Kari Nadeau

Understanding the immune responses to SARS-CoV-2 vaccination is critical to optimizing vaccination strategies for individuals with autoimmune diseases, such as systemic lupus erythematosus (SLE). Here, we comprehensively analyzed innate and adaptive immune responses in 19 patients with SLE receiving a complete 2-dose Pfizer-BioNTech mRNA vaccine (BNT162b2) regimen compared with a control cohort of 56 healthy control (HC) volunteers. Patients with SLE exhibited impaired neutralizing antibody production and antigen-specific CD4+ and CD8+ T cell responses relative to HC. Interestingly, antibody responses were only altered in patients with SLE treated with immunosuppressive therapies, whereas impairment of antigen-specific CD4+ and CD8+ T cell numbers was independent of medication. Patients with SLE also displayed reduced levels of circulating CXC motif chemokine ligands, CXCL9 …

Increased fossil fuel usage has increased CO2 concentrations leading to global warming and climate change with increased frequency and intensity of extreme weather events such as thunderstorms, wildfires, droughts, heat waves, and others. These changes increase the risk of adverse health effects for all human beings. However, these experiences do not impact everyone equally. Underserved communities, including people of color, the elderly, people living with chronic conditions, and socioeconomically disadvantaged groups have greater vulnerability to the impacts of climate change. These vulnerabilities are a result of multiple factors such as disparities in healthcare, lower educational status, systemic racism, and many others. These social inequities are exacerbated by extreme weather events, which act as threat multipliers increasing disparities in health outcomes. It is clear that without human action, these …

Background Immunological traits and functions have been consistently associated with environmental exposures and are thought to shape allergic disease susceptibility and protection. In particular, specific exposures in early life may have more significant effects on the developing immune system, with potentially long‐term impacts. Methods We performed RNA‐Seq on peripheral blood mononuclear cells (PBMCs) from 150 children with atopic dermatitis and healthy nonallergic children in rural and urban settings from the same ethnolinguistic AmaXhosa background in South Africa. We measured environmental exposures using questionnaires. Results A distinct PBMC gene expression pattern was observed in those children with atopic dermatitis (132 differentially expressed genes [DEGs]). However, the predominant influences on the immune cell transcriptome were related to early life exposures including …

It is widely accepted and rigorously evidenced that topical corticosteroids (TCS) are effective treatments for atopic dermatitis (AD). Although TCS are known to have various adverse effects, including skin atrophy, telangiectasia, and perioral dermatitis, clear instructions from prescribers on how and where to apply and when to taper or stop use can mitigate these risks, in addition to close monitoring by the prescribing clinician before refilling prescriptions. An emphasis on the basics of AD management, such as liberal emollient use, can reduce the requirement for TCS. 1 One of the most divisive and debated adverse effects of TCS is topical steroid withdrawal (TSW). First described in 1969, the last 15 years have seen a sharp increase in publications mentioning TSW in the medical literature. There has also been a trend in coverage and discussion of the condition across social media alongside the topic of steroid …

Understanding antigen-specific T-cell responses, for example, following virus infections or allergen exposure, is of high relevance for the development of vaccines and therapeutics. We aimed on optimizing immunophenotyping of T cells after antigen stimulation by improving staining procedures for flow and mass cytometry. Our method can be used for primary cells of both mouse and human origin for the detection of low-frequency T-cell response using a dual-barcoding system for individual samples and conditions. First, live-cell barcoding was performed using anti-CD45 antibodies prior to an in vitro T-cell stimulation assay. Second, to discriminate between stimulation conditions and prevent cell loss, sample barcoding was combined with a commercial barcoding solution. This dual-barcoding approach is cell sparing and, therefore, particularly relevant for samples with low cell numbers. To further reduce cell loss and to increase debarcoding efficiency of multiplexed samples, we combined our dual-barcoding approach with a new centrifugation-free washing system by laminar flow (Curiox™). Finally, to demonstrate the benefits of our established protocol, we assayed virus-specific T-cell response in SARS-CoV-2–vaccinated and SARS-CoV-2–infected patients and compared with healthy non-exposed individuals by a high-parameter CyTOF analysis. We could reveal a heterogeneity of phenotypes among responding CD4, CD8, and gd-T cells following antigen-specific stimulations. Our protocol allows to assay antigen-specific responses of minute populations of T cells to virus-derived peptides, allergens, or other antigens from the same donor …

MethodsATAC-seq was utilized to assess chromatin accessibility in CD4+ T cell subsets (Naïve, Th2, and Th1 cells), obtained from asthmatic and non-asthmatic participants, including discordant twin pairs and non-twin individuals. The inclusion of asthma-discordant monozygotic twins, matched for genetics, age, sex, cohort effects and maternal influences, enhances the power in detecting disease-related epigenetic differences compared to unrelated cases and controls.ResultsWe identified differential peaks between asthmatic and non-asthmatic samples in CD4+ T cell types. We determined the transcription factor (TF) motifs enriched in these cell-type specific differential peaks. Specifically, TF JUNB in the AP-1 family exhibited increased expression in asthmatic twins compared to their non-asthmatic twin pairs, and we elucidated the network of JUNB with other TFs. GSEA analysis indicated that genes proximal to …

Climate change is a contributing cause to these cases of asthma, COPD, and allergic rhinitis. And it is increasing the frequency and severity of new cases and exacerbations of these and other respiratory disorders. While climate change is not the most frequent cause of cases of chronic respiratory disorders, many cases are climate-sensitive. 1Higher temperatures increase airborne concentrations of ozone if there are sufficiently high levels of nitrogen oxides, volatile organic compounds (VOCs), and other ozone precursors. 2 Higher temperature also contributes to increased probability of wildfires—and, in desert regions, sand and dust storms—which produce particulate matter and other airborne pollutants that contribute to newonset and exacerbation of respiratory disorders. And higher temperature leads to increased pollen production and longer pollen seasons, increasing the incidence and severity of allergic rhinitis.

Cannabis, the most commonly used recreational drug, is illicit in many areas of the world. With increasing decriminalization and legalization, cannabis use is increasing in the United States and other countries. The adverse effects of cannabis are unclear because its status as a Schedule 1 drug in the United States restricts research. Despite a paucity of data, cannabis is commonly perceived as a benign or even beneficial drug. However, recent studies show that cannabis has adverse cardiovascular and pulmonary effects and is linked with malignancy. Moreover, case reports have shown an association between cannabis use and neuropsychiatric disorders. With growing availability, cannabis misuse by minors has led to increasing incidences of overdose and toxicity. Though difficult to detect, cannabis intoxication may be linked to impaired driving and motor vehicle accidents. Overall, cannabis use is on the rise …

In the published article, there was an error in the section Metabolomics/lipidomics in FA development. The sentence “Untargeted serum metabolomics from infants identified an increase in several unsaturated fatty acids, such as free fatty acid (FFA) 16: 1 (palmitoleic acid) and FFA 20: 1 (eicosenoic acid), and a decrease in conjugated bile acids, such as glycocholic acid and taurocholic acid, in infants with FA (80).”[80: Huang et al., 2014] was referring to a study in atopic dermatitis as opposed to food allergy. This sentence has been removed from the manuscript.

Background Allergic rhinitis (AR) is a common condition that is frequently associated with atopic inferior turbinate hypertrophy (ITH) resulting in nasal obstruction. Current guidelines support the use of subcutaneous allergen immunotherapy (SCIT) when patients fail pharmacologic management. However, there is a lack of consensus regarding the role of inferior turbinate reduction (ITR), a treatment that we hypothesize is cost‐effective compared with other available treatments. Methods We conducted a cost‐effectiveness analysis comparing the following treatment combinations over a 5‐year time horizon for AR patients presenting with atopic nasal obstruction who fail initial pharmacotherapy: (1) continued pharmacotherapy alone, (2) allergy testing and SCIT, (3) allergy testing and SCIT and then ITR for SCIT nonresponders, and (4) ITR and then allergy testing and SCIT for ITR nonresponders. Results were …

Elucidating effects of the environmental pollutant benzo[a]pyrene [BaP] on cardiac arrhythmogenicity Elucidating effects of the environmental pollutant benzo[a]pyrene [BaP] on cardiac arrhythmogenicity J Mol Cell Cardiol. 2024 Apr 20:S0022-2828(24)00057-9. doi: 10.1016/j.yjmcc.2024.04.013. Online ahead of print. Authors Johnson Y Yang 1 , Gema Mondéjar-Parreño 1 , James WS Jahng 1 , Yu Lu 1 , Naomi Hamburg 2 , Kari C Nadeau 3 , Daniel J Conklin 4 , Ronglih Liao 1 , Mark Chandy 5 , Joseph C Wu 6 Affiliations 1 Stanford Cardiovascular Institute, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. 2 Boston Medical Center, Boston University Chobanian & Avedisian School of Medicine, Boston University School of Public Health, Boston, MA, USA. 3 Department of Environmental Health, Harvard TH Chan School of Public Health, …

The glycosylation of IgG plays a critical role during human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, activating immune cells and inducing cytokine production. However, the role of IgM N-glycosylation has not been studied during human acute viral infection. The analysis of IgM N-glycosylation from healthy controls and hospitalized coronavirus disease 2019 (COVID-19) patients reveals increased high-mannose and sialylation that correlates with COVID-19 severity. These trends are confirmed within SARS-CoV-2-specific immunoglobulin N-glycan profiles. Moreover, the degree of total IgM mannosylation and sialylation correlate significantly with markers of disease severity. We link the changes of IgM N-glycosylation with the expression of Golgi glycosyltransferases. Lastly, we observe antigen-specific IgM antibody-dependent complement deposition is elevated in severe COVID-19 …

MethodsWe performed a post hoc analysis of PGIS in the POISED trial (NCT02103270) to understand the impact of PGIS on participant outcomes. PGIS was defined as at least 4 instances of abdominal pain, vomiting, and/or reflux over a 14-day period of OIT dosing.ResultsA total of 36 out of 95 participants who received peanut OIT met the definition of PGIS. The age and gender distributions were comparable between those with and without PGIS (65% male; ages 7-49 years). Baseline median peanut sIgE was significantly higher (115 kUA/L vs. 68 KUA/L; p= 0.03) and median sIgG4/sIgE ratio was significantly lower (2.8 vs. 7.6; p= 0.003) among those with and without PGIS respectively. Despite a longer time (55 vs 46 weeks; p= 0.001) to reach the maintenance dose for the PGIS group, there were no significant differences in study completion rates (week 117 per protocol, 83% vs 86%, p= 0.91) or desensitization …

MethodsCashew or shrimp allergic participants aged 7-55 years were enrolled in the phase 2 clinical trial-MOTIF (NCT03504774) and underwent cognate allergen-specific OIT to a maintenance dose of 1,000 mg until week 52. Oral food challenge (OFC) at weeks 52 and 58 evaluated desensitization and sustained unresponsiveness (SU) respectively to a cumulative allergen dose of 2043 mg. We examined immune changes in allergen-reactive CD4+ T cells and plasma at baseline, week 52, and week 58 using flow cytometry and Luminex.ResultsWe enrolled 40 cashew and 12 shrimp allergic participants, of whom 25 cashew-treated (62.5%) and 7 shrimp-treated (58.3%) participants completed and passed week 58 OFC. Overall, cashew and shrimp OIT was safe with only mild (90%) or moderate (10%) adverse events, with gastrointestinal symptoms (31%) being the most common. OIT induced a significant …

We review current knowledge on the trends and drivers of global wildfire activity, advances in the measurement of wildfire smoke exposure, and evidence on the health effects of this exposure. We describe methodological issues in estimating the causal effects of wildfire smoke exposures on health and quantify their importance, emphasizing the role of nonlinear and lagged effects. We conduct a systematic review and meta-analysis of the health effects of wildfire smoke exposure, finding positive impacts on all-cause mortality and respiratory hospitalizations but less consistent evidence on cardiovascular morbidity. We conclude by highlighting priority areas for future research, including leveraging recently developed spatially and temporally resolved wildfire-specific ambient air pollution data to improve estimates of the health effects of wildfire smoke exposure.

Systematic review using GRADE of the impact of exposure to volatile organic compounds (VOCs), cleaning agents, mould/damp, pesticides on the risk of (i) new‐onset asthma (incidence) and (ii) adverse asthma‐related outcomes (impact). MEDLINE, EMBASE and Web of Science were searched for indoor pollutant exposure studies reporting on new‐onset asthma and critical and important asthma‐related outcomes. Ninety four studies were included: 11 for VOCs (7 for incidenceand 4 for impact), 25 for cleaning agents (7 for incidenceand 8 for impact), 48 for damp/mould (26 for incidence and 22 for impact) and 10 for pesticides (8 for incidence and 2 for impact). Exposure to damp/mould increases the risk of new‐onset wheeze (moderate certainty evidence). Exposure to cleaning agents may be associated with a higher risk of new‐onset asthma and with asthma severity (low level of certainty). Exposure to …

BackgroundShort-term increases in air pollution are associated with poor asthma and COPD outcomes. Short-term elevations in fine particulate matter (PM2.5) due to wildfire smoke are becoming more common.Research QuestionAre short-term increases in PM2.5 and ozone in wildfire season and in winter inversion season associated with a composite of emergency or inpatient hospitalization for asthma and COPD?Study Design and MethodsCase-crossover analyses evaluated 63,976 and 18,514 patients hospitalized for primary discharge diagnoses of asthma and COPD, respectively, between January 1999 and March 2022. Patients resided on Utah’s Wasatch Front where PM2.5 and ozone were measured by Environmental Protection Agency-based monitors. ORs were calculated using Poisson regression adjusted for weather variables.ResultsAsthma risk increased on the same day that PM2.5 increased …

Global warming and climate change have increased the pollen burden and the frequency and intensity of wildfires, sand and dust storms, thunderstorms, and heatwaves—with concomitant increases in air pollution, heat stress, and flooding. These environmental stressors alter the human exposome and trigger complex immune responses. In parallel, pollutants, allergens, and other environmental factors increase the risks of skin and mucosal barrier disruption and microbial dysbiosis, while a loss of biodiversity and reduced exposure to microbial diversity impairs tolerogenic immune development. The resulting immune dysregulation is contributing to an increase in immune-mediated diseases such as asthma and other allergic diseases, autoimmune diseases, and cancer. It is now abundantly clear that multisectoral, multidisciplinary, and transborder efforts based on Planetary Health and One Health approaches (which consider the dependence of human health on the environment and natural ecosystems) are urgently needed to adapt to and mitigate the effects of climate change. Key actions include reducing emissions and improving air quality (through reduced fossil fuel use), providing safe housing (e.g., improving weatherization), improving diets (i.e., quality and diversity) and agricultural practices, and increasing environmental biodiversity and green spaces. There is also a pressing need for collaborative, multidisciplinary research to better understand the pathophysiology of immune diseases in the context of climate change. New data science techniques, biomarkers, and economic models should be used to measure the impact of climate …

Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B lymphocytes by mass cytometry (CyTOF) was observed in the multidomain deficit cluster. Circulating fibroblast growth factor 21 (FGF21) was …

Background Food allergy is a leading cause of anaphylaxis worldwide. Allergen‐specific immunotherapy is the only treatment shown to modify the natural history of allergic disease, but application to food allergy has been hindered by risk of severe allergic reactions and short‐lived efficacy. Allergen‐derived peptides could provide a solution. PVX108 comprises seven short peptides representing immunodominant T‐cell epitopes of major peanut allergens for treatment of peanut allergy. Methods Pre‐clinical safety of PVX108 was assessed using ex vivo basophil activation tests (n = 185). Clinical safety and tolerability of single and repeat PVX108 doses were evaluated in a first‐in‐human, randomized, double‐blind, placebo‐controlled trial in peanut‐allergic adults (46 active, 21 placebo). The repeat‐dose cohort received six doses over 16 weeks with safety monitored to 21 weeks. Exploratory immunological …