The vast diversity of B-cell receptors (BCR) and secreted antibodies enables the recognition of, and response to, a wide range of epitopes, but this diversity has also limited our understanding of ...humoral immunity. We present a public database of more than 37 million unique BCR sequences from three healthy adult donors that is many fold deeper than any existing resource, together with a set of online tools designed to facilitate the visualization and analysis of the annotated data. We estimate the clonal diversity of the naive and memory B-cell repertoires of healthy individuals, and provide a set of examples that illustrate the utility of the database, including several views of the basic properties of immunoglobulin heavy chain sequences, such as rearrangement length, subunit usage, and somatic hypermutation positions and dynamics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Monoclonal antibodies (mAbs) targeting the immune checkpoint anti-programmed cell death protein 1 (aPD-1) have demonstrated impressive benefits for the treatment of some cancers; however, these drugs ...are not always effective, and we still have a limited understanding of the mechanisms that contribute to their efficacy or lack thereof. We used in vivo imaging to uncover the fate and activity of aPD-1 mAbs in real time and at subcellular resolution in mice. We show that aPD-1 mAbs effectively bind PD-1
tumor-infiltrating CD8
T cells at early time points after administration. However, this engagement is transient, and aPD-1 mAbs are captured within minutes from the T cell surface by PD-1
tumor-associated macrophages. We further show that macrophage accrual of aPD-1 mAbs depends both on the drug's Fc domain glycan and on Fcγ receptors (FcγRs) expressed by host myeloid cells and extend these findings to the human setting. Finally, we demonstrate that in vivo blockade of FcγRs before aPD-1 mAb administration substantially prolongs aPD-1 mAb binding to tumor-infiltrating CD8
T cells and enhances immunotherapy-induced tumor regression in mice. These investigations yield insight into aPD-1 target engagement in vivo and identify specific Fc/FcγR interactions that can be modulated to improve checkpoint blockade therapy.
T and B cell receptor loci undergo combinatorial rearrangement, generating a diverse immune receptor repertoire, which is vital for recognition of potential antigens. Here we use a multiplex PCR with ...a mixture of primers targeting the rearranged variable and joining segments to capture receptor diversity. Differential hybridization kinetics can introduce significant amplification biases that alter the composition of sequence libraries prepared by multiplex PCR. Using a synthetic immune receptor repertoire, we identify and minimize such biases and computationally remove residual bias after sequencing. We apply this method to a multiplex T cell receptor gamma sequencing assay. To demonstrate accuracy in a biological setting, we apply the method to monitor minimal residual disease in acute lymphoblastic leukaemia patients. A similar methodology can be extended to any adaptive immune locus.
An individual's T cell repertoire dynamically encodes their pathogen exposure history. To determine whether pathogen exposure signatures can be identified by documenting public T cell receptors ...(TCRs), we profiled the T cell repertoire of 666 subjects with known cytomegalovirus (CMV) serostatus by immunosequencing. We developed a statistical classification framework that could diagnose CMV status from the resulting catalog of TCRβ sequences with high specificity and sensitivity in both the original cohort and a validation cohort of 120 different subjects. We also confirmed that three of the identified CMV-associated TCRβ molecules bind CMV in vitro, and, moreover, we used this approach to accurately predict the HLA-A and HLA-B alleles of most subjects in the first cohort. As all memory T cell responses are encoded in the common format of somatic TCR recombination, our approach could potentially be generalized to a wide variety of disease states, as well as other immunological phenotypes, as a highly parallelizable diagnostic strategy.
An Update on the Self-care of Heart Failure Index Riegel, Barbara; Lee, Christopher S; Dickson, Victoria Vaughan ...
The Journal of cardiovascular nursing,
2009-November/December, Letnik:
24, Številka:
6
Journal Article
Recenzirano
Odprti dostop
BACKGROUND:The Self-care of Heart Failure Index (SCHFI) is a measure of self-care defined as a naturalistic decision-making process involving the choice of behaviors that maintain physiological ...stability (maintenance) and the response to symptoms when they occur (management). In the 5 years since the SCHFI was published, we have added items, refined the response format of the maintenance scale and the SCHFI scoring procedure, and modified our advice about how to use the scores.
OBJECTIVE:The objective of this article was to update users on these changes.
METHODS:In this article, we address 8 specific questions about reliability, item difficulty, frequency of administration, learning effects, social desirability, validity, judgments of self-care adequacy, clinically relevant change, and comparability of the various versions.
RESULTS:The addition of items to the self-care maintenance scale did not significantly change the coefficient α, providing evidence that the structure of the instrument is more powerful than the individual items. No learning effect is associated with repeated administration. Social desirability is minimal. More evidence is provided of the validity of the SCHFI. A score of 70 or greater can be used as the cut-point to judge self-care adequacy, although evidence is provided that benefit occurs at even lower levels of self-care. A change in a scale score more than one-half of an SD is considered clinically relevant. Because of the standardized scores, results obtained with prior versions can be compared with those from later versions.
CONCLUSION:The SCHFI v.6 is ready to be used by investigators. By publication in this format, we are putting the instrument in the public domain; permission is not required to use the SCHFI.
To assess the impact of differential hearing loss on QOL in sporadic unilateral vestibular schwannoma.
Cross-sectional observational multicenter study including 422 patients with vestibular ...schwannoma and formal audiometry within 1 year of survey administration, analyzed using multivariable regression.
Among 422 patients included, the median age was 57 (range, 18-81) years; 223 (53%) were women. Among 390 patients with complete audiometric data, American Academy of Otolaryngology-Head and Neck Surgery class was A in 134 (34%), B in 69 (18%), C in 26 (7%), and D in 161 (41%). A total of 335 of 390 (86%) reported subjective ipsilateral hearing loss (median severity, 6/10 1 = normal, 10 = deaf), 166 (43%) reported ipsilateral inability to use the telephone, 155 (37%) reported that hearing loss had affected personal relationships, and 213 (51%) reported difficulty with conversations. After adjusting for age and sex, the odds ratio (OR) for hearing loss adversely affecting relationships was 4.4 for class B hearing vs class A (95% CI, 2.1-9.4; P<.0001). The OR for difficulty with conversations was 2.7 for class B vs class A (95% CI, 1.4-5.3; P=.003). The OR for lost ipsilateral telephone use was 6.3 for class B vs class A (95% CI, 3.2-13.0; P<.0001). Differences between class B and class C were not significant. WRS outperformed PTA as a predictor of hearing-related QOL. The optimal threshold for predicting a significant adverse impact on QOL was WRS less than 72% to 76%.
Hearing loss adversely affects QOL after only modest audiometric disability. The WRS alone appears to be a much more reliable predictor of hearing-related QOL than PTA or American Academy of Otolaryngology-Head and Neck Surgery class.
The adaptive immune system uses several strategies to generate a repertoire of T- and B-cell antigen receptors with sufficient diversity to recognize the universe of potential pathogens. In αβ T ...cells, which primarily recognize peptide antigens presented by major histocompatibility complex molecules, most of this receptor diversity is contained within the third complementarity-determining region (CDR3) of the T-cell receptor (TCR) α and β chains. Although it has been estimated that the adaptive immune system can generate up to 1016 distinct αβ pairs, direct assessment of TCR CDR3 diversity has not proved amenable to standard capillary electrophoresis-based DNA sequencing. We developed a novel experimental and computational approach to measure TCR CDR3 diversity based on single-molecule DNA sequencing, and used this approach to determine the CDR3 sequence in millions of rearranged TCRβ genes from T cells of 2 adults. We find that total TCRβ receptor diversity is at least 4-fold higher than previous estimates, and the diversity in the subset of CD45RO+ antigen-experienced αβ T cells is at least 10-fold higher than previous estimates. These methods should prove valuable for assessment of αβ T-cell repertoire diversity after hematopoietic cell transplantation, in states of congenital or acquired immunodeficiency, and during normal aging.
The T cell receptor (TCR) protein is a heterodimer composed of an α chain and a β chain. TCR genes undergo somatic DNA rearrangements to generate the diversity of T cell binding specificities needed ...for effective immunity. Recently, high-throughput immunosequencing methods have been developed to profile the TCR α (TCRA) and TCR β (TCRB) repertoires. However, these methods cannot determine which TCRA and TCRB chains combine to form a specific TCR, which is essential for many functional and therapeutic applications. We describe and validate a method called pairSEQ, which can leverage the diversity of TCR sequences to accurately pair hundreds of thousands of TCRA and TCRB sequences in a single experiment. Our TCR pairing method uses standard laboratory consumables and equipment without the need for single-cell technologies. We show that pairSEQ can be applied to T cells from both blood and solid tissues, such as tumors.
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