scholarly journals Case Report: DOCK8 Deficiency Without Hyper-IgE in a Child With a Large Deletion

2021 ◽  
Vol 9 ◽  
Author(s):  
Edna Venegas-Montoya ◽  
Aidé Tamara Staines-Boone ◽  
Luz María Sánchez-Sánchez ◽  
Jorge Alberto García-Campos ◽  
Rubén Antonio Córdova-Gurrola ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Clinical Laboratory ◽  
Failure To Thrive ◽  
Large Deletion ◽  
High Serum ◽  
Primary Immune Deficiency ◽  
Chronic Mucocutaneous Candidiasis ◽  
Cutaneous Infections ◽  
Immune Synapse ◽  
Dock8 Deficiency

Autosomal recessive (AR) DOCK8 deficiency is a well-known actinopathy, a combined primary immune deficiency with impaired actin polymerization that results in altered cell mobility and immune synapse. DOCK8-deficient patients present early in life with eczema, viral cutaneous infections, chronic mucocutaneous candidiasis, bacterial pneumonia, and abscesses, together with eosinophilia, thrombocytosis, lymphopenia, and variable dysgammaglobulinemia that usually includes Hyper-IgE. In fact, before its genetic etiology was known, patients were described as having a form of Hyper-IgE syndrome, a name now deprecated in favor of genetic defects. We describe a school-age male patient with a clinical picture suggestive of DOCK8 deficiency, except for high serum IgE or a family history: early onset, failure to thrive, eczema, warts, condyloma, bronchiolitis, pneumonia, recurrent otitis media, bronchiectasis, candidiasis, leukocytosis, eosinophilia, high IgA, low IgG, and low CD4+ T cells. We were able to confirm the diagnosis through protein expression and whole-exome sequencing. We review the clinical, laboratory, and genetic features of 200 DOCK8-deficient patients; at least 4 other patients have had no elevated IgE, and about 40% do not have Hyper-IgE (above 1,000 IU/mL). Despite this, the constellation of signs, symptoms, and findings allow the suspicion of DOCK8 deficiency and other actinopathies.

scholarly journals COVID-19 infection: epidemiological, clinical, and radiological expression among adult population

2020 ◽  
Vol 51 (1) ◽  
Author(s):  
Eman Ragab ◽  
Asrar Helal Mahrous ◽  
Ghadeer Maher El Sheikh
Keyword(s):  
Serum Ferritin ◽  
Clinical Laboratory ◽  
Adult Population ◽  
Significant Risk ◽  
High Serum ◽  
Male Gender ◽  
Lower Sensitivity ◽  
Significant Difference ◽  
D Dimer

Abstract Background High-resolution computed tomography (HRCT) has proved to be an important diagnostic tool throughout the COVID-19 pandemic outbreaks. Increasing number of the infected personnel and shortage of real-time transcriptase polymerase chain reaction (RT-PCR) as well as its lower sensitivity made the CT a backbone in diagnosis, assessment of severity, and follow-up of the cases. Results Two hundred forty patients were evaluated retrospectively for clinical, laboratory, and radiological expression in COVID-19 infection. One hundred eighty-six non-severe cases with home isolation and outpatient treatment and 54 severe cases needed hospitalization and oxygen support. Significant difference between both groups was encountered regarding the age, male gender, > 38° fever, dyspnea, chest pain, hypertension, ≤ 93 oxygen saturation, intensive care unit (ICU) admission, elevated D-dimer, high serum ferritin and troponin levels, and high CT-severity score (CT-SS) of the severe group. CT-SS showed a negative correlation with O2 saturation and patients’ outcome (r − 0.73/p 0.001 and r − 0.56/p 0.001, respectively). Bilateral peripherally distributed ground glass opacities (GGOs) were the commonest imaging feature similar to the literature. Conclusion Older age, male gender, smoking, hypertension, low O2 saturation, increased CT score, high serum ferritin, and high D-dimer level are the most significant risk factors for severe COVID-19 pneumonia. Follow-up of the recovered severe cases is recommended to depict possible post COVID-19 lung fibrosis.

scholarly journals The C-terminus SH3-binding domain of Kv1.3 is required for the actin-mediated immobilization of the channel via cortactin

2015 ◽  
Vol 26 (9) ◽  
pp. 1640-1651 ◽  
Author(s):  
Peter Hajdu ◽  
Geoffrey V. Martin ◽  
Ameet A. Chimote ◽  
Orsolya Szilagyi ◽  
Koichi Takimoto ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Actin Polymerization ◽  
Actin Dynamics ◽  
Actin Network ◽  
Immune Synapse ◽  
Proximity Ligation ◽  
C Terminus ◽  
Kv1.3 Channels ◽  
And Migration ◽  
Channel Polarization

Kv1.3 channels play a pivotal role in the activation and migration of T-lymphocytes. These functions are accompanied by the channels' polarization, which is essential for associated downstream events. However, the mechanisms that govern the membrane movement of Kv1.3 channels remain unclear. F-actin polymerization occurs concomitantly to channel polarization, implicating the actin cytoskeleton in this process. Here we show that cortactin, a factor initiating the actin network, controls the membrane mobilization of Kv1.3 channels. FRAP with EGFP-tagged Kv1.3 channels demonstrates that knocking down cortactin decreases the actin-based immobilization of the channels. Using various deletion and mutation constructs, we show that the SH3 motif of Kv1.3 mediates the channel immobilization. Proximity ligation assays indicate that deletion or mutation of the SH3 motif also disrupts interaction of the channel with cortactin. In T-lymphocytes, the interaction between HS1 (the cortactin homologue) and Kv1.3 occurs at the immune synapse and requires the channel's C-terminal domain. These results show that actin dynamics regulates the membrane motility of Kv1.3 channels. They also provide evidence that the SH3 motif of the channel and cortactin plays key roles in this process.

scholarly journals Sarcolemmal deficiency of sarcoglycan complex in an 18-month-old Turkish boy with a large deletion in the beta sarcoglycan gene

2015 ◽  
Vol 18 (2) ◽  
pp. 71-76 ◽  
Author(s):  
G Diniz ◽  
H Tekgul ◽  
F Hazan ◽  
K Yararbas ◽  
A Tukun
Keyword(s):  
Dna Analysis ◽  
Molecular Genetic ◽  
Dystrophin Gene ◽  
Homozygous Deletion ◽  
Large Deletion ◽  
Clinical Findings ◽  
High Serum ◽  
Muscle Enzyme ◽  
Enzyme Elevation ◽  
Additional Support

Abstract Limb-girdle muscular dystrophy type 2E (LGMD-2E) is caused by autosomal recessive defects in the beta sarcoglycan (SGCB) gene located on chromosome 4q12. In this case report, the clinical findings, histopathological features and molecular genetic data in a boy with β sarcoglycanopathy are presented. An 18-month-old boy had a very high serum creatinine phosphokinase (CPK) level that was accidentally determined. The results of molecular analyses for the dystrophin gene was found to be normal. He underwent a muscle biopsy which showed dystrophic features. Immunohistochemistry showed that there was a total loss of sarcolemmal sarcoglycan complex. DNA analysis revealed a large homozygous deletion in the SCGB gene. During 4 years of follow-up, there was no evidence to predict a severe clinical course except the muscle enzyme elevation and myopathic electromyography (EMG) finding. The presented milder phenotype of LGMD-2E with a large deletion in the SGCB gene provided additional support for the clinical heterogeneity and pathogenic complexity of the disease.

CANCER Resistance Surveillance Program: Initial Results from Hematology–Oncology Centers in North America

2003 ◽  
Vol 37 (1) ◽  
pp. 47-56 ◽  
Author(s):  
Alan H Mutnick ◽  
Jeffrey T Kirby ◽  
Ronald N Jones ◽  
Keyword(s):  
North America ◽  
Clinical Laboratory ◽  
National Committee ◽  
Surveillance Program ◽  
Cancer Resistance ◽  
Coagulase Negative Staphylococci ◽  
Gram Positive ◽  
Cutaneous Infections ◽  
Cancer Program ◽  
Klebsiella Spp

OBJECTIVE The CANCER (Chemotherapy Alliance for Neutropenics and the Control of Emerging Resistance) surveillance program was initiated to collect culture data on antimicrobial and antifungal agents in hospitals treating neutropenic patients in North America, as a means to monitor the development of microbial resistance. METHODS A total of 2042 isolates from bloodstream, respiratory, urinary, and cutaneous infections in 2000–2001 were submitted by 33 oncology centers, clinics, and hospitals in North America, sent to a central laboratory, and tested by National Committee for Clinical Laboratory Standards methods against 42 different antimicrobials. RESULTS Staphylococcus aureus, Escherichia coli, coagulase-negative staphylococci, Enterococcus spp., and Klebsiella spp. represented the most frequently isolated pathogens during the initial benchmark year. The incidence of extended-spectrum β-lactamase–producing phenotypes ranged from 1.6% to 4.6% among E. coli and Klebsiella spp. Amikacin, tobramycin, polymyxin B, and piperacillin/tazobactam provided the highest susceptibility rates against Pseudomonas aeruginosa isolates. Yeast bloodstream isolates demonstrated complete susceptibility to amphotericin B, but 14% of strains were considered to have high-level fluconazole resistance. CONCLUSIONS Elevated resistance rates when compared to general hospital strains were not observed in the CANCER program during the baseline year of this novel longitudinal, resistance surveillance program. The prevalence of gram-positive pathogens, although representing more than 50% of all bacterial isolates, was slightly lower than that reported previously by other investigators. Continued evaluation for antimicrobial resistance as well as changes in the prevalence of gram-positive pathogens requires the use of longitudinal surveillance programs such as the CANCER program. Such initiatives allow the development of therapeutic strategies for coping with changes in resistance and pathogen prevalence in this dynamic at-risk patient environment.

scholarly journals Hypercalcemia in an Infant With Pseudohypoaldosteronism Type 1

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A134-A135
Author(s):  
Henry Jeng ◽  
Julia Rodica Broussard
Keyword(s):  
Vitamin D ◽  
Renal Disease ◽  
Failure To Thrive ◽  
High Serum ◽  
Acth Stimulation ◽  
Renal Malformations ◽  
25 Oh Vitamin D ◽  
Pseudohypoaldosteronism Type ◽  
Electrolyte Abnormalities

Abstract Background: Pseudohypoaldosteronism type 1 (PHA1) is an aldosterone resistance syndrome due to insensitivity of target tissues to aldosterone action, with supraphysiologic aldosterone and renin levels. PHA1 presents usually in infancy and is divided into autosomal dominant (AD) and autosomal recessive (AR) form. A secondary form of PHA1 associated with UTI and/or renal malformations was described. In AD PHA1, salt loss is due to renal mineralocorticoid resistance while hyponatremia in AR PHA1 is caused by multi-organ salt loss. PHA1 has variable signs/symptoms associated with hyponatremia and hyperkalemia; thus, this clinical picture can be attributed to more common conditions such as dehydration, poor feeding, congenital adrenal hyperplasia. Clinical Case: A 5-month old male was admitted for airway evaluation. He was a 23-week gestation preemie, with chronic lung disease, failure to thrive. Patient was found to have hyponatremia, hyperkalemia, high FeNa of 1.3% (intrinsic renal disease) and elevated BUN/Cr (92/1.15). Renal US found echogenic kidneys with poor cortical medullary differentiation suggesting renal disease. Further evaluation noted high aldosterone (1700 ng/dL) and renin (400 ng/mL/hr) levels. He was placed on low protein formula to help optimize BUN level. Baby was diagnosed with secondary PHA1 due to renal disease and started on NaCl supplementation. This led to normalization of BUN, creatinine and improvement in electrolytes. Patient also had high serum calcium ranging from 11.1 to 12.0 mg/dL. Hyponatremia, hyperkalemia, hypercalcemia could be attributed to possible CAH, however state screen and ACTH stimulation test were normal. Further workup showed high 25-OH-vitamin D > 99 ng/mL, PTH 46.9 pg/mL, phosphorous 5.4 mg/dL and 1,25-OH-vitamin D 63.1 pg/mL. Urine Ca/cr ratio was 0.522. Vitamin D supplementation was stopped and daily total fluids increased. Subsequently, there was improvement in serum Ca at 10.9 mg/dL and 25-OH Vitamin D of 74 pg/mL. Next Generation Sequencing (NGS) was carried out, with a focus on the etiology of persisting hypercalcemia, including familial forms of hypercalcemia and Williams Syndrome. NGS revealed a likely pathogenic variant, c.2365 + 2T>C (p.?), in NR3C2, consistent with a diagnosis of AD PHA 1. Conclusion: This is a case of AD PHA1, marked by renal mineralocorticoid receptor resistance associated with persisting hypercalcemia. Initial hypercalcemia could be explained by hypervitaminosis D. It is important to note that electrolyte abnormalities, including persistent hypercalcemia, could be also secondary to the kidney disease found on renal US. There are only few reports of hypercalcemia in patients with PHA1 in the literature. In children with electrolyte abnormalities and failure to thrive, monitoring of serum and urine electrolytes would facilitate early accurate diagnosis and timely treatment.

scholarly journals The Wdr1-LIMK-Cofilin Axis Controls B Cell Antigen Receptor-Induced Actin Remodeling and Signaling at the Immune Synapse

2021 ◽  
Vol 9 ◽  
Author(s):  
Madison Bolger-Munro ◽  
Kate Choi ◽  
Faith Cheung ◽  
Yi Tian Liu ◽  
May Dang-Lawson ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Actin Filaments ◽  
Actin Polymerization ◽  
Cell Spreading ◽  
B Cell Antigen Receptor ◽  
Actin Remodeling ◽  
Immune Synapse ◽  
Cell Antigen ◽  
Bcr Signaling

When B cells encounter membrane-bound antigens, the formation and coalescence of B cell antigen receptor (BCR) microclusters amplifies BCR signaling. The ability of B cells to probe the surface of antigen-presenting cells (APCs) and respond to APC-bound antigens requires remodeling of the actin cytoskeleton. Initial BCR signaling stimulates actin-related protein (Arp) 2/3 complex-dependent actin polymerization, which drives B cell spreading as well as the centripetal movement and coalescence of BCR microclusters at the B cell-APC synapse. Sustained actin polymerization depends on concomitant actin filament depolymerization, which enables the recycling of actin monomers and Arp2/3 complexes. Cofilin-mediated severing of actin filaments is a rate-limiting step in the morphological changes that occur during immune synapse formation. Hence, regulators of cofilin activity such as WD repeat-containing protein 1 (Wdr1), LIM domain kinase (LIMK), and coactosin-like 1 (Cotl1) may also be essential for actin-dependent processes in B cells. Wdr1 enhances cofilin-mediated actin disassembly. Conversely, Cotl1 competes with cofilin for binding to actin and LIMK phosphorylates cofilin and prevents it from binding to actin filaments. We now show that Wdr1 and LIMK have distinct roles in BCR-induced assembly of the peripheral actin structures that drive B cell spreading, and that cofilin, Wdr1, and LIMK all contribute to the actin-dependent amplification of BCR signaling at the immune synapse. Depleting Cotl1 had no effect on these processes. Thus, the Wdr1-LIMK-cofilin axis is critical for BCR-induced actin remodeling and for B cell responses to APC-bound antigens.

scholarly journals Microtubules restrict F-actin to the immune synapse via GEF-H1 to maintain polarity in lymphocytes

2022 ◽  
Author(s):  
Judith Pineau ◽  
Léa Pinon ◽  
Olivier Mesdjian ◽  
Jacques Fattaccioli ◽  
Ana-Maria Lennon Duménil ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cell Polarity ◽  
Actin Polymerization ◽  
Synapse Formation ◽  
Lymphocyte Activation ◽  
Immune Synapse ◽  
Humoral Immune ◽  
High Affinity ◽  
Humoral Immune Responses ◽  
And Function

Immune synapse formation is a key step for lymphocyte activation. In B lymphocytes, the immune synapse controls the production of high-affinity antibodies, thereby defining the efficiency of humoral immune responses. While the key roles played by both the actin and microtubule cytoskeletons in the formation and function of the immune synapse have become increasingly clear, how the different events involved in synapse formation are coordinated in space and time by actin-microtubule interactions is not understood. Using a microfluidic pairing device, we studied with unprecedented resolution the dynamics of the various events leading to immune synapse formation and maintenance. Our results identify two groups of events, local and global dominated, respectively, by actin and microtubules dynamics. They further highlight an unexpected role for microtubules and the GEF-H1-RhoA axis in restricting F-actin polymerization at the immune synapse to define the cell polarity axis, allowing the formation and maintenance of a unique competent immune synapse.

scholarly journals Raquitismo: Ressurgimento do Passado

2015 ◽  
Vol 28 (2) ◽  
pp. 263
Author(s):  
Margarida Valério ◽  
Sara Pimentel Marcos ◽  
Conceição Santos ◽  
Maria João Leiria
Keyword(s):  
Dietary Habits ◽  
Clinical Laboratory ◽  
Failure To Thrive ◽  
Developed Countries ◽  
Vitamin Supplementation ◽  
Radiographic Images ◽  
Bone Demineralization ◽  
Nutritional Rickets ◽  
The Past ◽  
Black Infant

In the past decade rickets has re-emerged in developed countries due to changes in lifestyles and dietary habits. We describe a case of a 28-month-old black infant with failure to thrive. He was exclusively breastfed until nine months of age, without vitamin supplementation, and never ingested milk products due to alleged cow’s milk intolerance. His examination revealed bowlegs, rachitic rosary and wide wrists. Alkaline phosphatase and intact parathyroid hormone levels were elevated, and calcidiol was decreased. Radiographic images showed bone demineralization, fraying and cupping of the distal radius and ulna. Nutritional rickets was considered and treatment with colecalciferol and calcium carbonate was initiated, with clinical, laboratory and radiologic improvement. In this case, a group of factors contributed to severe nutritional rickets, alerting to the re-emergence of this disease.

Treatment of MCL Cells with Combined Rituximab and Lenalidomide Enhances NK-Mediated Synapse Formation and Cell Killing.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1687-1687
Author(s):  
Svetlana Gaidarova ◽  
Laura G Corral ◽  
Emilia Glezer ◽  
Peter H Schafer ◽  
Antonia Lopez-Girona
Keyword(s):  
Nk Cells ◽  
Actin Polymerization ◽  
Synapse Formation ◽  
Fold Increase ◽  
Cell Types ◽  
Employment Equity ◽  
Immune Synapse ◽  
Immunological Synapses ◽  
Immune Synapses ◽  
Equity Ownership

Abstract Abstract 1687 Poster Board I-713 Introduction Mantle cell lymphoma (MCL) is a subtype of aggressive B-cell non-Hodgkin's Lymphoma (NHL) characterized by poor prognosis and very few therapeutic options that improve survival. Lenalidomide is an immunomodulatory agent that has demonstrated significant clinical activity in the treatment of patients with MCL. A mechanism attributed to lenalidomide, which has also been demonstrated in B-CLL models, is the restoration of impaired T-cell activity to form immunological synapses, thus enhancing T-cell effector functions thereby eliminating aberrant tumor B cells. Natural killer (NK) cells are another cell type that eliminates aberrant cell types via a mechanism dependent on active formation of immunological synapses. By engaging in both direct killing and ADCC, NK cells are an important component of innate immunity eliminating transformed cell types. Here we assess the effect of lenalidomide on the ability of NK cells to form immune synapses with MCL cell lines and cell samples from MCL patients. We also evaluate whether lenalidomide-mediated immunologic activity is altered when lenalidomide is combined with rituximab, an anti-CD20 antibody shown to eliminate MCL cells through the ADCC mechanism. Methods To measure immune synapse formation, NK and JeKo-1 cells were pre-treated with DMSO or 1μM lenalidomide for 24 or 48 hrs. JeKo-1 cells (labeled with red PKH26) were incubated for 30 min with or without 10 μg/ml rituximab, and cell conjugates were fixed and stained with Phalloidin-FITC to measure mean fluorescent intensity and F-actin formation. Adenylate kinase (AK) release and 7AAD staining were used to measure NK-mediated cytotoxicity after NK and MCL cells were co-cultured at different target-to-effector ratios, and with and without rituximab. Flow cytometry was used to measure relative expression of cell surface markers CD56 (N-CAM), CD54 (I-CAM1), and NKG2D in both JeKo-1 cells and in B-cell samples from MCL patients. Results Addition of lenalidomide enhanced the formation of immunological synapses between JeKo-1 cells and NK cells, increasing the number of synapses approximately 3-fold after 24 hrs of treatment. When lenalidomide was combined with rituximab the number of synapses increased 3.5-fold. A significant increase in the number of synapses also occurred when NK cells co-cultured with MCL patient samples were treated with lenalidomide (2.5-fold increase) and lenalidomide plus rituximab (3-fold increase). Lenalidomide also augmented the intensity of F-actin at the synaptic site, which indicates more matured synapses rich with F-actin. The increased synapse-forming activity resulting from treatment with rituximab plus lenalidomide also translated into enhanced NK-mediated cytotoxicity. After 48 hours of concurrent treatment with lenalidomide and rituximab, approximately 80% of JeKo-1 cells released AK compared with approximately 45% after treatment with lenalidomide alone. Comparable cell killing data upon treatment with lenalidomide plus rituximab was obtained using a 7AAD assay. Finally, to understand the mechanism by which lenalidomide enhances the formation of immune synapses and augments the rituximab-dependent NK cell-mediated cytotoxicity in MCL cells, we studied the effect of lenalidomide on effector and target cells separately. In the NK cells, lenalidomide treatment induced F-actin polymerization and polarization, and the accumulation of perforin, which is evidence for effector cell activation. Previously we showed that lenalidomide treatment of tumor cells induces changes in actin structure and increases expression of cell surface markers, including CD54 and co-stimulatory molecules, which correlated with increased antigen presentation properties of tumor cells. Here we show that lenalidomide and rituximab induced F-actin polymerization and polarization in the JeKo-1 cells when administered individually and in combination, and resulted in slightly increased cytotoxicity. Conclusion Our results suggest that in MCL, combined use of lenalidomide and rituximab enhances NK-mediated immune synapse formation and the resultant cytotoxicity. Combining lenalidomide with rituximab may also enhance the anti-tumor immune response mediated through enhanced activity of NK cells. These studies suggest that lenalidomide plus rituximab may have clinical utility in the treatment of patients with MCL. Disclosures Gaidarova: Celgene: Employment, Equity Ownership. Corral:Celgene: Employment. Glezer:Celgene: Employment, Equity Ownership. Schafer:Celgene: Employment. Lopez-Girona:Celgene: Employment.

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