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"Collin, Matthew"
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Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells
Key Points
In contrast to most dendritic-cell populations, Langerhans cells repopulate locally throughout life in the steady state, independently of any input from the blood circulation.
In contrast to quiescent skin, in major inflammatory skin injuries (such as exposure to ultraviolet B radiation) Langerhans cells are replaced by circulating monocytes.
Langerhans cells repopulate locally after a lethal dose of radiation and remain of host origin following congenic bone-marrow transplantation. By contrast, following allogeneic bone-marrow transplantation, cutaneous graft-versus-host disease occurs and leads to the elimination of recipient Langerhans cells and their replacement with donor-derived cells.
Langerhans cells are absent in mice that lack the macrophage colony-stimulating factor (M-CSF) receptor but remain unaffected in mice that lack the receptor for FMS-like-tyrosine-kinase 3 ligand (FLT3).
Langerin is not uniquely expressed by Langerhans cells in the skin, but is also expressed by dendritic cells in stratified epithelial surfaces and by a subset of dendritic cells that is present in most connective tissues, including the dermis, lung, kidney and liver. Langerin
+
dendritic cells can be distinguished from Langerhans cells based on the expression of the integrin CD103 and the low expression of CD11b.
Our understanding of the origin, phenotype and function of epidermal Langerhans cells and langerin-expressing dendritic cells has expanded in recent years, details of which, as well as the challenges that remain, are discussed in this Review.
Langerhans cells (LCs) are a specialized subset of dendritic cells (DCs) that populate the epidermal layer of the skin. Langerin is a lectin that serves as a valuable marker for LCs in mice and humans. In recent years, new mouse models have led to the identification of other langerin
+
DC subsets that are not present in the epidermis, including a subset of DCs that is found in most non-lymphoid tissues. In this Review we describe new developments in the understanding of the biology of LCs and other langerin
+
DCs and discuss the challenges that remain in identifying the role of different DC subsets in tissue immunity.
Journal Article
Illicit Financial Flows
There is a growing consensus that the presence of illegal and harmful cross-border financial flows is one of the factors impeding economic and human development. In recent years, a new conceptual framework for describing these “illicit” financial flows (IFFs) has emerged that combines issues ranging from cross-border money laundering to tax evasion. This article summarizes and clarifies recent empirical work in this area. Three types of studies are considered and critiqued: (i) methods of measuring IFFs, (ii) constructed risk indicators, and (iii) forensic studies that aim to uncover instances where illicit flows have occurred. The article discusses the limitations of all three approaches and proposes ways in which the research agenda on IFFs could be reasonably advanced, given the hidden nature of the subject.
Journal Article
Blueprint for a High-Performance Biomaterial: Full-Length Spider Dragline Silk Genes
Spider dragline (major ampullate) silk outperforms virtually all other natural and manmade materials in terms of tensile strength and toughness. For this reason, the mass-production of artificial spider silks through transgenic technologies has been a major goal of biomimetics research. Although all known arthropod silk proteins are extremely large (>200 kiloDaltons), recombinant spider silks have been designed from short and incomplete cDNAs, the only available sequences. Here we describe the first full-length spider silk gene sequences and their flanking regions. These genes encode the MaSp1 and MaSp2 proteins that compose the black widow's high-performance dragline silk. Each gene includes a single enormous exon (>9000 base pairs) that translates into a highly repetitive polypeptide. Patterns of variation among sequence repeats at the amino acid and nucleotide levels indicate that the interaction of selection, intergenic recombination, and intragenic recombination governs the evolution of these highly unusual, modular proteins. Phylogenetic footprinting revealed putative regulatory elements in non-coding flanking sequences. Conservation of both upstream and downstream flanking sequences was especially striking between the two paralogous black widow major ampullate silk genes. Because these genes are co-expressed within the same silk gland, there may have been selection for similarity in regulatory regions. Our new data provide complete templates for synthesis of recombinant silk proteins that significantly improve the degree to which artificial silks mimic natural spider dragline fibers.
Journal Article
Evidence from Multiple Species that Spider Silk Glue Component ASG2 is a Spidroin
Spiders in the superfamily Araneoidea produce viscous glue from aggregate silk glands. Aggregate glue coats prey-capture threads and hampers the escape of prey from webs, thereby increasing the foraging success of spiders. cDNAs for Aggregate Spider Glue 1 (ASG1) and 2 (ASG2) have been previously described from the golden orb-weaver,
Nephila clavipes
and Western black widow,
Latrodectus hesperus
. To further investigate aggregate glues, we assembled
ASG1
and
ASG2
from genomic target capture libraries constructed from three species of cob-web weavers and three species of orb-web weavers, all araneoids. We show that ASG1 is unlikely to be a glue, but rather is part of a widespread arthropod gene family, the peritrophic matrix proteins. For ASG2, we demonstrate its remarkable architectural and sequence similarities to spider silk fibroins, indicating that ASG2 is a member of the spidroin gene family. Thus, spidroins have diversified into glues in addition to task-specific, high performance fibers.
Journal Article
Long-term results and GvHD after prophylactic and preemptive donor lymphocyte infusion after allogeneic stem cell transplantation for acute leukemia
We report on 318 patients with acute leukemia, receiving donor lymphocyte infusion (DLI) in complete hematologic remission (CHR) after allogeneic stem cell transplantation (alloSCT). DLI were applied preemptively (preDLI) for minimal residual disease (MRD, n = 23) or mixed chimerism (MC, n = 169), or as prophylaxis in high-risk patients with complete chimerism and molecular remission (proDLI, n = 126). Median interval from alloSCT to DLI1 was 176 days, median follow-up was 7.0 years. Five-year cumulative relapse incidence (CRI), non-relapse mortality (NRM), leukemia-free and overall survival (LFS/OS) of the entire cohort were 29.1%, 12.7%, 58.2%, and 64.3%. Cumulative incidences of acute graft-versus-host disease (aGvHD) grade II–IV°/chronic GvHD were 11.9%/31%. Nineteen patients (6%) died from DLI-induced GvHD. Age ≥60 years (p = 0.046), advanced stage at transplantation (p = 0.003), shorter interval from transplantation (p = 0.018), and prior aGvHD ≥II° (p = 0.036) were risk factors for DLI-induced GvHD. GvHD did not influence CRI, but was associated with NRM and lower LFS/OS. Efficacy of preDLI was demonstrated by decreasing MRD/increasing blood counts in 71%, and increasing chimerism in 70%. Five-year OS after preDLI for MRD/MC was 51%/68% among responders, and 37% among non-responders. The study describes response and outcome of DLI in CHR and helps to identify candidates without increased risk of severe GvHD.
Journal Article
Odontogenic ameloblast-associated (ODAM) is inactivated in toothless/enamelless placental mammals and toothed whales
Background
The gene for odontogenic ameloblast-associated (
ODAM
) is a member of the secretory calcium-binding phosphoprotein gene family.
ODAM
is primarily expressed in dental tissues including the enamel organ and the junctional epithelium, and may also have pleiotropic functions that are unrelated to teeth. Here, we leverage the power of natural selection to test competing hypotheses that
ODAM
is tooth-specific versus pleiotropic. Specifically, we compiled and screened complete protein-coding sequences, plus sequences for flanking intronic regions, for
ODAM
in 165 placental mammals to determine if this gene contains inactivating mutations in lineages that either lack teeth (baleen whales, pangolins, anteaters) or lack enamel on their teeth (aardvarks, sloths, armadillos), as would be expected if the only essential functions of
ODAM
are related to tooth development and the adhesion of the gingival junctional epithelium to the enamel tooth surface.
Results
We discovered inactivating mutations in all species of placental mammals that either lack teeth or lack enamel on their teeth. A surprising result is that
ODAM
is also inactivated in a few additional lineages including all toothed whales that were examined. We hypothesize that
ODAM
inactivation is related to the simplified outer enamel surface of toothed whales. An alternate hypothesis is that
ODAM
inactivation in toothed whales may be related to altered antimicrobial functions of the junctional epithelium in aquatic habitats. Selection analyses on
ODAM
sequences revealed that the composite dN/dS value for pseudogenic branches is close to 1.0 as expected for a neutrally evolving pseudogene. DN/dS values on transitional branches were used to estimate
ODAM
inactivation times. In the case of pangolins,
ODAM
was inactivated ~ 65 million years ago, which is older than the oldest pangolin fossil (
Eomanis
, 47 Ma) and suggests an even more ancient loss or simplification of teeth in this lineage.
Conclusion
Our results validate the hypothesis that the only essential functions of
ODAM
that are maintained by natural selection are related to tooth development and/or the maintenance of a healthy junctional epithelium that attaches to the enamel surface of teeth.
Journal Article
Ikaros family zinc finger 1 regulates dendritic cell development and function in humans
Ikaros family zinc finger 1 (IKZF1) is a haematopoietic transcription factor required for mammalian B-cell development. IKZF1 deficiency also reduces plasmacytoid dendritic cell (pDC) numbers in mice, but its effects on human DC development are unknown. Here we show that heterozygous mutation of
IKZF1
in human decreases pDC numbers and expands conventional DC1 (cDC1). Lenalidomide, a drug that induces proteosomal degradation of IKZF1, also decreases pDC numbers in vivo, and reduces the ratio of pDC/cDC1 differentiated from progenitor cells in vitro in a dose-dependent manner. In addition, non-classical monocytes are reduced by IKZF1 deficiency in vivo. DC and monocytes from patients with IKZF1 deficiency or lenalidomide-treated cultures secrete less IFN-α, TNF and IL-12. These results indicate that human DC development and function are regulated by IKZF1, providing further insights into the consequences of
IKZF1
mutation on immune function and the mechanism of immunomodulation by lenalidomide.
IKZF1 is a transcription factor known to regulate mammalian B-cell development. Here the authors show that IKZF1 is required for human pDC development and regulation of DC cytokine production in patients with IKZF1 haploinsufficiency, findings which are recapitulated in lenalidomide-induced IKZF1 deficiency.
Journal Article
Reading the Ts and DCs of thymopoiesis
Dendritic-cell-biased thymic seeding progenitors provide stromal support for early T cell development through the expression of membrane-bound TNF.
Journal Article
Lipopolysaccharide inhalation recruits monocytes and dendritic cell subsets to the alveolar airspace
Mononuclear phagocytes (MPs) including monocytes, macrophages and dendritic cells (DCs) are critical innate immune effectors and initiators of the adaptive immune response. MPs are present in the alveolar airspace at steady state, however little is known about DC recruitment in acute pulmonary inflammation. Here we use lipopolysaccharide inhalation to induce acute inflammation in healthy volunteers and examine the impact on bronchoalveolar lavage fluid and blood MP repertoire. Classical monocytes and two DC subsets (DC2/3 and DC5) are expanded in bronchoalveolar lavage fluid 8 h after lipopolysaccharide inhalation. Surface phenotyping, gene expression profiling and parallel analysis of blood indicate recruited DCs are blood-derived. Recruited monocytes and DCs rapidly adopt typical airspace-resident MP gene expression profiles. Following lipopolysaccharide inhalation, alveolar macrophages strongly up-regulate cytokines for MP recruitment. Our study defines the characteristics of human DCs and monocytes recruited into bronchoalveolar space immediately following localised acute inflammatory stimulus in vivo.
The diversity of human mononuclear phagocyte subsets remains to be characterized in many tissue-specific and functional contexts, including pulmonary inflammation. Here the authors characterize dendritic cell and monocyte subset recruitment to the bronchoalveolar space in a human LPS inhalation model.
Journal Article