 1week, 1month, 3months, and 6months prior to blood draw were associated with Th cell subset (Th1, Th2, Th17, and Treg) percentages and methylation of CpG sites (IL4, IL10, IFNgamma, and FoxP3). Linear regression models were adjusted for weight, age, season, race, and asthma, using a Q value as the false-discovery-rate-adjusted p-value across all genes.RESULTS: Short-term and mid-term AAP exposures to fine particulate matter (PM2.5), nitrogen dioxide (NO2) carbon monoxide (CO), and polycyclic aromatic hydrocarbons (PAH456) were associated with percentages of immune cells. A decrease in Th1 cell percentage was negatively associated with PM2.5 (1 mo/3 mo: Q<0.05), NO2 (1 mo/3 mo/6 mo: Q<0.05), and PAH456 (1week/1 mo/3 mo: Q<0.05). Th2 cell percentages were negatively associated with PM2.5 (1week/1 mo/3 mo/6 mo: Q<0.06), and NO2 (1week/1 mo/3 mo/6 mo: Q<0.06). Th17 cell percentage was negatively associated with NO2 (3 mo/6 mo: Q<0.01), CO (1week/1 mo: Q<0.1), PM2.5 (3 mo/6 mo: Q<0.05), and PAH456 (1 mo/3 mo/6 mo: Q<0.08). Methylation of the IL10 gene was positively associated with CO (1week/1 mo/3 mo: Q<0.01), NO2 (1 mo/3 mo/6 mo: Q<0.08), PAH456 (1week/1 mo/3 mo: Q<0.01), and PM2.5 (3 mo: Q=0.06) while IL4 gene methylation was positively associated with concentrations of CO (1week/1 mo/3 mo/6 mo: Q<0.09). Also, IFNgamma gene methylation was positively associated with CO (1week/1 mo/3 mo: Q<0.05) and PAH456 (1week/1 mo/3 mo: Q<0.06).CONCLUSION: Exposure to several AAPs was negatively associated with T-helper subsets involved in pro-inflammatory and anti-inflammatory responses during pregnancy. Methylation of IL4, IL10, and IFNgamma genes with pollution exposure confirms previous research. These results offer insights into the detrimental effects of air pollution during pregnancy, the demand for more epigenetic studies, and mitigation strategies to decrease pollution exposure during pregnancy.

    View details for DOI 10.1186/s13148-022-01254-2

    View details for PubMedID 35287715

  • Exposure to ambient air pollutants during pregnancy is linked to IL4, IL10, and IFN gamma gene methylation and fewer Th1, Th2, and Th17 cell populations Aguilera, J., Han, X., Cao, S., Prunicki, M., Nadeau, K. MOSBY-ELSEVIER. 2022: AB139
  • Food Allergies: An Example of Translational Research. Immunology and allergy clinics of North America Krempski, J. W., Warren, C., Han, X., Zhang, W., He, Z., Lejeune, S., Nadeau, K. 2021; 41 (2): 143–63


    Food allergies have been rising in prevalence since the 1990s, imposing substantial physical, psychosocial, and economic burdens on affected patients and their families. Until recently, the only therapy for food allergy was strict avoidance of the allergenic food. Recent advances in translational studies, however, have led to insights into allergic sensitization and tolerance. This article provides an overview of cutting-edge research into food allergy and immune tolerance mechanisms utilizing mouse models, human studies, and systems biology approaches. This research is being translated and implemented in the clinical setting to improve diagnosis and reduce food allergy's public health burden.

    View details for DOI 10.1016/j.iac.2021.01.003

    View details for PubMedID 33863476

  • Targeted DNA methylation profiling reveals epigenetic signatures in peanut allergy. JCI insight Zhou, X. n., Han, X. n., Lyu, S. C., Bunning, B. J., Kost, L. n., Chang, I. n., Cao, S. n., Sampath, V. n., Nadeau, K. C. 2021


    DNA methylation (DNAm) has been shown to play a role in mediating food allergy, however, the mechanism by which it does so is poorly understood. In this study, we used targeted NextGen bisulfite sequencing to evaluate DNAm levels in 125 targeted highly informative genomic regions containing 602 CpG sites on 70 immune-related genes to understand whether DNAm can differentiate peanut allergy (PA) vs non-allergy (NA). We found PA-associated DNAm signatures associated with 12 genes (7 novel to food allergy, 3 associated with Th1/Th2, and 2 associated with innate immunity) as well as DNAm signature combinations with superior diagnostic potential compared to serum peanut specific-IgE for PA vs. NA. Further, we found that following peanut protein stimulation, peripheral blood mononuclear cell (PBMCs) from PA participants showed increased production of cognate cytokines compared to NA participants. The varying responses between PA and NA participants may be associated with the interaction between the modification of DNAm and the interference of environment. Using Euclidean distance analysis, we found that the distances of methylation profile comprising 12 DNAm signatures between PA and NA pairs in monozygotic (MZ) twins were smaller than that in randomly paired genetically unrelated individuals, suggesting that PA related DNAm signatures may be associated with genetic factors.

    View details for DOI 10.1172/jci.insight.143058

    View details for PubMedID 33571165

  • Advances and novel developments in mechanisms of allergic inflammation. Allergy Han, X., Krempski, J. W., Nadeau, K. 2020


    In the past decade, research in the molecular and cellular underpinnings of basic and clinical immunology has significantly advanced our understanding of allergic disorders, allowing scientists and clinicians to diagnose and treat disorders such as asthma, allergic and nonallergic rhinitis, and food allergy. In this review, we discuss several significant recent developments in basic and clinical research as well as important future research directions in allergic inflammation. Certain key regulatory cytokines, genes, and molecules have recently been shown to play key roles in allergic disorders. For example,interleukin-33 (IL-33)plays an important role in refractory disorders such as asthma, allergic rhinitis, and food allergy, mainly by inducing T helper (Th) 2 immune responses. Further, the cytokine TSLP has been shown to be a key factor in maintaining immune homeostasis and regulating inflammatory responses at mucosal barriers and targeting TSLP-mediated signaling is considered an attractive therapeutic strategy. We discuss interleukin 4 receptor pathways, which recently has shown to play a critical role among the allergic inflammatory pathways that drive allergic disorders and pathogenesis. The alarmin IL-33 has found to play a major role in type-2 immune responses in allergic diseases and clinical trials with IL33 inhibitors are underway in food allergy. Further, the cytokine Thymic Stromal Lymphopoietin (TSLP)has recently been shown a factor in maintaining immune homeostasis and regulating type-2 inflammatory responses at mucosal barriers in allergic inflammation. Also, new immune and genetic studies found that IL-4R pathways play a critical role among the allergic inflammatory pathways that drive allergic disorders and pathogenesis. In addition, new findings establish an important T cell-intrinsic role of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) proteolytic activity in the suppression of autoimmune responses. We have seen how mutations in the filaggrin gene are significant risk factor for allergic diseases such as atopic dermatitis, asthma, allergic rhinitis, food allergy (FA), and contact allergy and hand eczema. We are only beginning to understand the mechanisms by which the human microbiota may be regulating the immune system, and how sudden changes in the composition of the microbiota may have profound effects, linked with an increased risk of developing chronic inflammatory disorders, including allergies. New research has shown the important but complex role monocytes play in such disorders as food allergies. Finally, we discuss some of the new directions of research in this area, particularly the important use of biologicals in oral immunotherapy, advances in gene therapy, multi-food therapy, novel diagnostics in diagnosing allergic disorders, and the central role that OMICS plays in creating molecular signatures and biomarkers of allergic disorders such as food allergy. Such exciting new developments and advances has significantly moved forth our ability to understand the mechanisms underlying allergic diseases for improved patient care.

    View details for DOI 10.1111/all.14632

    View details for PubMedID 33068299