Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease

Chronic beryllium disease (CBD) is a granulomatous disorder characterized by an influx of beryllium (Be)-specific CD4+ T cells into the lung. The vast majority of these T cells recognize Be in an HLA-DP–restricted manner, and peptide is required for T cell recognition. However, the peptides that stimulate Be-specific T cells are unknown. Using positional scanning libraries and fibroblasts expressing HLA-DP2, the most prevalent HLA-DP molecule linked to disease, we identified mimotopes and endogenous self-peptides that bind to MHCII and Be, forming a complex recognized by pathogenic CD4+ T cells in CBD. These peptides possess aspartic and glutamic acid residues at p4 and p7, respectively, that surround the putative Be-binding site and cooperate with HLA-DP2 in Be coordination. Endogenous plexin A peptides and proteins, which share the core motif and are expressed in lung, also stimulate these TCRs. Be-loaded HLA-DP2–mimotope and HLA-DP2–plexin A4 tetramers detected high frequencies of CD4+ T cells specific for these ligands in all HLA-DP2+ CBD patients tested. Thus, our findings identify the first ligand for a CD4+ T cell involved in metal-induced hypersensitivity and suggest a unique role of these peptides in metal ion coordination and the generation of a common antigen specificity in CBD

Antiviral CD8(+) T Cells Restricted by Human Leukocyte Antigen Class II Exist during Natural HIV Infection and Exhibit Clonal Expansion.

CD8(+) T cell recognition of virus-infected cells is characteristically restricted by major histocompatibility complex (MHC) class I, although rare examples of MHC class II restriction have been reported in Cd4-deficient mice and a macaque SIV vaccine trial using a recombinant cytomegalovirus vector. Here, we demonstrate the presence of human leukocyte antigen (HLA) class II-restricted CD8(+) T cell responses with antiviral properties in a small subset of HIV-infected individuals. In these individuals, T cell receptor β (TCRβ) analysis revealed that class II-restricted CD8(+) T cells underwent clonal expansion and mediated killing of HIV-infected cells. In one case, these cells comprised 12% of circulating CD8(+) T cells, and TCRα analysis revealed two distinct co-expressed TCRα chains, with only one contributing to binding of the class II HLA-peptide complex. These data indicate that class II-restricted CD8(+) T cell responses can exist in a chronic human viral infection, and may contribute to immune control

Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease

Chronic beryllium disease (CBD) is a granulomatous disorder characterized by an influx of beryllium (Be)-specific CD4(+) T cells into the lung. The vast majority of these T cells recognize Be in an HLA-DP–restricted manner, and peptide is required for T cell recognition. However, the peptides that stimulate Be-specific T cells are unknown. Using positional scanning libraries and fibroblasts expressing HLA-DP2, the most prevalent HLA-DP molecule linked to disease, we identified mimotopes and endogenous self-peptides that bind to MHCII and Be, forming a complex recognized by pathogenic CD4(+) T cells in CBD. These peptides possess aspartic and glutamic acid residues at p4 and p7, respectively, that surround the putative Be-binding site and cooperate with HLA-DP2 in Be coordination. Endogenous plexin A peptides and proteins, which share the core motif and are expressed in lung, also stimulate these TCRs. Be-loaded HLA-DP2–mimotope and HLA-DP2–plexin A4 tetramers detected high frequencies of CD4(+) T cells specific for these ligands in all HLA-DP2(+) CBD patients tested. Thus, our findings identify the first ligand for a CD4(+) T cell involved in metal-induced hypersensitivity and suggest a unique role of these peptides in metal ion coordination and the generation of a common antigen specificity in CBD

Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

The Effectiveness of Incarceration-Based Drug Treatment on Criminal Behavior: A Systematic Review

Many, if not most, incarcerated offenders have substance abuse problems. Without effective treatment, these substance-abusing offenders are likely to persist in non-drug offending. The period of incarceration offers an opportunity to intervene in the cycle of drug abuse and crime. Although many types of incarceration-based drug treatment programs are available (e.g., therapeutic communities and group counseling), the effectiveness of these programs is unclear. The objective of this research synthesis is to systematically review quasi-experimental and experimental (RCT) evaluations of the effectiveness of incarceration-based drug treatment programs in reducing post-release recidivism and drug relapse. A secondary objective of this synthesis is to examine variation in effectiveness by programmatic, sample, and methodological features. In this update of the original 2006 review (see Mitchell, Wilson, and MacKenzie, 2006), studies made available since the original review were included in an effort to keep current with emerging research. This synthesis of evaluations of incarceration-based drug treatment programs found that such programs are modestly effective in reducing recidivism. These findings most strongly support the effectiveness of therapeutic communities, as these programs produced relatively consistent reductions in recidivism and drug use. Both counseling and incarceration-based narcotic maintenance programs had mixed effects. Counseling programs were associated with reductions in recidivism but not drug use; whereas, incarceration-based narcotic maintenance programs were associated with reductions in drug use but not recidivism. Note that our findings regarding the effectiveness of incarceration-based narcotic maintenance programs differ from a larger review of community-based narcotic maintenance programs (see Egli, Pina, Christensen, Aebi, and Killias, 2009). Finally, boot camp programs for drug offenders had negligible effects on both recidivism and drug use

Structural characteristics of lipocalin allergens: Crystal structure of the immunogenic dog allergen Can f 6.

Lipocalins represent the most important protein family of the mammalian respiratory allergens. Four of the seven named dog allergens are lipocalins: Can f 1, Can f 2, Can f 4, and Can f 6. We present the structure of Can f 6 along with data on the biophysical and biological activity of this protein in comparison with other animal lipocalins. The Can f 6 structure displays the classic lipocalin calyx-shaped ligand binding cavity within a central β-barrel similar to other lipocalins. Despite low sequence identity between the different dog lipocalin proteins, there is a high degree of structural similarity. On the other hand, Can f 6 has a similar primary sequence to cat, horse, mouse lipocalins as well as a structure that may underlie their cross reactivity. Interestingly, the entrance to the ligand binding pocket is capped by a His instead of the usually seen Tyr that may help select its natural ligand binding partner. Our highly pure recombinant Can f 6 is able to bind to human IgE (hIgE) demonstrating biological antigenicity

Vav-2 controls NFAT-dependent transcription inB- but not T-lymphocytes

We show here that Vav-2 is tyrosine phosphorylated following antigen receptor engagement in both B- and T-cells, but potentiates nuclear factor of activated T cells (NFAT)-dependent transcription only in B cells. Vav-2 function requires the N-terminus, as well as functional Dbl homology and SH2 domains. More over, the enhancement of NFAT-dependent transcription by Vav-2 can be inhibited by a number of dominant-negative GTPases. The ability of Vav-2 to potentiate NFAT-dependent transcription correlates with its ability to promote a sustained calcium flux. Thus, Vav-2 augments the calcium signal in B cells but not T cells, and a truncated form of Vav-2 can neither activate NFAT nor augment calcium signaling. The CD19 co-receptor physically interacts with Vav-2 and synergistically enhances Vav-2 phosphorylation induced by the B-cell receptor (BCR). In addition, we found that Vav-2 augments CD19-stimulated NFAT- dependent transcription, as well as transcription from the CD5 enhancer. These data suggest a role for Vav-2 in transducing BCR signals to the transcription factor NFAT and implicate Vav-2 in the integration of BCR and CD19 signaling