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1.
Mol Genet Metab Rep ; 40: 101117, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39101156

RESUMEN

Background: Biochemical testing is a common first-tier approach in the setting of genetic evaluation of patients with unexplained developmental delay. However, results can be unclear, and a plan for second-tier analysis must be determined based on the patient's biochemical results and clinical presentation - in many cases, triggering a diagnostic odyssey. Case presentation: A male patient from the United States presenting with unexplained developmental delay, microcephaly, hypotonia, and feeding difficulties was referred for clinical genetic evaluation at age 8 months. Biochemical testing revealed an isolated marked elevation of glutaric acid on urine organic acid profile, without elevations of related metabolites. Further testing included GCDH sequencing, a neurometabolic gene panel, chromosomal microarray, Prader Willi/Angelman testing, and lysosomal disease enzyme panel, all of which were non-diagnostic. The patient had persistent developmental delay and hypotonia, dystonia, sensorineural hearing loss, and abnormal brain myelination on magnetic resonance imaging. Whole exome sequencing (WES) was performed and revealed a dual diagnosis of glutaric aciduria III (GA III) and BCAP31-related disorder, an X-linked intellectual disability syndrome, caused by a novel pathogenic variant. Conclusions: GA III has historically been considered clinically benign, with few reported cases. This patient's presenting symptoms were similar to those commonly seen in GA I and GA II, however the biochemical abnormalities were not consistent with these disorders, prompting additional molecular and biochemical testing. Ultimately, WES confirmed a diagnosis of BCAP31-related syndrome, a rare neurological disorder, which explained the patient's presenting symptoms. WES also identified a secondary diagnosis of GA III. We present a patient with two rare genetic conditions, highlighting the importance of deep phenotyping and the utility of WES in the setting of a patient with dual genetic diagnoses.

2.
HGG Adv ; 5(3): 100288, 2024 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-38566418

RESUMEN

Biallelic loss-of-function variants in the MUSK gene result in two allelic disorders: (1) congenital myasthenic syndrome (CMS; OMIM: 616325), a neuromuscular disorder that has a range of severity from severe neonatal-onset weakness to mild adult-onset weakness, and (2) fetal akinesia deformation sequence (OMIM: 208150), a form of pregnancy loss characterized by severe muscle weakness in the fetus. The MUSK gene codes for muscle-specific kinase (MuSK), a receptor tyrosine kinase involved in the development of the neuromuscular junction. Here, we report a case of neonatal-onset MUSK-related CMS in a patient harboring compound heterozygous deletions in the MUSK gene, including (1) a deletion of exons 2-3 leading to an in-frame MuSK protein lacking the immunoglobulin 1 (Ig1) domain and (2) a deletion of exons 7-11 leading to an out-of-frame, truncated MuSK protein. Individual domains of the MuSK protein have been elucidated structurally; however, a complete MuSK structure generated by machine learning algorithms has clear inaccuracies. We modify a predicted AlphaFold structure and integrate previously reported domain-specific structural data to suggest a MuSK protein that dimerizes in two locations (Ig1 and the transmembrane domain). We analyze known pathogenic variants in MUSK to discover domain-specific genotype-phenotype correlations; variants that lead to a loss of protein expression, disruption of the Ig1 domain, or Dok-7 binding are associated with the most severe phenotypes. A conceptual model is provided to explain the severe phenotypes seen in Ig1 variants and the poor response of our patient to pyridostigmine.


Asunto(s)
Proteínas Tirosina Quinasas Receptoras , Receptores Colinérgicos , Humanos , Síndromes Miasténicos Congénitos/genética , Síndromes Miasténicos Congénitos/patología , Síndromes Miasténicos Congénitos/diagnóstico , Dominios Proteicos/genética , Proteínas Tirosina Quinasas Receptoras/genética , Receptores Colinérgicos/genética , Receptores Colinérgicos/metabolismo , Receptores Colinérgicos/química , Índice de Severidad de la Enfermedad , Masculino , Femenino , Recién Nacido
3.
JIMD Rep ; 64(5): 303-311, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37701330

RESUMEN

Glycogen storage disease Ia (GSD Ia), also known as von Gierke disease, is caused by pathogenic variants in the G6PC1 gene (OMIM 232200) which encodes glucose-6-phosphatase. Deficiency of glucose-6-phosphatase impairs the processes of gluconeogenesis and glycogenolysis by preventing conversion of glucose-6-phosphate to glucose. Clinical features include fasting hypoglycemia, lactic acidosis, hypertriglyceridemia, hyperuricemia, hepatomegaly, and development of hepatocellular adenomas (HCAs) with potential for malignant transformation. Additionally, patients with GSD Ia often exhibit short stature, in some instances due to growth hormone (GH) deficiency. Patients with short stature caused by GH deficiency typically receive GH injections. Here, we review the literature and describe a female with GSD Ia who had short stature, failure of growth progression, and suspected GH deficiency. This patient received GH injections from ages 11 to 14 years under careful monitoring of an endocrinologist and developed HCAs during that time. To date, there is no reported long-term follow up data on patients with GSD Ia who have received GH therapy, and therefore the clinical outcomes post-GH therapy are unclear.

4.
Mol Genet Metab Rep ; 36: 100989, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37670900

RESUMEN

Importance: Implementation of newborn screening (NBS) in the United States now detects infants with late-onset Pompe disease (LOPD), a lysosomal storage disease characterized by slowly progressive muscle weakness, and detailed clinical evaluation has identified early muscle weakness. Biomarkers may be uninformative; thus, non-invasive imaging is needed to assess early LOPD muscle changes. Muscle ultrasound (US) measuring echointensity (EI) is a non-invasive measure of muscle health. Objective: In this study, we aimed to evaluate if EI can identify characteristic patterns of muscle involvement in LOPD patients identified by NBS. Design/setting: Prospective, cross-sectional, single time point study. Setting: One-center study. Participants: We examined 20 infants with NBS-identified LOPD (ages 5-20 months). All had standardized physical therapy assessments. Exposures: Creatine Kinase (CK) and Urine Hexose Tetrasaccharide (Glc4) were obtained. Muscle US of deltoid, biceps brachii, forearm flexors, thoracic paraspinals, gluteus maximus, quadriceps, tibialis anterior and medial gastrocnemius was performed. Main outcomes and measures: Mean EI was calculated for all involved muscle groups. Quantitative EI Sum Scores were calculated as total EI divided by number of muscle groups assessed. We performed a comprehensive literature review to compare our results to previous LOPD muscle ultrasound studies. Results: Six of 20 participants had elevated CK and 15 had ≥50% of the most common concerning kinematic physical findings; with normal urine Glc4 in all except one. Based upon muscle EI, the most affected muscles were quadriceps and medial gastrocnemius, with notable elevated EI in thoracic paraspinals. Biceps brachii was the most frequently affected upper extremity muscle. EI sum scores correlated moderately with increasing CK. Statistically significant positive correlation was found between posterior pelvic tilt in sitting and EI of gluteus maximus. Sonographic pattern of muscle involvement was similar to previous studies assessing older patients with LOPD. Conclusions and relevance: In this study, muscle EI was elevated most often in the quadriceps, tibialis anterior, medial gastrocnemius, thoracic paraspinals, and biceps brachii. Involved muscles generally fit the profile of physical and muscle ultrasound/MRI exam findings in LOPD patients. Muscle ultrasound is recommended for rapid, focused muscle assessment in LOPD, especially those identified via NBS. Future studies should focus on this pattern of ultrasonographic abnormality and changes over time.

5.
Clin Exp Metastasis ; 2023 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-37606814

RESUMEN

Most cancers and in particular carcinomas metastasise via the lymphatics to draining lymph nodes from where they can potentially achieve systemic dissemination by invasion of high endothelial blood venules (HEVs) in the paracortex [1, 2]. Currently however, the mechanisms by which tumours invade and migrate within the lymphatics are incompletely understood, although it seems likely they exploit at least some of the normal physiological mechanisms used by immune cells to access lymphatic capillaries and traffic to draining lymph nodes in the course of immune surveillance, immune modulation and the resolution of inflammation [3, 4]. Typically these include directional guidance via chemotaxis, haptotaxis and durotaxis, adhesion to the vessel surface via receptors including integrins, and junctional re-modelling by MMPs (Matrix MetalloProteinases) and ADAMs (A Disintegrin And Metalloproteinases) [5-7]. This short review focusses on a newly emerging mechanism for lymphatic entry that involves the large polysaccharide hyaluronan (HA) and its key lymphatic and immune cell receptors respectively LYVE-1 (Lymphatic Vessel Endothelial receptor) and CD44, and outlines recent work which indicates this axis may also be used by some tumours to aid nodal metastasis.

6.
Bariatr Surg Pract Patient Care ; 18(1): 8-12, 2023 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-36950501

RESUMEN

Objective: To examine if preoperative weight loss correlates to postoperative weight loss 2 and 3 years after surgery. Methods: A review was conducted of bariatric surgery patients who underwent either gastric bypass or sleeve gastrectomy during 2015-2018 and had 3-year follow-up data. Demographic and outcome data were collected. A best-fit regression model for weight loss was constructed. Results: Eight hundred fifty-nine patients underwent surgery during the selected period, of which 199 patients (23%) were analyzed. Eighty-two percent of patients had gastric bypass and 82% were female. Preoperative percent excess weight loss (%EWL) was not significantly associated with 2- and 3-year postoperative %EWL (p = 0.18). Patients demonstrated significant weight regain at 3 years postoperatively versus 1 year (p < 0.01). Higher preoperative weight loss was associated with lower %EWL 3 years postoperatively versus 1 year (p = 0.04). Postoperative %EWL had a significant negative association with higher preoperative weight, diabetes, baseline use of a mobility device, and sleeve gastrectomy. Conclusions: In a cohort of bariatric surgery patients, there was no statistically significant association between preoperative and midterm postoperative %EWL. Postoperative %EWL was negatively associated with several patient-specific factors and increasing time since operation.

7.
Cells ; 10(10)2021 09 29.
Artículo en Inglés | MEDLINE | ID: mdl-34685572

RESUMEN

Recent advances in our understanding of the lymphatic system, its function, development, and role in pathophysiology have changed our views on its importance. Historically thought to be solely involved in the transport of tissue fluid, lipids, and immune cells, the lymphatic system displays great heterogeneity and plasticity and is actively involved in immune cell regulation. Interference in any of these processes can be deleterious, both at the developmental and adult level. Preclinical studies into the cardiac lymphatic system have shown that invoking lymphangiogenesis and enhancing immune cell trafficking in ischaemic hearts can reduce myocardial oedema, reduce inflammation, and improve cardiac outcome. Understanding how immune cells and the lymphatic endothelium interact is also vital to understanding how the lymphatic vascular network can be manipulated to improve immune cell clearance. In this Review, we examine the different types of immune cells involved in fibrotic repair following myocardial infarction. We also discuss the development and function of the cardiac lymphatic vasculature and how some immune cells interact with the lymphatic endothelium in the heart. Finally, we establish how promoting lymphangiogenesis is now a prime therapeutic target for reducing immune cell persistence, inflammation, and oedema to restore heart function in ischaemic heart disease.


Asunto(s)
Enfermedades Cardiovasculares/inmunología , Sistema Linfático/inmunología , Humanos
8.
Cells ; 10(8)2021 08 12.
Artículo en Inglés | MEDLINE | ID: mdl-34440831

RESUMEN

Entry to the afferent lymphatics marks the first committed step for immune cell migration from tissues to draining lymph nodes both for the generation of immune responses and for timely resolution of tissue inflammation. This critical process occurs primarily at specialised discontinuous junctions in initial lymphatic capillaries, directed by chemokines released from lymphatic endothelium and orchestrated by adhesion between lymphatic receptors and their immune cell ligands. Prominent amongst the latter is the large glycosaminoglycan hyaluronan (HA) that can form a bulky glycocalyx on the surface of certain tissue-migrating leucocytes and whose engagement with its key lymphatic receptor LYVE-1 mediates docking and entry of dendritic cells to afferent lymphatics. Here we outline the latest insights into the molecular mechanisms by which the HA glycocalyx together with LYVE-1 and the related leucocyte receptor CD44 co-operate in immune cell entry, and how the process is facilitated by the unusual character of LYVE-1 • HA-binding interactions. In addition, we describe how pro-inflammatory breakdown products of HA may also contribute to lymphatic entry by transducing signals through LYVE-1 for lymphangiogenesis and increased junctional permeability. Lastly, we outline some future perspectives and highlight the LYVE-1 • HA axis as a potential target for immunotherapy.


Asunto(s)
Receptores de Hialuranos/metabolismo , Ácido Hialurónico/metabolismo , Sistema Linfático/metabolismo , Animales , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Glicocálix/metabolismo , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Proteínas de Transporte Vesicular/metabolismo
9.
Life Sci Alliance ; 4(5)2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33687996

RESUMEN

DCs play a vital role in immunity by conveying antigens from peripheral tissues to draining lymph nodes, through afferent lymphatic vessels. Critical to the process is initial docking to the lymphatic endothelial receptor LYVE-1 via its ligand hyaluronan on the DC surface. How this relatively weak binding polymer is configured for specific adhesion to LYVE-1, however, is unknown. Here, we show that hyaluronan is anchored and spatially organized into a 400-500 nm dense glycocalyx by the leukocyte receptor CD44. Using gene knockout and by modulating CD44-hyaluronan interactions with monoclonal antibodies in vitro and in a mouse model of oxazolone-induced skin inflammation, we demonstrate that CD44 is required for DC adhesion and transmigration across lymphatic endothelium. In addition, we present evidence that CD44 can dynamically control the density of the hyaluronan glycocalyx, regulating the efficiency of DC trafficking to lymph nodes. Our findings define a previously unrecognized role for CD44 in lymphatic trafficking and highlight the importance of the CD44:HA:LYVE-1 axis in its regulation.


Asunto(s)
Glicocálix/metabolismo , Receptores de Hialuranos/metabolismo , Vasos Linfáticos/metabolismo , Animales , Movimiento Celular , Células Dendríticas , Endotelio Linfático/citología , Endotelio Linfático/metabolismo , Femenino , Ácido Hialurónico/metabolismo , Ganglios Linfáticos/citología , Ganglios Linfáticos/metabolismo , Masculino , Proteínas de Transporte de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL
10.
Development ; 148(3)2021 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-33462113

RESUMEN

Macrophages are components of the innate immune system with key roles in tissue inflammation and repair. It is now evident that macrophages also support organogenesis, but few studies have characterized their identity, ontogeny and function during heart development. Here, we show that the distribution and prevalence of resident macrophages in the subepicardial compartment of the developing heart coincides with the emergence of new lymphatics, and that macrophages interact closely with the nascent lymphatic capillaries. Consequently, global macrophage deficiency led to extensive vessel disruption, with mutant hearts exhibiting shortened and mis-patterned lymphatics. The origin of cardiac macrophages was linked to the yolk sac and foetal liver. Moreover, the Cx3cr1+ myeloid lineage was found to play essential functions in the remodelling of the lymphatic endothelium. Mechanistically, macrophage hyaluronan was required for lymphatic sprouting by mediating direct macrophage-lymphatic endothelial cell interactions. Together, these findings reveal insight into the role of macrophages as indispensable mediators of lymphatic growth during the development of the mammalian cardiac vasculature.


Asunto(s)
Corazón/crecimiento & desarrollo , Vasos Linfáticos , Macrófagos/metabolismo , Animales , Receptor 1 de Quimiocinas CX3C/genética , Adhesión Celular , Línea Celular , Células Endoteliales , Regulación del Desarrollo de la Expresión Génica , Técnicas de Sustitución del Gen , Humanos , Inflamación , Linfangiogénesis , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Organogénesis/genética , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Saco Vitelino
11.
Nat Commun ; 11(1): 4697, 2020 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-32943639

RESUMEN

Unassisted metastasis through the lymphatic system is a mechanism of dissemination thus far ascribed only to cancer cells. Here, we report that Streptococcus pyogenes also hijack lymphatic vessels to escape a local infection site, transiting through sequential lymph nodes and efferent lymphatic vessels to enter the bloodstream. Contrasting with previously reported mechanisms of intracellular pathogen carriage by phagocytes, we show S. pyogenes remain extracellular during transit, first in afferent and then efferent lymphatics that carry the bacteria through successive draining lymph nodes. We identify streptococcal virulence mechanisms important for bacterial lymphatic dissemination and show that metastatic streptococci within infected lymph nodes resist and subvert clearance by phagocytes, enabling replication that can seed intense bloodstream infection. The findings establish the lymphatic system as both a survival niche and conduit to the bloodstream for S. pyogenes, explaining the phenomenon of occult bacteraemia. This work provides new perspectives in streptococcal pathogenesis with implications for immunity.


Asunto(s)
Ganglios Linfáticos/microbiología , Metástasis Linfática , Vasos Linfáticos/microbiología , Infecciones Estreptocócicas/microbiología , Streptococcus pyogenes/patogenicidad , Animales , Bacteriemia/microbiología , Bacteriemia/patología , Modelos Animales de Enfermedad , Femenino , Interleucina-8/metabolismo , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Metástasis Linfática/patología , Sistema Linfático , Vasos Linfáticos/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neutrófilos/microbiología , Fagocitosis , Infecciones Estreptocócicas/inmunología , Infecciones Estreptocócicas/patología , Streptococcus pyogenes/genética , Virulencia
12.
Case Rep Urol ; 2020: 6162158, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32257505

RESUMEN

Renal artery injury from blunt abdominal trauma is a rare condition that is typically managed nonoperatively in hemodynamically stable patients. Revascularization can be achieved by stenting or surgical reconstruction of the renal artery. All attempts at revascularization should minimize warm ischemic time. Here, we discuss a patient postmotor vehicle accident who presented to Ryder Trauma Center with intra-abdominal bleeding. He underwent emergency exploratory laparotomy with splenectomy and abdominal packing. Postoperative CT scan revealed a contrast nonenhancing left kidney. The patient then returned to the operating room and underwent in situ renal artery reconstruction after >4 hours of warm ischemia. The patient survived a 2-month hospital course and was discharged home after prolonged in-hospital stay and intensive care treatment. Nuclear medicine scan showed scarring and atrophy of the reattached kidney with 16.3% of overall function attributed to the affected kidney. This case shows that patients with renal artery injury can be managed operatively with arterial reconstruction. Reducing warm ischemic time is critical in preserving kidney function.

13.
J Biol Chem ; 295(15): 5036-5050, 2020 04 10.
Artículo en Inglés | MEDLINE | ID: mdl-32034091

RESUMEN

Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) mediates the docking and entry of dendritic cells to lymphatic vessels through selective adhesion to its ligand hyaluronan in the leukocyte surface glycocalyx. To bind hyaluronan efficiently, LYVE-1 must undergo surface clustering, a process that is induced efficiently by the large cross-linked assemblages of glycosaminoglycan present within leukocyte pericellular matrices but is induced poorly by the shorter polymer alone. These properties suggested that LYVE-1 may have limited mobility in the endothelial plasma membrane, but no biophysical investigation of these parameters has been carried out to date. Here, using super-resolution fluorescence microscopy and spectroscopy combined with biochemical analyses of the receptor in primary lymphatic endothelial cells, we provide the first evidence that LYVE-1 dynamics are indeed restricted by the submembranous actin network. We show that actin disruption not only increases LYVE-1 lateral diffusion but also enhances hyaluronan-binding activity. However, unlike the related leukocyte HA receptor CD44, which uses ERM and ankyrin motifs within its cytoplasmic tail to bind actin, LYVE-1 displays little if any direct interaction with actin, as determined by co-immunoprecipitation. Instead, as shown by super-resolution stimulated emission depletion microscopy in combination with fluorescence correlation spectroscopy, LYVE-1 diffusion is restricted by transient entrapment within submembranous actin corrals. These results point to an actin-mediated constraint on LYVE-1 clustering in lymphatic endothelium that tunes the receptor for selective engagement with hyaluronan assemblages in the glycocalyx that are large enough to cross-bridge the corral-bound LYVE-1 molecules and thereby facilitate leukocyte adhesion and transmigration.


Asunto(s)
Citoesqueleto de Actina/fisiología , Endotelio Linfático/metabolismo , Endotelio Vascular/metabolismo , Receptores de Hialuranos/metabolismo , Ácido Hialurónico/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Células Cultivadas , Endotelio Linfático/citología , Endotelio Vascular/citología , Humanos , Receptores de Hialuranos/genética , Proteínas de Transporte Vesicular/genética
14.
J Dermatolog Treat ; 31(1): 2-12, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28789577

RESUMEN

Introduction: Boron compounds are being investigated as therapies for dermatologic conditions. Several features of boron chemistry make this element an ideal component in dermatologic treatments. We review the published dermatologically-relevant clinical trials and case studies pertaining to boron compounds.Methods: PubMed was utilized to query terms boron, chemistry, drug, development, dermatology, atopic dermatitis, psoriasis, onychomycosis, tavaborole, AN 2690, crisaborole, and AN 2728. Clinical trials, case studies, animal studies and in vitro studies. Pertaining to atopic dermatitis, psoriasis and onychomycosis were included.Results: Crisaborole 2% topical solution reduced atopic dermatitis lesions by ∼60% when compared to pretreatment baseline. Crisaborole maintains its dose-dependent effect in treatment of psoriasis and significantly reduces psoriatic plaques when compared to controls. Adverse effects were mild, frequency of events varied between studies. Crisaborole was well tolerated when applied to sensitive skin. Topical tavaborole significantly reduced or eliminated onychomycosis with minimal side effects compared to placebo. Tavaborole was effective in treating recalcitrant onychomycosis.Discussion: Boron-based compounds form stable interactions with enzyme targets and are safe medications for the treatment of atopic dermatitis, psoriasis, and onychomycosis. The mild and rare side effects of topical boron-based compounds may make them ideal treatments for individuals with sensitive skin and pediatric populations.


Asunto(s)
Compuestos de Boro/uso terapéutico , Enfermedades de la Piel/tratamiento farmacológico , Compuestos de Boro/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Dermatitis Atópica/tratamiento farmacológico , Diseño de Fármacos , Eccema/tratamiento farmacológico , Humanos , Onicomicosis/tratamiento farmacológico , Psoriasis/tratamiento farmacológico , Resultado del Tratamiento
15.
Invest Ophthalmol Vis Sci ; 60(4): 1050-1062, 2019 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-30897620

RESUMEN

Purpose: We recently reported that the glycosaminoglycan hyaluronan (HA), which promotes inflammatory angiogenesis in other vascular beds, is an abundant component of the limbal extracellular matrix. Consequently, we have explored the possibility that HA contributes to lymphangiogenesis in the inflamed cornea. Methods: To study the role of HA on lymphangiogenesis, we used mice lacking the hyaluronan synthases and injury models that induce lymphangiogenesis. Results: Here we report that HA regulates corneal lymphangiogenesis, both during post-natal development and in response to adult corneal injury. Furthermore, we show that injury to the cornea by alkali burn upregulates both HA production and lymphangiogenesis and that these processes are ablated in HA synthase 2 deficient mice. Conclusion: These findings raise the possibility that therapeutic blockade of HA-mediated lymphangiogenesis might prevent the corneal scarring and rejection that frequently results from corneal transplantation.


Asunto(s)
Ácido Hialurónico/fisiología , Limbo de la Córnea/metabolismo , Linfangiogénesis/fisiología , Vasos Linfáticos/fisiología , Animales , Quemaduras Químicas/fisiopatología , Proliferación Celular , Supervivencia Celular , Células Endoteliales/efectos de los fármacos , Quemaduras Oculares/inducido químicamente , Ácido Hialurónico/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Reacción en Cadena en Tiempo Real de la Polimerasa , Hidróxido de Sodio
16.
Front Immunol ; 10: 471, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30923528

RESUMEN

The lymphatics fulfill a vital physiological function as the conduits through which leucocytes traffic between the tissues and draining lymph nodes for the initiation and modulation of immune responses. However, until recently many of the molecular mechanisms controlling such migration have been unclear. As a result of careful research, it is now apparent that the process is regulated at multiple stages from initial leucocyte entry and intraluminal crawling in peripheral tissue lymphatics, through to leucocyte exit in draining lymph nodes where the migrating cells either participate in immune responses or return to the circulation via efferent lymph. Furthermore, it is increasingly evident that most if not all leucocyte populations migrate in lymph and that such migration is not only important for immune modulation, but also for the timely repair and resolution of tissue inflammation. In this article, I review the latest research findings in these areas, arising from new insights into the distinctive ultrastructure of lymphatic capillaries and lymph node sinuses. Accordingly, I highlight the emerging importance of the leucocyte glycocalyx and its novel interactions with the endothelial receptor LYVE-1, the intricacies of endothelial chemokine secretion and sequestration that direct leucocyte trafficking and the significance of the process for normal immune function and pathology.


Asunto(s)
Movimiento Celular/inmunología , Endotelio Linfático/inmunología , Leucocitos/inmunología , Vasos Linfáticos/inmunología , Proteínas de Transporte Vesicular/inmunología , Endotelio Linfático/citología , Humanos , Leucocitos/citología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Vasos Linfáticos/citología
17.
Matrix Biol ; 78-79: 219-235, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-29425695

RESUMEN

LYVE-1, a close relative of the leucocyte receptor, CD44, is the main receptor for hyaluronan (HA) in lymphatic vessel endothelium and a widely used marker for distinguishing between blood and lymphatic vessels. Enigmatic for many years because of its anomalous HA-binding characteristics, the function of LYVE-1 has just recently been identified as that of a lymphatic docking receptor for dendritic cells, selectively engaging with their surface HA glycocalyx to regulate entry to peripheral lymphatics and migration to downstream lymph nodes for immune activation. Furthermore, LYVE-1 mediates the trafficking of macrophages, and is also exploited by HA-encapsulated Group A streptococci for lymphatic invasion and host dissemination. Consistent with a role in lymphatic trafficking, the interaction of LYVE-1 with HA and its degradation products can also activate intracellular signalling pathways for endothelial junctional retraction and lymphatic endothelial proliferation. Here we outline the latest findings on the receptor in the context of its peculiar biochemical properties and speculate on how the interaction of LYVE-1 with different HA sizes and conformations might variably influence cell function as a consequence of avidity and receptor crosslinking. Finally, we evaluate evidence that LYVE-1 can also bind growth factors and associate with kinase-linked growth factor receptors and conclude on how the LYVE-1·HA axis may be exploited as a target to either block inflammation or tissue allograft rejection, or potentiate vaccine and drug delivery.


Asunto(s)
Ácido Hialurónico/metabolismo , Leucocitos/metabolismo , Proteínas de Transporte Vesicular/química , Proteínas de Transporte Vesicular/metabolismo , Animales , Células Dendríticas/metabolismo , Humanos , Receptores de Hialuranos/química , Receptores de Hialuranos/metabolismo , Ácido Hialurónico/química , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Peso Molecular , Unión Proteica , Receptores de Factores de Crecimiento/metabolismo , Transducción de Señal
19.
J Clin Invest ; 128(8): 3402-3412, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-29985167

RESUMEN

Myocardial infarction (MI) arising from obstruction of the coronary circulation engenders massive cardiomyocyte loss and replacement by non-contractile scar tissue, leading to pathological remodeling, dysfunction, and ultimately heart failure. This is presently a global health problem for which there is no effective cure. Following MI, the innate immune system directs the phagocytosis of dead cell debris in an effort to stimulate cell repopulation and tissue renewal. In the mammalian adult heart, however, the persistent influx of immune cells, coupled with the lack of an inherent regenerative capacity, results in cardiac fibrosis. Here, we reveal that stimulation of cardiac lymphangiogenesis with VEGF-C improves clearance of the acute inflammatory response after MI by trafficking immune cells to draining mediastinal lymph nodes (MLNs) in a process dependent on lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1). Deletion of Lyve1 in mice, preventing docking and transit of leukocytes through the lymphatic endothelium, results in exacerbation of chronic inflammation and long-term deterioration of cardiac function. Our findings support targeting of the lymphatic/immune cell axis as a therapeutic paradigm to promote immune modulation and heart repair.


Asunto(s)
Movimiento Celular , Leucocitos/metabolismo , Linfangiogénesis , Sistema Linfático/metabolismo , Infarto del Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Animales , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Leucocitos/patología , Sistema Linfático/patología , Ratones , Ratones Noqueados , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Miocitos Cardíacos/patología , Factor C de Crecimiento Endotelial Vascular/genética , Factor C de Crecimiento Endotelial Vascular/metabolismo , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo
20.
Immunity ; 49(2): 326-341.e7, 2018 08 21.
Artículo en Inglés | MEDLINE | ID: mdl-30054204

RESUMEN

The maintenance of appropriate arterial tone is critically important for normal physiological arterial function. However, the cellular and molecular mechanisms remain poorly defined. Here, we have shown that in the mouse aorta, resident macrophages prevented arterial stiffness and collagen deposition in the steady state. Using phenotyping, transcriptional profiling, and targeted deletion of Csf1r, we have demonstrated that these macrophages-which are a feature of blood vessels invested with smooth muscle cells (SMCs) in both mouse and human tissues-expressed the hyaluronan (HA) receptor LYVE-l. Furthermore, we have shown they possessed the unique ability to modulate collagen expression in SMCs by matrix metalloproteinase MMP-9-dependent proteolysis through engagement of LYVE-1 with the HA pericellular matrix of SMCs. Our study has unveiled a hitherto unknown homeostatic contribution of arterial LYVE-1+ macrophages through the control of collagen production by SMCs and has identified a function of LYVE-1 in leukocytes.


Asunto(s)
Colágeno/metabolismo , Glicoproteínas/metabolismo , Receptores de Hialuranos/metabolismo , Macrófagos/metabolismo , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/metabolismo , Rigidez Vascular/fisiología , Animales , Aorta/fisiología , Femenino , Glicoproteínas/genética , Humanos , Ácido Hialurónico/metabolismo , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Proteínas de Transporte de Membrana , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética
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