31 items pinned
Genome-wide association study and meta-analysis in multiple populations identifies new loci for peanut allergy and establishes c11orf30/EMSY as a genetic risk factor for food allergy.
Abstract: Peanut allergy (PA) is a complex disease with both environmental and genetic risk factors. Previously PA loci were identified in FLG and HLA in candidate gene studies, and loci in HLA in a genome-wide association study and meta-analysis.To investigate genetic susceptibility to PA.Eight hundred and fifty cases and 926 hyper-controls and >7.8 million genotyped and imputed single nucleotide polymorphisms (SNPs) were analyzed in a genome-wide association study to identify susceptibility variants for PA in the Canadian population. Meta-analysis of two phenotypes (PA and food allergy) was conducted using 7 studies from the Canadian, American (2), Australian, German and Dutch (2) populations.A SNP near ITGA6 reached genome-wide significance with PA (p=1.80×10(-8)), while SNPs associated with SKAP1, MMP12/MMP13, CTNNA3, ARHGAP24, ANGPT4, c11orf30 (EMSY), and EXOC4 reached a threshold suggestive of association (p≤1.49×10(-6)). In the meta-analysis of PA, loci in or near ITGA6, ANGPT4, MMP12/MMP13, c11orf30 and EXOC4 were significant (p≤1.49×10(-6)). When a phenotype of any food allergy was used for meta-analysis, the c11orf30 locus reached genome-wide significance (p=7.50×10(-11)), while SNPs associated with ITGA6, ANGPT4, MMP12/MMP13, EXOC4 and additional c11orf30 SNPs were suggestive (p≤1.49×10(-6)). Functional annotation indicated SKAP1 regulates expression of CBX1, which co-localizes with the EMSY protein coded by c11orf30.This study identifies multiple novel loci as risk factors for PA and food allergy and establishes c11orf30 as a risk locus for both peanut and food allergy. Multiple genes (c11orf30/EMSY, SKAP1 and CTNNA3) identified by this study are involved in epigenetic regulation of gene expression.
Pub.: 17 Oct '17, Pinned: 19 Oct '17
Increase in anaphylaxis-related hospitalizations but no increase in fatalities: an analysis of United Kingdom national anaphylaxis data, 1992-2012.
Abstract: The incidence of anaphylaxis might be increasing. Data for fatal anaphylaxis are limited because of the rarity of this outcome.We sought to document trends in anaphylaxis admissions and fatalities by age, sex, and cause in England and Wales over a 20-year period.We extracted data from national databases that record hospital admissions and fatalities caused by anaphylaxis in England and Wales (1992-2012) and crosschecked fatalities against a prospective fatal anaphylaxis registry. We examined time trends and age distribution for fatal anaphylaxis caused by food, drugs, and insect stings.Hospital admissions from all-cause anaphylaxis increased by 615% over the time period studied, but annual fatality rates remained stable at 0.047 cases (95% CI, 0.042-0.052 cases) per 100,000 population. Admission and fatality rates for drug- and insect sting-induced anaphylaxis were highest in the group aged 60 years and older. In contrast, admissions because of food-triggered anaphylaxis were most common in young people, with a marked peak in the incidence of fatal food reactions during the second and third decades of life. These findings are not explained by age-related differences in rates of hospitalization.Hospitalizations for anaphylaxis increased between 1992 and 2012, but the incidence of fatal anaphylaxis did not. This might be due to increasing awareness of the diagnosis, shifting patterns of behavior in patients and health care providers, or both. The age distribution of fatal anaphylaxis varies significantly according to the nature of the eliciting agent, which suggests a specific vulnerability to severe outcomes from food-induced allergic reactions in the second and third decades.
Pub.: 04 Dec '14, Pinned: 18 Oct '17
Dose of Allergens in a Peanut Snack (Bamba(®)) Associated with Prevention of Peanut Allergy.
Abstract: This letter reports the dose of specific allergens (Ara h 1, Ara h 2 and Ara h 6) in the peanut snack (Bamba(®)) that was successfully used to prevent peanut allergy in the Learning Early About Peanut (LEAP) study. The results provide weekly doses of specific allergen that are associated with prevention of peanut allergy.
Pub.: 16 Jul '17, Pinned: 18 Oct '17
Allergen-encoding bone marrow transfer inactivates allergic T cell responses, alleviating airway inflammation.
Abstract: Memory Th2 cell responses underlie the development and perpetuation of allergic diseases. Because these states result from immune dysregulation, established Th2 cell responses represent a significant challenge for conventional immunotherapies. New approaches that overcome the detrimental effects of immune dysregulation are required. We tested whether memory Th2 cell responses were silenced using a therapeutic approach where allergen expression in DCs is transferred to sensitized recipients using BM cells as a vector for therapeutic gene transfer. Development of allergen-specific Th2 responses and allergen-induced airway inflammation was blocked by expression of allergen in DCs. Adoptive transfer studies showed that Th2 responses were inactivated by a combination of deletion and induction of T cell unresponsiveness. Transfer of BM encoding allergen expression targeted to DCs terminated, in an allergen-specific manner, Th2 responses in sensitized recipients. Importantly, when preexisting airway inflammation was present, there was effective silencing of Th2 cell responses, airway inflammation was alleviated, and airway hyperreactivity was reversed. The effectiveness of DC-targeted allergen expression to terminate established Th2 responses in sensitized animals indicates that exploiting cell-intrinsic T cell tolerance pathways could lead to development of highly effective immunotherapies.
Pub.: 02 Jun '17, Pinned: 18 Oct '17
Farm dust and endotoxin protect against allergy through A20 induction in lung epithelial cells.
Abstract: Growing up on a dairy farm protects children from allergy, hay fever, and asthma. A mechanism linking exposure to this endotoxin (bacterial lipopolysaccharide)-rich environment with protection has remained elusive. Here we show that chronic exposure to low-dose endotoxin or farm dust protects mice from developing house dust mite (HDM)-induced asthma. Endotoxin reduced epithelial cell cytokines that activate dendritic cells (DCs), thus suppressing type 2 immunity to HDMs. Loss of the ubiquitin-modifying enzyme A20 in lung epithelium abolished the protective effect. A single-nucleotide polymorphism in the gene encoding A20 was associated with allergy and asthma risk in children growing up on farms. Thus, the farming environment protects from allergy by modifying the communication between barrier epithelial cells and DCs through A20 induction.
Pub.: 05 Sep '15, Pinned: 17 Oct '17
How colonization by microbiota in early life shapes the immune system.
Abstract: Microbial colonization of mucosal tissues during infancy plays an instrumental role in the development and education of the host mammalian immune system. These early-life events can have long-standing consequences: facilitating tolerance to environmental exposures or contributing to the development of disease in later life, including inflammatory bowel disease, allergy, and asthma. Recent studies have begun to define a critical period during early development in which disruption of optimal host-commensal interactions can lead to persistent and in some cases irreversible defects in the development and training of specific immune subsets. Here, we discuss the role of early-life education of the immune system during this "window of opportunity," when microbial colonization has a potentially critical impact on human health and disease.
Pub.: 30 Apr '16, Pinned: 17 Oct '17
Hookworm recombinant protein promotes regulatory T cell responses that suppress experimental asthma.
Abstract: In the developed world, declining prevalence of some parasitic infections correlates with increased incidence of allergic and autoimmune disorders. Moreover, experimental human infection with some parasitic worms confers protection against inflammatory diseases in phase 2 clinical trials. Parasitic worms manipulate the immune system by secreting immunoregulatory molecules that offer promise as a novel therapeutic modality for inflammatory diseases. We identify a protein secreted by hookworms, anti-inflammatory protein-2 (AIP-2), that suppressed airway inflammation in a mouse model of asthma, reduced expression of costimulatory markers on human dendritic cells (DCs), and suppressed proliferation ex vivo of T cells from human subjects with house dust mite allergy. In mice, AIP-2 was primarily captured by mesenteric CD103(+) DCs and suppression of airway inflammation was dependent on both DCs and Foxp3(+) regulatory T cells (Tregs) that originated in the mesenteric lymph nodes (MLNs) and accumulated in distant mucosal sites. Transplantation of MLNs from AIP-2-treated mice into naïve hosts revealed a lymphoid tissue conditioning that promoted Treg induction and long-term maintenance. Our findings indicate that recombinant AIP-2 could serve as a novel curative therapeutic for allergic asthma and potentially other inflammatory diseases.
Pub.: 01 Nov '16, Pinned: 17 Oct '17
Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy.
Abstract: Despite guidelines recommending avoidance of peanuts during infancy in the United Kingdom (UK), Australia, and, until recently, North America, peanut allergy (PA) continues to increase in these countries.We sought to determine the prevalence of PA among Israeli and UK Jewish children and evaluate the relationship of PA to infant and maternal peanut consumption.A clinically validated questionnaire determined the prevalence of PA among Jewish schoolchildren (5171 in the UK and 5615 in Israel). A second validated questionnaire assessed peanut consumption and weaning in Jewish infants (77 in the UK and 99 in Israel).The prevalence of PA in the UK was 1.85%, and the prevalence in Israel was 0.17% (P < .001). Despite accounting for atopy, the adjusted risk ratio for PA between countries was 9.8 (95% CI, 3.1-30.5) in primary school children. Peanut is introduced earlier and is eaten more frequently and in larger quantities in Israel than in the UK. The median monthly consumption of peanut in Israeli infants aged 8 to 14 months is 7.1 g of peanut protein, and it is 0 g in the UK (P < .001). The median number of times peanut is eaten per month was 8 in Israel and 0 in the UK (P < .0001).We demonstrate that Jewish children in the UK have a prevalence of PA that is 10-fold higher than that of Jewish children in Israel. This difference is not accounted for by differences in atopy, social class, genetic background, or peanut allergenicity. Israeli infants consume peanut in high quantities in the first year of life, whereas UK infants avoid peanuts. These findings raise the question of whether early introduction of peanut during infancy, rather than avoidance, will prevent the development of PA.
Pub.: 13 Nov '08, Pinned: 17 Oct '17
The Skin as a Route of Allergen Exposure: Part II. Allergens and Role of the Microbiome and Environmental Exposures.
Abstract: This second part of the article aims to highlight recent contributions in the literature that enhance our understanding of the cutaneous immune response to allergen.Several properties of allergens facilitate barrier disruption and cutaneous sensitization. There is a strong epidemiologic relationship between the microbiome, both the gut and skin, and atopic dermatitis (AD). The mechanisms connecting these two entities remain enigmatic; however, recent murine models show that commensal skin bacteria play an active role in supporting skin barrier homeostasis and defense against microbial penetration. Likewise, the association between the lack of colonization with Staph species and AD development suggests a potentially functional role for these organisms in regulating the skin barrier and response to environmental allergens. In undisrupted skin, evidence suggests that the cutaneous route may promote allergen tolerance. Properties of environmental allergens and commensal bacteria add to the complex landscape of skin immunity. Further investigation is needed to elucidate how these properties regulate the cutaneous immune response to allergen.
Pub.: 18 Feb '17, Pinned: 17 Oct '17
Effect of Avoidance on Peanut Allergy after Early Peanut Consumption.
Abstract: In a randomized trial, the early introduction of peanuts in infants at high risk for allergy was shown to prevent peanut allergy. In this follow-up study, we investigated whether the rate of peanut allergy remained low after 12 months of peanut avoidance among participants who had consumed peanuts during the primary trial (peanut-consumption group), as compared with those who had avoided peanuts (peanut-avoidance group).At the end of the primary trial, we instructed all the participants to avoid peanuts for 12 months. The primary outcome was the percentage of participants with peanut allergy at the end of the 12-month period, when the participants were 72 months of age.We enrolled 556 of 628 eligible participants (88.5%) from the primary trial; 550 participants (98.9%) had complete primary-outcome data. The rate of adherence to avoidance in the follow-up study was high (90.4% in the peanut-avoidance group and 69.3% in the peanut-consumption group). Peanut allergy at 72 months was significantly more prevalent among participants in the peanut-avoidance group than among those in the peanut-consumption group (18.6% [52 of 280 participants] vs. 4.8% [13 of 270], P<0.001). Three new cases of allergy developed in each group, but after 12 months of avoidance there was no significant increase in the prevalence of allergy among participants in the consumption group (3.6% [10 of 274 participants] at 60 months and 4.8% [13 of 270] at 72 months, P=0.25). Fewer participants in the peanut-consumption group than in the peanut-avoidance group had high levels of Ara h2 (a component of peanut protein)-specific IgE and peanut-specific IgE; in addition, participants in the peanut-consumption group continued to have a higher level of peanut-specific IgG4 and a higher peanut-specific IgG4:IgE ratio.Among children at high risk for allergy in whom peanuts had been introduced in the first year of life and continued until 5 years of age, a 12-month period of peanut avoidance was not associated with an increase in the prevalence of peanut allergy. Longer-term effects are not known. (Funded by the National Institute of Allergy and Infectious Diseases and others; LEAP-On ClinicalTrials.gov number, NCT01366846.).
Pub.: 05 Mar '16, Pinned: 17 Oct '17
The immunology of the allergy epidemic and the hygiene hypothesis.
Abstract: The immunology of the hygiene hypothesis of allergy is complex and involves the loss of cellular and humoral immunoregulatory pathways as a result of the adoption of a Western lifestyle and the disappearance of chronic infectious diseases. The influence of diet and reduced microbiome diversity now forms the foundation of scientific thinking on how the allergy epidemic occurred, although clear mechanistic insights into the process in humans are still lacking. Here we propose that barrier epithelial cells are heavily influenced by environmental factors and by microbiome-derived danger signals and metabolites, and thus act as important rheostats for immunoregulation, particularly during early postnatal development. Preventive strategies based on this new knowledge could exploit the diversity of the microbial world and the way humans react to it, and possibly restore old symbiotic relationships that have been lost in recent times, without causing disease or requiring a return to an unhygienic life style.
Pub.: 20 Sep '17, Pinned: 12 Oct '17
Immunological Outcomes of Antibody Binding to Glycans Shared between Microorganisms and Mammals.
Abstract: Glycans constitute basic cellular components of living organisms across biological kingdoms, and glycan-binding Abs participate in many cellular interactions during immune defense against pathogenic organisms. Glycan epitopes are expressed as carbohydrate-only entities or as oligomers or polymers on proteins and lipids. Such epitopes on glycoproteins may be formed by posttranslational modifications or neoepitopes resulting from metabolic-catabolic processes and can be altered during inflammation. Pathogenic organisms can display host-like glycans to evade the host immune response. However, Abs to glycans, shared between microorganisms and the host, exist naturally. These Abs are able to not only protect against infectious disease, but also are involved in host housekeeping functions and can suppress allergic disease. Despite the reactivity of these Abs to glycans shared between microorganisms and host, diverse tolerance-inducing mechanisms permit the B cell precursors of these Ab-secreting cells to exist within the normal B cell repertoire.
Pub.: 20 Nov '16, Pinned: 01 Jul '17
Pulmonary α-1,3-Glucan-Specific IgA-Secreting B Cells Suppress the Development of Cockroach Allergy.
Abstract: There is a higher incidence of allergic conditions among children living in industrialized countries than those in developing regions. One explanation for this is reduced neonatal exposure to microbes and the consequent lack of immune stimulation. Sensitivity to cockroach allergen is highly correlated with the development of severe asthma. In this study, we determined that an Ab to microbial α-1,3-glucan binds an Enterobacter species and cockroach allergen. Neonatal, but not adult, mice immunized with this α-1,3-glucan-bearing Enterobacter (MK7) are protected against cockroach allergy. Following exposure to cockroach allergen, α-1,3-glucan-specific IgA-secreting cells are present in the lungs of mice immunized with MK7 as neonates but not in the lungs of those immunized as adults. Mice that are unable to generate anti-α-1,3-glucan IgA Abs were immunized with MK7 as neonates and were no longer protected against cockroach allergy. Thus, neonatal, but not adult, exposure to α-1,3-glucan results in suppressed development of cockroach allergy via pulmonary α-1,3-glucan-specific IgA-secreting cells.
Pub.: 02 Sep '16, Pinned: 01 Jul '17
Neonatal exposure to pneumococcal phosphorylcholine modulates the development of house dust mite allergy during adult life.
Abstract: Currently, ∼20% of the global population suffers from an allergic disorder. Allergies and asthma occur at higher rates in developed and industrialized countries. It is clear that many human atopic diseases are initiated neonatally and herald more severe IgE-mediated disorders, including allergic asthma, which is driven by the priming of Th2 effector T cells. The hygiene hypothesis attempts to link the increased excessively sanitary conditions early in life to a default Th2 response and increasing allergic phenomena. Despite the substantial involvement of IgE Abs in such conditions, little attention has been paid to the effects of early microbial exposure on the B cell repertoire prior to the initiation of these diseases. In this study, we use Ab-binding assays to demonstrate that Streptococcus pneumoniae and house dust mite (HDM) bear similar phosphorylcholine (PC) epitopes. Neonatal C57BL/6 mice immunized with a PC-bearing pneumococcal vaccine expressed increased frequencies of PC-specific B cells in the lungs following sensitizing exposure to HDM as adults. Anti-PC IgM Abs in the lung decreased the interaction of HDM with pulmonary APCs and were affiliated with lowered allergy-associated cell infiltration into the lung, IgE production, development of airway hyperresponsiveness, and Th2 T cell priming. Thus, exposure of neonatal mice to PC-bearing pneumococci significantly reduced the development of HDM-induced allergic disease during adult life. Our findings demonstrate that B cells generated against conserved epitopes expressed by bacteria, encountered early in life, are also protective against the development of allergic disease during adult life.
Pub.: 10 May '15, Pinned: 01 Jul '17
Development of allergic immunity in early life.
Abstract: The growth and maturity of the peripheral immune system and subsequent development of pulmonary immunity in early life is dictated by host, environmental and microbial factors. Dysregulation during the critical window of immune development in the postnatal years results in disease which impacts on lifelong lung health. Asthma is a common disease in childhood and is often preceded by wheezing illnesses during the preschool years. However, the mechanisms underlying development of wheeze and how and why only some children progress to asthma is unknown. Human studies to date have generally focused on peripheral immune development, with little assessment of local tissue pathology in young children. Moreover, mechanisms underlying the interactions between inflammation and tissue repair at mucosal surfaces in early life remain unknown. Disappointingly, mechanistic studies in mice have predominantly used adult models. This review will consider the aspects of the neonatal immune system which might contribute to the development of early life wheezing disorders and asthma, and discuss the external environmental factors which may influence this process.
Pub.: 29 Jun '17, Pinned: 01 Jul '17
The Neonatal CD8+ T Cell Repertoire Rapidly Diversifies during Persistent Viral Infection.
Abstract: CMV is the most common congenital infection in the United States. The major target of congenital CMV is the brain, with clinical manifestations including mental retardation, vision impairment, and sensorineural hearing loss. Previous reports have shown that CD8(+) T cells are required to control viral replication and significant numbers of CMV-specific CD8(+) T cells persist in the brain even after the initial infection has been cleared. However, the dynamics of CD8(+) T cells in the brain during latency remain largely undefined. In this report, we used TCR sequencing to track the development and maintenance of neonatal clonotypes in the brain and spleen of mice during chronic infection. Given the discontinuous nature of tissue-resident memory CD8(+) T cells, we hypothesized that neonatal TCR clonotypes would be locked in the brain and persist into adulthood. Surprisingly, we found that the Ag-specific T cell repertoire in neonatal-infected mice diversified during persistent infection in both the brain and spleen, while maintaining substantial similarity between the CD8(+) T cell populations in the brain and spleen in both early and late infection. However, despite the diversification of, and potential interchange between, the spleen and brain Ag-specific T cell repertoires, we observed that germline-encoded TCR clonotypes, characteristic of neonatal infection, persisted in the brain, albeit sometimes in low abundance. These results provide valuable insights into the evolution of CD8(+) T cell repertoires following neonatal CMV infection and thus have important implications for the development of therapeutic strategies to control CMV in early life.
Pub.: 15 Jan '16, Pinned: 30 Jun '17
A Wave of Regulatory T Cells into Neonatal Skin Mediates Tolerance to Commensal Microbes.
Abstract: The skin is a site of constant dialog between the immune system and commensal bacteria. However, the molecular mechanisms that allow us to tolerate the presence of skin commensals without eliciting destructive inflammation are unknown. Using a model system to study the antigen-specific response to S. epidermidis, we demonstrated that skin colonization during a defined period of neonatal life was required for establishing immune tolerance to commensal microbes. This crucial window was characterized by an abrupt influx of highly activated regulatory T (Treg) cells into neonatal skin. Selective inhibition of this Treg cell wave completely abrogated tolerance. Thus, the host-commensal relationship in the skin relied on a unique Treg cell population that mediated tolerance to bacterial antigens during a defined developmental window. This suggests that the cutaneous microbiome composition in neonatal life is crucial in shaping adaptive immune responses to commensals, and disrupting these interactions might have enduring health implications.
Pub.: 21 Nov '15, Pinned: 01 Jul '17
The Microbiome, Timing, and Barrier Function in the Context of Allergic Disease
Abstract: Allergic disease affects millions. Despite many advances in our understanding of the immune system in the past century, the physiologic underpinning for the existence of allergy remains largely mysterious. Food allergies, in particular, have increased dramatically in recent years, adding a new sense of urgency to unraveling this mystery. The concurrence of significant lifestyle changes in Western societies with increasing disease prevalence implies a causal link. Demographic variables that influence the composition and function of the commensal microbiota early in life seem to be most important. Identifying the evolutionary and physiologic foundations of allergic disease and defining what about our modern environment is responsible for its increased incidence will provide insights critical to the development of new approaches to prevention and treatment.
Pub.: 19 Apr '16, Pinned: 24 Jun '17
A novel model for IFN-γ-mediated autoinflammatory syndromes.
Abstract: Autoinflammatory disease and hyperinflammatory syndromes represent a growing number of diseases associated with inappropriately controlled inflammation in multiple organs. Systemic inflammation commonly results from dysregulated activation of innate immune cells, and therapeutic targeting of the IL-1β pathway has been used to ameliorate some of these diseases. Some hyperinflammatory syndromes, however, such as hemophagocytic lymphohistiocytosis and the newly classified proteasome disability syndromes, are refractory to such treatments, suggesting that other factors or environmental stressors may be contributing. In comparing two cytokine reporter mouse strains, we identify IFN-γ as a mediator of systemic autoinflammatory disease. Chronically elevated levels of IFN-γ resulted in progressive multiorgan inflammation and two copies of the mutant allele resulted in increased mortality accompanied by myeloproliferative disease. Disease was alleviated by genetic deletion of T-bet. These studies raise the possibility that therapeutics targeting the IFN-γ pathway might be effective in hyperinflammatory conditions refractory to IL-1β-targeted therapies.
Pub.: 01 Feb '15, Pinned: 01 Jul '17
Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity.
Abstract: Interleukin 4 (IL-4) and IL-13 are critical for responses to parasitic helminthes. We used genetically engineered reporter mice to assess the temporal and spatial production of these cytokines in vivo. In lymph nodes, IL-4, but not IL-13, was made by follicular helper T cells (T(FH) cells). In contrast, tissue type 2 helper T cells (T(H)2 cells) produced both cytokines. There was also divergent production of IL-4 and IL-13 among cells of the innate immune system, whereby basophils produced IL-4, whereas innate helper type 2 cells (Ih2 cells) produced IL-13. IL-13 production by T(H)2 and Ih2 cells was dependent on the transcription factor GATA-3, which was present in large amounts in these cells, and in contrast to the small amount of GATA-3 in T(FH) cells and basophils. The distinct localization and cellular expression of IL-4 and IL-13 explains their unique roles during allergic immunity.
Pub.: 06 Dec '11, Pinned: 01 Jul '17
A two-step process for cytokine production revealed by IL-4 dual-reporter mice.
Abstract: To monitor IL-4 expression at the single-cell level, we generated mice with insertions of different reporter genes into both copies of the Il4 gene that permitted the simultaneous analysis of IL-4 transcripts via GFP and IL-4 protein secretion by use of huCD2. Innate and adaptive cells competent for IL-4 production were marked by GFP, while cells that presently or recently secreted IL-4 additionally displayed huCD2. After challenge with the strictly enteric helminth, Heligmosomoides polygyrus, GFP-positive innate and adaptive cells disseminated widely, but IL-4 secretion was predominantly mediated by CD4+ T cells in the intestines and draining lymphoid organs. IL-4-competent cells persisted in cured animals, and memory responses reflected rapid cytokine production at the site of rechallenge. These data reveal a two-step process for cytokine production: the first generating poised cells that disseminate systemically and the second inducing the rapid production of the cytokine in response to local stimulation.
Pub.: 18 Oct '05, Pinned: 01 Jul '17
Developmental regulation of Foxp3 expression during ontogeny.
Abstract: Thymectomy of neonatal mice can result in the development of autoimmune pathology. It has been proposed that thymic output of regulatory T (T reg) cells is delayed during ontogeny and that the development of autoimmune disease in neonatally thymectomized mice is caused by the escape of self-reactive T cells before thymectomy without accompanying T reg cells. However, the kinetics of T reg cell production within the thymus during ontogeny has not been assessed. We demonstrate that the development of Foxp3-expressing T reg cells is substantially delayed relative to nonregulatory thymocytes during ontogeny. Based on our data, we speculate that induction of Foxp3 in developing thymocytes and, thus, commitment to the T reg cell lineage is facilitated by a signal largely associated with the thymic medulla.
Pub.: 06 Oct '05, Pinned: 01 Jul '17