History Of Antigen Exposure Research Articles

Real-Life Diagnostic Performance of the Hypersensitivity Pneumonitis Guidelines: A Multicenter Cohort Study.

Hypersensitivity pneumonitis (HP) is a heterogeneous interstitial lung disease (ILD) that may be difficult to confidently diagnose. Recently, the 2020 ATS/JRS/ALAT HP diagnostic guidelines were published, yet data validating their performance in real-life settings are scarce. We aimed to assess the diagnostic performance of the HP guidelines compared to the gold-standard multidisciplinary discussion (MDD). For this purpose, we included consecutive ILD patients that underwent diagnostic bronchoscopy between 2017 and 2020 in three large medical centers. Four diagnostic factors (antigen exposure history, chest computed tomography pattern, bronchoalveolar lavage lymphocyte count, and histology results) were used to assign guidelines-based HP diagnostic confidence levels for each patient. A sensitivity analysis was performed, with MDD diagnosis as the reference standard. Overall, 213 ILD patients were included, 45 (21%) with an MDD diagnosis of HP. The guidelines' moderate (≥70%) confidence threshold produced optimal performance with 73% sensitivity for HP, 89% specificity, and a J-index of 0.62. The area under the receiver operating characteristic curve (AUC) for a correct guidelines-based diagnosis was 0.86. The guidelines had better performance for non-fibrotic than fibrotic HP (AUC 0.92 vs. 0.82). All diagnostic factors, except bronchoalveolar lavage lymphocyte count, were independent predictors for MDD diagnosis of HP in a multivariate analysis. In conclusion, the HP guidelines exhibited a good diagnostic performance compared to MDD diagnosis in real-life setting.

The Challenging Diagnosis of Interstitial Lung Disease in Children-One Case Report and Literature Review.

Childhood interstitial lung disease (chILD) includes a heterogeneous spectrum of rare respiratory disorders in children associated with substantial morbi-mortality. Interstitial tissue, and other pulmonary structures, epithelium, blood vessels, or pleura are involved, resulting in a restrictive lung disfunction. Respiratory symptoms set in progressively and are often subtle, making thorough clinical history and physical examination fundamental. The etiology often is obscure. The clinical presentation mimics pneumonia or asthma, leading to a diagnostic delay. Challenging diagnosis may require genetic tests, bronchoalveolar lavage, or lung biopsy. Alongside general supportive therapeutic measures, anti-inflammatory, immunosuppressive or antifibrotic agents may be used, based on data derived from adult studies. However, if accurate diagnosis and treatment are delayed, irreversible chronic respiratory failure may ensue, impacting prognosis. The most frequent chILD is hypersensitivity pneumonitis (HP), although it is rare in children. HP is associated with exposure to an environmental antigen, resulting in inflammation of the airways. Detailed antigen exposure history and identification of the inciting trigger are the cornerstones of diagnostic. This article provides the current state of chILD, revealing specific features of HP, based on a clinical case report of a patient admitted in our clinic, requiring extensive investigations for diagnosis, with a favorable long-term outcome.

SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memory CD8+ T cells.

Although mRNA vaccine efficacy against severe COVID-19 remains high, variant emergence has prompted booster immunizations. However, repeated antigen exposure effects on SARS-CoV-2 memory T cells are poorly understood. Here, we utilize MHC-multimers with scRNAseq to profile SARS-CoV-2-responsive T cells ex vivo from humans with one, two, or three antigen exposures, including vaccination, primary, and breakthrough infection. Exposure order determined the distribution between spike- and non-spike-specific responses, with vaccination after infection leading to expansion of spike-specific T cells and differentiation to CCR7-CD45RA+ effectors. In contrast, individuals after breakthrough infection mount vigorous non-spike-specific responses. Analysis of over 4,000 epitope-specific T cell receptor sequences demonstrates that all exposures elicit diverse repertoires characterized by shared TCR motifs, confirmed by monoclonal TCR characterization, with no evidence for repertoire narrowing from repeated exposure. Our findings suggest that breakthrough infections diversify the T cell memory repertoire and current vaccination protocols continue to expand and differentiate spike-specific memory.

A Systematically Derived Exposure Assessment Instrument for Chronic Hypersensitivity Pneumonitis

Chronic hypersensitivity pneumonitis (CHP) is an immune-mediated interstitial lung disease (ILD) caused by inhalational exposure to environmental antigens, resulting in parenchymal fibrosis. By definition, a diagnosis of CHP assumes a history of antigen exposure, but only half of all patients eventually diagnosed with CHP will have a causative antigen identified. Individual clinician variation in eliciting a history of antigen exposure may affect the frequency and confidence of CHP diagnosis. A list of potential causative exposures were derived from a systematic review of the literature. A Delphi method was applied to an international panel of ILD experts to obtain consensus regarding technique for the elicitation of exposure to antigens relevant to a diagnosis of CHP. The consensus threshold was set at 80%agreement, and median≤ 2, interquartile range= 0 on a 5-point Likert scale (1, strongly agree; 2, tend to agree; 3, neither agree nor disagree; 4, disagree; 5, strongly disagree). In two rounds, 36/40 experts participated. Experts agreed on 18 exposure items to ask every patient with suspected CHP. Themes included CHP inducing exposures, features that contribute to an exposure's relevance, and quantification of a relevant exposure. Based on the results from the literature review and Delphi process, a CHP exposure assessment instrument was derived. Using cognitive interviews, the instrument was revised by patients with ILD for readability and usability. This Delphi survey provides items that ILD experts agree are important to ask in all patients presenting with suspected CHP and provides basis for a systematically derived CHP exposure assessment instrument. Clinical utility of this exposure assessment instrument may be affected by different local prevalence patterns of exposures. Ongoing research is required to clinically validate these items and consider their impact in more geographically diverse settings.

CLINICAL EXPOSURE ASSESSMENT IN CHRONIC HYPERSENSITIVITY PNEUMONITIS: A DELPHI PROJECT

SESSION TITLE: Wednesday Abstract Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM PURPOSE: Chronic hypersensitivity pneumonitis (CHP) is an immune mediated form of interstitial lung disease, caused by inhalational exposure to an environmental antigens, resulting in parenchymal fibrosis. Guidelines suggest a detailed history is taken to identify exposures to inducing antigens, but presently there are no validated tools to facilitate an evidence-based approach to this task. Technical variation in eliciting a history of antigen exposure may affect the frequency and confidence of CHP diagnosis. METHODS: A Delphi method was applied to an international panel of ILD experts, to obtain consensus regarding technique for the elicitation of exposure to relevant antigens from possible CHP patients. Items were derived from a systematic review of the literature. The consensus threshold was set at 80% agreement, and median ≥ 2 and IQR = 0. RESULTS: In two rounds, 36/40 experts participated. Themes included: possible CHP inducing exposures, features that contribute to an exposure’s relevance, quantification of a relevant exposure, and ancillary tests. Experts agreed on 21 exposure items to ask every patient with suspected CHP, including organic particulate matter: water damage/flooding, standing water, humidifiers/vaporisers/air conditioners, hot tubs/pools/spas, humid internal environment, visible and smelly mold, moldy hay/silage, moldy wood, organic matter (manure/compost), musical instruments (e.g. trombone/saxophone), metal working fluids; animal and plant proteins: birds, down or feather products, vegetable production including mushroom workers, food production (i.e. salami, cheese, popcorn, wheat, sugarcane, malt, other); and chemical exposures: isocyanates, and exposure to vapours, dusts, gases, mists, or fumes. A minimum relevant duration of exposure required was agreed to be 1-12 months, and a temporal relationship between exposure and onset of symptoms and improvement on exposure avoidance increased the likelihood the exposure was linked to disease. A positive antibody test was agreed to increase the diagnostic likelihood of CHP, but was not considered a requirement for diagnosis. Consensus was unable to be reached in the dose/quantification of exposure, nor the use of an occupational hygienist. CONCLUSIONS: This Delphi survey provides items that ILD experts agree are important to ask in all patients presenting with suspected CHP. CLINICAL IMPLICATIONS: Ongoing research is required to validate these items in the clinical setting. DISCLOSURES: No relevant relationships by Hayley Barnes, source=Web Response No relevant relationships by Harold Collard, source=Web Response No relevant relationships by Ian Glaspole, source=Web Response No relevant relationships by Phil Molyneaux, source=Web Response No relevant relationships by Julie Morisset, source=Web Response No relevant relationships by Glen Westall, source=Web Response

Longitudinal immunosequencing in healthy people reveals persistent T cell receptors rich in highly public receptors

BackgroundThe adaptive immune system maintains a diversity of T cells capable of recognizing a broad array of antigens. Each T cell’s specificity for antigens is determined by its T cell receptors (TCRs), which together across all T cells form a repertoire of millions of unique receptors in each individual. Although many studies have examined how TCR repertoires change in response to disease or drugs, few have explored the temporal dynamics of the TCR repertoire in healthy individuals.ResultsHere we report immunosequencing of TCR β chains (TCRβ) from the blood of three healthy individuals at eight time points over one year. TCRβ repertoires of all peripheral-blood T cells and sorted memory T cells clustered clearly by individual, systematically demonstrating that TCRβ repertoires are specific to individuals across time. This individuality was absent from TCRβs from naive T cells, suggesting that the differences resulted from an individual’s antigen exposure history, not genetic background. Many characteristics of the TCRβ repertoire (e.g., diversity, clonality) were stable across time, although we found evidence of T cell expansion dynamics even within healthy individuals. We further identified a subset of “persistent” TCRβs present across all time points. These receptors were rich in clonal and highly public receptors and may play a key role in immune system maintenance.ConclusionsOur results highlight the importance of longitudinal sampling of the immune system, providing a much-needed baseline for TCRβ dynamics in healthy individuals. Such a baseline will improve interpretation of changes in the TCRβ repertoire during disease or treatment.

Antigen Exposure History Defines CD8 T Cell Dynamics and Protection during Localized Pulmonary Infections.

Unlike systemic infections, little is known about the role of repeated localized infections on (re)shaping pathogen-specific memory CD8 T cell responses. Here, we used primary (1°) and secondary (2°) intranasal influenza virus infections of mice as a model to study intrinsic memory CD8 T cell properties. We show that secondary antigen exposure, relative to a single infection, generates memory CD8 T cell responses of superior magnitude in multiple tissue compartments including blood, spleen, draining lymph nodes, and lung. Unexpectedly, regardless of the significantly higher number of 2° memory CD8 T cells, similar degree of protection against pulmonary challenge was observed in both groups of mice containing 1° or 2° memory CD8 T cells. Mechanistically, using pertussis toxin-induced migration block, we showed that superior antigen-driven proliferation and ability to relocate to the site of infection allowed 1° memory CD8 T cells to accumulate in the infected lung during the first few days after challenge, compensating for the initially lower cell numbers. Taken together, the history of antigen exposures to localized pulmonary infections, through altering basic cell biology, dictates dynamic properties of protective memory CD8 T cell responses. This knowledge has important implications for a design of novel and an improvement of existing vaccines and immunization strategies.

IGHV gene features and MYD88 L265P mutation separate the three marginal zone lymphoma entities and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas

To clarify the relationships between marginal zone lymphomas (MZLs) and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas (WM/LPLs), immunoglobulin heavy chain variable gene (IGHV) features were analyzed and the occurrence of MYD88 L265P mutations was identified in a series of 123 patients: 53 MZLs from the spleen (SMZLs), 11 from lymph nodes (NMZLs), 28 mucosa-associated lymphatic tissue (MALT) lymphomas and 31 WM/LPLs. SMZLs were characterized by overrepresentation of IGHV1-2 gene rearrangements with a canonical motif, without selection pressure and with long CDR3 segments. NMZLs had increased frequencies of IGHV3 genes. The IGHV gene was unmutated in most cases, often with long CDR3 segments. MALT lymphomas were usually associated with a mutated IGHV gene, but with the absence of selection pressure. WM/LPLs were associated with an IGHV3-23 overrepresentation and high IGHV mutation rate, with features of selection pressure and short CDR3 segments. MYD88 L265P mutations were almost restricted exclusively to WM/LPL patients. Taken all diagnoses together, all patients with MYD88 L265P mutations had an immunoglobulin M peak and almost all patients except one had bone marrow infiltration. These results demonstrate that the history of antigen exposure of the four entities studied was different and MYD88 L265P was specifically associated with WM/LPLs. WM/LPL may thus be functionally associated with constitutive nuclear factor-κB activation.

Protective Capacity of Memory CD8 + T Cells Is Dictated by Antigen Exposure History and Nature of the Infection

Infection or vaccination confers heightened resistance to pathogen rechallenge because of quantitative and qualitative differences between naive and primary memory T cells. Herein, we show that secondary (boosted) memory CD8+ T cells were better than primary memory CD8+ T cells in controlling some, but not all acute infections with diverse pathogens. However, secondary memory CD8+ T cells were less efficient than an equal number of primary memory cells at preventing chronic LCMV infection and are more susceptible to functional exhaustion. Importantly, localization of memory CD8+ T cells within lymph nodes, which is reduced by antigen restimulation, was critical for both viral control in lymph nodes and for the sustained CD8+ T cell response required to prevent chronic LCMV infection. Thus, repeated antigen stimulation shapes memory CD8+ T cell populations to either enhance or decrease per cell protective immunity in a pathogen-specific manner, a concept of importance in vaccine design against specific diseases.

Immune repertoire high-throughput sequence analysis (IRAS) web service (65.20)

Abstract An immune repertoire is the sum of functionally diverse B and T cells, which is shaped by genetic polymorphism, antigen exposure history and regulation and modulation of the immune system. High-throughput sequencing techniques allow us to take a snapshot of the diversity of the immune repertoire, which is a fundamental determinant of the competence of the immune system. However, many researchers are overwhelmed by the task of managing and analyzing the flooding amount of sequence data generated by next-generation DNA sequencers. To make the immune repertoire high-throughput sequencing technology accessible to greater numbers of investigators, we have developed a web based immune repertoire sequence data analysis and management system (IRAS). IRAS is backed by a Linux cluster, where V, D, J germline sequences can be mapped onto reads using the Smith-Waterman algorithm in a high-throughput manner. Mapping results are loaded into a MySQL database and reads are annotated with CDR1, 2, 3 regions. We have developed a web portal to allow easy access to those data, where 2D-plot, 3D-plot, various summary tables, statistical results and mapping alignments can be generated on the fly. The IRAS is open to public and welcome to use. Users can submit their sequence data and relevant metadata through the web portal.

Immunorepertoire analysis by multiplex PCR amplification and high throughput sequencing (42.6)

Abstract An immunorepertoire is the sum of functionally diverse B and T cells in one's circulation at any given moment. Three key factors shape the personal immunorepertoire: HLA type, antigen exposure history, and immunoregulation. Two major challenges have made studying the immunorepertoire difficult: the enormous diversity of V(D)Js, and the scarcity of each VDJ in a sample. To overcome these challenges, a powerful multiplex PCR method has been developed to amplify, inclusively and unbiased, all expressed VDJs in a sample. The amplicon mixture was sequenced directly with Roche 454 platform. In one run, for example, more than 73,000 and 119,000 unique V(D)Js were obtained from B and T cells, respectively. High resolution HLA typing was also carried out with the same sequencing run. This novel technology can be used to uncover possible disease mechanisms associated with abnormal immunorepertoires, to evaluate vaccine efficiency, to identify new biomarkers, and to develop new therapeutics. An online dababase and unique analytical tools have been developed for data sharing, deposition, and mining.

Cladosporium Species-Related Hypersensitivity Pneumonitis in Household Environments

Home-related chronic hypersensitivity pneumonitis (HP) is sometimes difficult to discriminate because patients do not have an obvious history of antigen exposure. We report two HP cases which developed in an office area and in a home: a 47-year-old woman with acute-onset HP and a 72-year-old woman with chronic HP followed up as idiopathic pulmonary fibrosis following isolation of Cladosporium cladosporioides and Cladosporium herbarum, respectively. Lymphocyte stimulating activity and antibody titer to these fungi were increased in these patients. Since Cladosporium spp. and several other fungi are present ubiquitously in our living environment, it is difficult to eliminate the antigen from the patients' environment to control the disease. Cladosporium spp. can be key antigens in inducing chronic HP in the home environment.

Top-down and bottom-up research in biodemography

Abstract The most efficient way to make scientific progress in biodemography is to encourage bi-directional exchange between 'top-down' and 'bottom-up' research. This will entail exchange along the continuum of research from microscopic intracellular processes to population-level consequences. In addition, our understanding of the biology of aging and its demographic consequences will be enriched by mutual influence between studies of mechanistic or 'proximate' causal processes and investigations of the evolutionary processes underlying the same phenomena. Researchers working at these different levels of explanation could be more productive if they were informed by research at other levels and interacted with scientists with complementary expertise. Such collaborations could be encouraged both through interdisciplinary workshops, research projects, program projects and training programs. 1. Overview The overarching theme of this essay is that given our current state of knowledge, the most efficient way to make scientific progress in biodemography is to encourage bi-directional exchange between 'top-down' and 'bottom-up' research. These terms are used in two senses here. First, they are used to refer to the continuum from microscopic intracellular processes to population-level consequences. In a second sense, 'bottom-up' is used to refer to mechanistic or 'proximate' explanations. 'Top-down' refers to 'ultimate,' or evolutionary explanations of phenomena, based on the action of natural selection working on genes and the phenotypic traits with which they are associated (Mayr 1961). Researchers working at these different levels of explanation could be more productive if they were informed by research at other levels and interacted with scientists with complementary expertise. Such collaborations could be encouraged both through interdisciplinary workshops, research projects, program projects and training programs. We now know that the processes linking genes to fertility and mortality outcomes, and the impacts of those processes on gene distributions in populations over generational time are both tremendously complex and highly structured. The genetic system is in many respects comparable to the generative grammars of human languages, which are capable of an almost infinite number of meaningful utterances. With a relatively small number of genes, based on only four base pairs, an immensely large number of phenotypes can be generated through additive and interactive effects of genes, gene-environment interactions and epigenetic processes. The action of natural selection brings order to those processes, but a very complex and difficult order to understand. Consider the immune system of higher organisms as an illuminating example. This type of immune system is generally thought to be composed of interacting components of innate and acquired cell-mediated responses (Rao 2005). The latter component is specifically designed to engage in life-long learning and to be capable of producing a very large distribution of lymphocyte cell types through processes of genetic recombination and differential cell reproduction due to the history of antigen exposure. This system is energetically expensive to build and produce, and competes directly with other processes affecting fitness, such as growth and reproduction. However, those large investments in the immune system evolved because they reduce mortality sufficiently over the life course in an ecological context of rapid reproductive rates of evolving populations of diverse pathogens. The overall effects on fitness of such expensive protection must be positive. The ultimate goal in the biodemography of aging should be to understand the processes linking genes to phenotypes, phenotypes to mortality and fertility outcomes, and those outcomes to gene distributions over generational time. This will require both mechanistic physical models and specific theories of how natural selection acts to order those processes, both within populations of a single species and among species in evolving ecosystems. …

Clues for the differential diagnosis of hypersensitivity pneumonitis as an expectant variant of diffuse parenchymal lung disease

Hypersensitivity pneumonitis, also called extrinsic allergic alveolitis, a type of diffuse parenchymal lung disease (DPLD), is an immunologically mediated pulmonary disease induced by inhalation of various antigens. As data on...