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The significance of estimating the spatial variability of the hydraulic conductivity K in natural aquifers is relevant to the possibility of defining the space and time evolution of a non-reactive plume, since the transport of a solute is mainly controlled by the heterogeneity of K. At the local scale, the spatial distribution of K can be inferred by combining the Lagrangian formulation of the transport with a Kalman filter-based technique and assimilating a sequence of time-lapse concentration C measurements, which, for example, can be evaluated on-site through the application of a geophysical method. The objective of this work is to compare the ensemble Kalman filter (EnKF) and the ensemble smoother (ES) capabilities to retrieve the hydraulic conductivity spatial distribution in a groundwater flow and transport modeling framework. The application refers to a two-dimensional synthetic aquifer in which a tracer test is simulated. Moreover, since Kalman filter-based methods are optimal only if each of the involved variables fit to a Gaussian probability density function (pdf) and since this condition may not be met by some of the flow and transport state variables, issues related to the non-Gaussianity of the variables are analyzed and different transformation of the pdfs are considered in order to evaluate their influence on the performance of the methods. The results show that the EnKF reproduces with good accuracy the hydraulic conductivity field, outperforming the ES regardless of the pdf of the concentrations. [ABSTRACT FROM AUTHOR]

Background: Immune dysregulation and SARS-CoV-2 plasma viremia have been implicated in fatal COVID-19 disease. However, how these two factors interact to shape disease outcomes is unclear., Methods: We carried out viral and immunological phenotyping on a prospective cohort of 280 patients with COVID-19 presenting to acute care hospitals in Boston, Massachusetts and Genoa, Italy between June 1, 2020 and February 8, 2022. Disease severity, mortality, plasma viremia, and immune dysregulation were assessed. A mouse model of lethal H1N1 influenza infection was used to analyze the therapeutic potential of Notch4 and pyroptosis inhibition in disease outcome., Results: Stratifying patients based on %Notch4 + Treg cells and/or the presence of plasma viremia identified four subgroups with different clinical trajectories and immune phenotypes. Patients with both high %Notch4 + Treg cells and viremia suffered the most disease severity and 90-day mortality compared to the other groups even after adjusting for baseline comorbidities. Increased Notch4 and plasma viremia impacted different arms of the immune response in SARS-CoV-2 infection. Increased Notch4 was associated with decreased Treg cell amphiregulin expression and suppressive function whereas plasma viremia was associated with increased monocyte cell pyroptosis. Combinatorial therapies using Notch4 blockade and pyroptosis inhibition induced stepwise protection against mortality in a mouse model of lethal H1N1 influenza infection., Conclusions: The clinical trajectory and survival outcome in hospitalized patients with COVID-19 is predicated on two cardinal factors in disease pathogenesis: viremia and Notch4 + Treg cells. Intervention strategies aimed at resetting the immune dysregulation in COVID-19 by antagonizing Notch4 and pyroptosis may be effective in severe cases of viral lung infection., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcomes were previously correlated with Notch4 expression on Tregs, here, we show that Tregs in MIS-C were destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that patients with MIS-C had enrichment of rare deleterious variants affecting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Tregs induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results identify a Notch1/CD22 signaling axis that disrupts Treg function in MIS-C and point to distinct immune checkpoints controlled by individual Treg Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.

Background: The mechanisms by which genetic and environmental factors interact to promote asthma remain unclear. Both the IL-4 receptor alpha chain R576 (IL-4RαR576) variant and Notch4 license asthmatic lung inflammation by allergens and ambient pollutant particles by subverting lung regulatory T (T reg ) cells in an IL-6-dependent manner., Objective: We examined the interaction between IL-4RαR576 and Notch4 in promoting asthmatic inflammation., Methods: Peripheral blood mononuclear cells (PBMCs) of asthmatics were analyzed for T helper type 2 cytokine production and Notch4 expression on T reg cells as a function of IL4R R576 allele. The capacity of IL-4RαR576 to upregulate Notch4 expression on T reg cells to promote severe allergic airway inflammation was further analyzed in genetic mouse models., Results: Asthmatics carrying the IL4R R576 allele had increased Notch4 expression on their circulating T reg cells as a function of disease severity and serum IL-6. Mice harboring the Il4ra R576 allele exhibited increased Notch4-dependent allergic airway inflammation that was inhibited upon T reg cell-specific Notch4 deletion or treatment with an anti-Notch4 antibody. Signaling via IL-4RαR576 upregulated the expression in lung T reg cells of Notch4 and its downstream mediators Yap1 and beta-catenin, leading to exacerbated lung inflammation. This upregulation was dependent on growth factor receptor-bound protein 2 (GRB2) and IL-6 receptor., Conclusion: These results identify an IL-4RαR576-regulated GRB2-IL-6-Notch4 circuit that promotes asthma severity by subverting lung T reg cell function., (© 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infections that occurs in the pediatric population. We sought to characterize T cell responses in MIS-C compared to COVID-19 and pediatric hyperinflammatory syndromes. MIS-C was distinct from COVID-19 and hyperinflammatory syndromes due to an expansion of T cells expressing TRBV11-2 that was not associated with HLA genotype. Children diagnosed with MIS-C, but who were negative for SARS-CoV-2 by PCR and serology, did not display Vβ skewing. There was no difference in the proportion of T cells that became activated after stimulation with SARS-CoV-2 peptides in children with MIS-C compared to convalescent COVID-19. The frequency of SARS-CoV-2-specific TCRs and the antigens recognized by these TCRs were comparable in MIS-C and COVID-19. Expansion of Vβ11-2 + T cells was a specific biomarker of MIS-C patients with laboratory confirmed SARS-CoV-2 infections. Children with MIS-C had robust antigen-specific T cell responses to SARS-CoV-2., Competing Interests: Declaration of Competing Interest LAH has received salary support from CARRA; consulting fees from Sobi, Pfizer, and Adaptive Biotechnologies; and investigator-initiated research grants from Bristol-Myers Squibb., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Atopic dermatitis (AD) and food allergy (FA) may share genetic risk factors. It is unknown whether genetic factors directly cause FA or are mediated through AD, as the dual-allergen hypothesis suggests., Objective: To test the hypothesis that AD mediates the relationship between an IL-4 receptor alpha chain gene (IL4RA) variant, the human IL-4 receptor alpha chain protein-R576 polymorphism, and FA., Methods: A total of 433 children with asthma enrolled in the School Inner-City Asthma Study underwent genotyping for the IL4RA 576 allele. Surveys were administered to determine FA, AD, and associated allergic responses. Mediation analysis was performed adjusting for race and ethnicity, age, sex, and household income. Multivariate models were used to determine the association between genotype and FA severity., Results: AD was reported in 193 (45%) and FA in 80 children (19%). Each risk allele increased odds of AD 1.39-fold ([1.03-1.87], P = .03), and AD increased odds of FA 3.67-fold ([2.05- 6.57], P < .01). There was an indirect effect of genotype, mediated by AD, predicting FA; each risk allele increased the odds of FA by 1.13 (odds ratio [95% CI], Q/R = 1.13 [1.02-1.24], R/R = 1.28 [1.04-1.51]; P < .01). Each risk allele increased the odds of severe FA symptoms 2.68-fold ([1.26-5.71], P = .01)., Conclusions: In a cohort of children with asthma, AD is part of the causal pathway between an IL4RA variant and FA. This variant is associated with increased risk of severe FA reactions. Addressing AD in children with an IL4RA polymorphism may modulate the risk of FA., (Copyright © 2022. Published by Elsevier Inc.)

Infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) provokes a potentially fatal pneumonia with multiorgan failure, and high systemic inflammation. To gain mechanistic insight and ferret out the root of this immune dysregulation, we modeled, by in vitro coculture, the interactions between infected epithelial cells and immunocytes. A strong response was induced in monocytes and B cells, with a SARS-CoV-2-specific inflammatory gene cluster distinct from that seen in influenza A or Ebola virus-infected cocultures, and which reproduced deviations reported in blood or lung myeloid cells from COVID-19 patients. A substantial fraction of the effect could be reproduced after individual transfection of several SARS-CoV-2 proteins (Spike and some nonstructural proteins), mediated by soluble factors, but not via transcriptional induction. This response was greatly muted in monocytes from healthy children, perhaps a clue to the age dependency of COVID-19. These results suggest that the inflammatory malfunction in COVID-19 is rooted in the earliest perturbations that SARS-CoV-2 induces in epithelia., (Copyright © 2021 the Author(s). Published by PNAS.)

A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections., Competing Interests: Declaration of interests T.A.C., H.H., M.B., P.S.L., P.C., and R.D.P. are inventors on provisional patent application US 63/038,186 titled “Methods and Compositions for treating coronavirus infectious disease.” H.H. and T.A.C. are co-founders of and hold equity in Alcea Therapeutics., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The mechanisms by which regulatory T (Treg) cells differentially control allergic and autoimmune responses remain unclear. We show that Treg cells in food allergy (FA) had decreased expression of transforming growth factor beta 1 (TGF-β1) because of interleukin-4 (IL-4)- and signal transducer and activator of transciription-6 (STAT6)-dependent inhibition of Tgfb1 transcription. These changes were modeled by Treg cell-specific Tgfb1 monoallelic inactivation, which induced allergic dysregulation by impairing microbiota-dependent retinoic acid receptor-related orphan receptor gamma t (ROR-γt) + Treg cell differentiation. This dysregulation was rescued by treatment with Clostridiales species, which upregulated Tgfb1 expression in Treg cells. Biallelic deficiency precipitated fatal autoimmunity with intense autoantibody production and dysregulated T follicular helper and B cell responses. These results identify a privileged role of Treg cell-derived TGF-β1 in regulating allergy and autoimmunity at distinct checkpoints in a Tgfb1 gene dose- and microbiota-dependent manner., Competing Interests: Declaration of Interests L.B., T.C., A.A.-G., and R.R. are inventors on published US patent no. US10391131B2, submitted by The Brigham and Women’s Hospital, Inc. and Children’s Medical Center Corporation, which covers methods and compositions for prevention and treatment of food allergy using microbial treatments. T.C, E.S.-V., A.A.-G. and R.R. have pending patent applications related to the use of probiotics in enforcing oral tolerance in food allergy (no. 62/798,224). L.B., T.C., and R.R. are co-founders of and/or have equity in Paretobio., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Elucidating the mechanisms that sustain asthmatic inflammation is critical for precision therapies. We found that interleukin-6- and STAT3 transcription factor-dependent upregulation of Notch4 receptor on lung tissue regulatory T (T reg ) cells is necessary for allergens and particulate matter pollutants to promote airway inflammation. Notch4 subverted T reg cells into the type 2 and type 17 helper (T H 2 and T H 17) effector T cells by Wnt and Hippo pathway-dependent mechanisms. Wnt activation induced growth and differentiation factor 15 expression in T reg cells, which activated group 2 innate lymphoid cells to provide a feed-forward mechanism for aggravated inflammation. Notch4, Wnt and Hippo were upregulated in circulating T reg cells of individuals with asthma as a function of disease severity, in association with reduced T reg cell-mediated suppression. Our studies thus identify Notch4-mediated immune tolerance subversion as a fundamental mechanism that licenses tissue inflammation in asthma.

The steep rise in food allergy (FA) has evoked environmental factors involved in disease pathogenesis, including the gut microbiota, diet, and their metabolites. Early introduction of solid foods synchronizes with the "weaning reaction," a time during which the microbiota imprints durable oral tolerance. Recent work has shown that children with FA manifest an early onset dysbiosis with the loss of Clostridiales species, which promotes the differentiation of ROR-γt + regulatory T cells to suppress FA. This process can be reversed in pre-clinical mouse models by targeted bacteriotherapy. Here, we review the dominant tolerance mechanisms enforced by the microbiota to suppress FA and discuss therapeutic intervention strategies that act to recapitulate the early life window of opportunity in stemming the FA epidemic., Competing Interests: Declaration of Interests T.A.C. is an inventor on a published US patent application, 15/801,811, that covers methods and compositions for the prevention and treatment of FA by using microbial treatments. T.A.C. and E.S.-V. have pending patent applications related to the use of probiotics in enforcing oral tolerance in FA (62/758,161 and 62/823,866). T.A.C. is founder of and has equity in Consortia Tx., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Food allergy (FA) affects an increasing proportion of children for reasons that remain obscure. Novel disease biomarkers and curative treatment options are strongly needed., Objective: We sought to apply untargeted metabolomic profiling to identify pathogenic mechanisms and candidate disease biomarkers in patients with FA., Methods: Mass spectrometry-based untargeted metabolomic profiling was performed on serum samples of children with either FA alone, asthma alone, or both FA and asthma, as well as healthy pediatric control subjects., Results: In this pilot study patients with FA exhibited a disease-specific metabolomic signature compared with both control subjects and asthmatic patients. In particular, FA was uniquely associated with a marked decrease in sphingolipid levels, as well as levels of a number of other lipid metabolites, in the face of normal frequencies of circulating natural killer T cells. Specific comparison of patients with FA and asthmatic patients revealed differences in the microbiota-sensitive aromatic amino acid and secondary bile acid metabolism. Children with both FA and asthma exhibited a metabolomic profile that aligned with that of FA alone but not asthma. Among children with FA, the history of severe systemic reactions and the presence of multiple FAs were associated with changes in levels of tryptophan metabolites, eicosanoids, plasmalogens, and fatty acids., Conclusions: Children with FA have a disease-specific metabolomic profile that is informative of disease mechanisms and severity and that dominates in the presence of asthma. Lower levels of sphingolipids and ceramides and other metabolomic alterations observed in children with FA might reflect the interplay between an altered microbiota and immune cell subsets in the gut., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4 + but lower than normal CD8 + cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1 nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth., (Published by Elsevier Inc.)

The role of dysbiosis in food allergy (FA) remains unclear. We found that dysbiotic fecal microbiota in FA infants evolved compositionally over time and failed to protect against FA in mice. Infants and mice with FA had decreased IgA and increased IgE binding to fecal bacteria, indicative of a broader breakdown of oral tolerance than hitherto appreciated. Therapy with Clostridiales species impacted by dysbiosis, either as a consortium or as monotherapy with Subdoligranulum variabile, suppressed FA in mice as did a separate immunomodulatory Bacteroidales consortium. Bacteriotherapy induced expression by regulatory T (Treg) cells of the transcription factor ROR-γt in a MyD88-dependent manner, which was deficient in FA infants and mice and ineffectively induced by their microbiota. Deletion of Myd88 or Rorc in Treg cells abrogated protection by bacteriotherapy. Thus, commensals activate a MyD88/ROR-γt pathway in nascent Treg cells to protect against FA, while dysbiosis impairs this regulatory response to promote disease.

Background: The 2003 Joint Task Force on Practice Parameters recommended standardizing allergen subcutaneous immunotherapy (SCIT). Data from longitudinal surveillance survey in North America reported a systemic reaction (SR) rate of 0.1% to 0.2% of injection visits. The rate of SR to standardized SCIT in pediatric patients has not been well evaluated., Objective: The objective of this study was to evaluate the rate of SRs to standardized SCIT in pediatric patients aged 5 to 18 years in a single tertiary care center in the United States., Methods: A retrospective chart review was conducted in 2 groups: group 1 started SCIT within a period extending from January 2009 to June 2012, whereas group 2 started SCIT within a period extending from January 2013 to June 2016. The protocol was modified in group 2 such that updosing and maintenance doses were adjusted in the spring for tree and grass pollen and in the fall for weed pollen., Results: There were a total of 128 patients in group 1 and 118 patients in group 2. The rate of SR was 0.429% in group 1 and 0.364% in group 2, which was not significant. There was no difference in the severity of SR in the 2 groups with no-fatal or near-fatal SR noted. Asthma was a significant risk factor in the younger age subgroup aged 5 to 11 years., Conclusions: Standardized SCIT appears to be associated with an SR rate of 0.429% to 0.364% of visits in pediatric patients. Protocol modification did not lead to a significant drop in SR. Larger multicenter studies are required to further evaluate the rate of SRs from standardized SCIT., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Peanut oral immunotherapy, using a variety of approaches, has been previously shown to induce desensitization in peanut-allergic subjects, but no products have been approved for clinical use by regulatory agencies., Objective: We performed the first phase 2 multicentered study to assess the safety and efficacy of AR101, a novel oral biologic drug product., Methods: A randomized, double-blind, placebo-controlled trial was conducted at 8 US centers. Eligible subjects were 4 to 26 years old, sensitized to peanut, and had dose-limiting symptoms to ≤143 mg of peanut protein in a screening double-blind, placebo-controlled food challenge (DBPCFC). Subjects were randomized 1:1 to daily AR101 or placebo and gradually up-dosed from 0.5 to 300 mg/day. The primary endpoint was the proportion of subjects in each arm able to tolerate ≥443 mg (cumulative peanut protein) at exit DBPCFC with no or mild symptoms., Results: Fifty-five subjects (29 AR101, 26 placebo) were enrolled. In the intention-to-treat analysis, 23 of 29 (79%) and 18 of 29 (62%) AR101 subjects tolerated ≥443 mg and 1043 mg at exit DBPCFC, respectively, versus 5 of 26 (19%) and 0 of 26 (0%) placebo subjects (both P < .0001). Compared with placebo, AR101 significantly reduced symptom severity during exit DBPCFCs and modulated peanut-specific cellular and humoral immune responses. Gastrointestinal (GI) symptoms were the most common treatment-related adverse events (AEs) in both groups, with 6 AR101 subjects (21%) withdrawing, 4 of those due primarily to recurrent GI AEs., Conclusions: In this study, AR101 demonstrated an acceptable safety profile and demonstrated clinical activity as a potential immunomodulatory treatment option in peanut-allergic children over the age of 4, adolescents, and young adults., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Combined immunodeficiency (CID) refers to inborn errors of human T cells that also affect B cells because of the T cell deficit or an additional B cell-intrinsic deficit. In this study, we report six patients from three unrelated families with biallelic loss-of-function mutations in RLTPR, the mouse orthologue of which is essential for CD28 signaling. The patients have cutaneous and pulmonary allergy, as well as a variety of bacterial and fungal infectious diseases, including invasive tuberculosis and mucocutaneous candidiasis. Proportions of circulating regulatory T cells and memory CD4 + T cells are reduced. Their CD4 + T cells do not respond to CD28 stimulation. Their CD4 + T cells exhibit a "Th2" cell bias ex vivo and when cultured in vitro, contrasting with the paucity of "Th1," "Th17," and T follicular helper cells. The patients also display few memory B cells and poor antibody responses. This B cell phenotype does not result solely from the T cell deficiency, as the patients' B cells fail to activate NF-κB upon B cell receptor (BCR) stimulation. Human RLTPR deficiency is a CID affecting at least the CD28-responsive pathway in T cells and the BCR-responsive pathway in B cells., (© 2016 Wang et al.)

Background: Recombination-activating gene (RAG) 1 and 2 deficiency is seen in patients with severe combined immunodeficiency (SCID) and Omenn syndrome. However, the spectrum of the disease has recently expanded to include a milder phenotype., Objective: We analyzed a 4-year-old boy who was initially given the diagnosis of selective immunoglobulin A deficiency (SIgAD) based on immunoglobulin serum levels without any opportunistic infections, rashes, hepatosplenomegaly, autoimmunity or granulomas. The patient was found to be infected with varicella zoster; however, the clinical course was not serious. He produced antiviral antibodies., Methods: We performed lymphocyte phenotyping, quantification of T cell receptor excision circles (TRECs) and kappa deleting recombination excision circles (KRECs), an analysis of target sequences of RAG1 and 2, a whole-genome SNP array, an in vitro V(D)J recombination assay, a spectratype analysis of the CDR3 region and a flow cytometric analysis of the bone marrow., Results: Lymphocyte phenotyping demonstrated that the ratio of CD4+ to CD8+ T cells was inverted and the majority of CD4+T cells expressed CD45RO antigens in addition to the almost complete lack of B cells. Furthermore, both TRECs and KRECs were absent. Targeted DNA sequencing and SNP array revealed that the patient carried a deletion of RAG1 and RAG2 genes on the paternally-derived chromosome 11, and two maternally-derived novel RAG1 missense mutations (E455K, R764H). In vitro analysis of recombination activity showed that both RAG1 mutant proteins had low, but residual function., Conclusions: The current case further expands the phenotypic spectrum of mild presentations of RAG deficiency, and suggests that TRECs and KRECs are useful markers for detecting hidden severe, as well as mild, cases.

Purpose: To identify mechanisms of disease in a child born to consanguineous parents, who presented with Omenn syndrome (OS) and was found to carry a heterozygous RAG1 mutation in peripheral blood DNA., Methods: Mutation analysis was performed on whole blood and buccal swab DNA. Recombination activity of the mutant RAG1 protein and diversity of T cell repertoire were tested., Results: Apparent heterozygosity for a novel, functionally null RAG1 mutation in peripheral blood DNA from a patient with OS was shown to be secondary to true somatic reversion. Analysis of T cell repertoire demonstrated expression of various TCRBV families, but an overall restricted pattern., Conclusions: This is the first case of true somatic reversion of a RAG1 mutation in a patient with OS. The reversion event likely occurred at a stage where only a limited pool of T cell progenitors capable of performing V(D)J recombination could be generated. This work emphasizes the importance of performing functional studies to investigate the significance of novel genetic variants, and to consider somatic reversion as a possible disease modifier in SCID.

Background: Total IgE in human subjects tracks strongly from birth onward through unknown mechanisms. Regulation of IgE might occur in relation to adaptive immune cytokine production. In vitro studies have assessed the role of individual cytokines in regulating IgE production in human subjects., Objective: We sought to investigate the association between IgE levels in vivo and the capacity of the individuals to produce adaptive immune cytokines., Methods: Blood samples from participants in the Tucson Infant Immune Study (children at birth and at 3 and 12 months of age, fathers, and mothers before and after delivery) were assessed for percentage of eosinophils and plasma total IgE levels. IFN-gamma, IL-4, IL-5, IL-13, and IL-10 levels were measured in supernatants of mitogen-stimulated PBMCs and examined cross-sectionally for relation to cytokine production by using simple regression, multiple regression with cytokines only and with other known predictors of IgE levels, and longitudinally by means of random effects modeling., Results: After adjusting for eosinophils and other predictors, IL-5 production (but not that of other cytokines) was associated directly with total IgE levels in children at 3 months (P = .009) and 12 months (P = .011) of age but not at birth. The IL-5/IgE association was present also in fathers (P = .040) and in mothers, both during pregnancy (P < .001) and after delivery (P = .030)., Conclusions: This study indicates that mitogen-stimulated IL-5 production is associated with in vivo total IgE levels, independent of the production of other cytokines and circulating eosinophils., Clinical Implications: Understanding the regulation of IgE in vivo might help elucidate the development of allergic responses in individuals.

Background: Recent epidemiologic evidence has challenged the paradigm suggesting a direct causal relationship between allergic sensitization and asthma., Objective: We sought to investigate the role of a familial predisposition for asthma in the development of atopy in children., Methods: Subjects were participants in the Tucson Children's Respiratory Study. Skin tests to aeroallergens were performed in parents and in children at ages 6, 11, and 16 years. Parents were considered asthmatic if they reported physician-confirmed asthma. Parents were divided into 4 phenotypes on the basis of skin sensitization (Skt+ or Skt-) and asthma status (As+ or As-): Skt-/As-, Skt-/As+, Skt+/As-, and Skt+/As+., Results: Children's allergic sensitization differed among parental phenotypes at all ages (P <.0001). Children in the Skt+/As- and Skt+/As+ groups were significantly more likely to be allergic than children in the Skt-/As- group at all ages. Among children with allergic parents, those with at least one parent with asthma were significantly more likely to have positive skin test responses than those with nonasthmatic parents at age 6 years (52.4% vs 37.4%, P <.005) and 11 years (70.1% vs 55.6%, P <.005) but not at age 16 years (82.3% vs 75.1%, P =.180). Results were independent of wheezing in the child and of the characteristics of atopy in parents. The Skt-/As+ group had too few subjects for meaningful comparisons., Conclusion: Among children of atopic parents, parental asthma is a risk factor for allergic sensitization in early childhood. The strong association between allergic sensitization and asthma is at least in part explained by an increased susceptibility to allergen sensitization in subjects predisposed to asthma.