Th1-skewed profile and excessive production of proinflammatory cytokines in a NFKB1-deficient patient with CVID and severe gastrointestinal manifestations

Publication date: Available online 29 July 2018

Source: Clinical Immunology

Author(s): Romina Dieli-Crimi, Mónica Martínez-Gallo, Clara Franco-Jarava, Maria Antolin, Laura Blasco, Ida Paramonov, Maria E. Semidey, Antoni Álvarez Fernández, Xavier Molero, Julio Velásquez, Andrea Martín-Nalda, Ricardo Pujol-Borrell, Roger Colobran

Abstract

Monoallelic loss-of-function mutations in NFKB1 were recently recognized as the most common monogenic cause of common variable immunodeficiency (CVID). The prototypic clinical phenotype of NFKB1-deficient patients includes common CVID features, such as hypogammaglobulinaemia and sinopulmonary infections, plus other highly variable individual manifestations. Here, we describe a patient with a profound CVID phenotype and severe gastrointestinal manifestations, including chronic and recurrent diarrhoea. Using an NGS customized panel of 323 genes related to primary immunodeficiencies, we identified a novel monoallelic loss-of-function mutation in NFKB1 leading to a truncated protein (c.1149delT/p.Gly384Glu ∗ 48). Interestingly, we also found a rare variant in NOD2 previously associated with Crohn's disease (p.His352Arg). Our patient had hypogammaglobulinaemia with a small number of B cells, most of which were naïve. The most noteworthy findings included marked skewing towards a Th1 phenotype in peripheral blood T cells and excessive production of proinflammatory cytokines (IL-1β, TNFα). The patient's 6-year-old daughter, a carrier of the NFKB1 mutation, is clinically asymptomatic, but has started to show cellular and molecular changes. This case of NFKB1 deficiency appears to be a combination of immunodeficiency and a hyperinflammatory state. The current situation of the patient's daughter provides a glimpse of the preclinical phase of the condition.

https://ift.tt/2uZbA4H

Autosomal Recessive Agammaglobulinemia - first case with a novel TCF3 mutation from Pakistan

Publication date: Available online 29 July 2018

Source: Clinical Immunology

Author(s): Sonia Qureshi, Muhammad Dawood Amir Sheikh, Farah Naz Qamar, Wayne Bainter, Janet Chou, Raif S. Geha

Abstract

Autosomal Recessive Agammaglobulinemia (ARA) is an uncommon type of primary immunodeficiency characterized by mutations in genes responsible for early B cell differentiation and function. One such gene is the TCF3 gene, which encodes a transcription factor important for immunoglobulin gene expression. We present the case of a 9 year old girl with history of diarrhea and recurrent pneumonias. Laboratory investigation showed significantly reduced levels of immunoglobulins along with a significant fall in the number of CD19+ cells. Genetic analysis identified a TCF3 gene base deletion covering exons 5–11.

https://ift.tt/2NOKzYE

Association of Positive Initial Margins With Survival Among Patients With Squamous Cell Carcinoma Treated With Total Laryngectomy.

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Association of Positive Initial Margins With Survival Among Patients With Squamous Cell Carcinoma Treated With Total Laryngectomy.

JAMA Otolaryngol Head Neck Surg. 2018 Jul 26;:

Authors: Tassone P, Savard C, Topf MC, Keane W, Luginbuhl A, Curry J, Cognetti D

Abstract
Importance: Frozen-section analysis of margin status is routinely performed during total laryngectomy for squamous cell carcinoma; in the case of positive initial frozen margins, re-resection to negative margins can often be accomplished. Some evidence suggests that positive initial margins may be associated with worse survival among patients with head and neck cancer even when final margins are negative, but the significance of positive initial frozen margins in total laryngectomy is poorly understood.
Objective: To determine the association between disease-free survival and positive initial margins among patients treated with total laryngectomy for squamous cell carcinoma.
Design, Setting, and Participants: In this retrospective cohort study conducted at a tertiary care center, records of 237 consecutive patients treated with total laryngectomy for squamous cell carcinoma from February 2008 to July 2016 were reviewed for demographic characteristics, disease staging, pathologic markers, and outcomes. Margins were considered to be positive if they contained invasive carcinoma, carcinoma in situ, or severe dysplasia. Data analysis was performed from March to June 2018.
Interventions: All patients had undergone total laryngectomy for squamous cell carcinoma.
Main Outcomes and Measures: Variables associated with disease-free survival were analyzed using a univariable and multivariable Cox proportional hazards model.
Results: Among all 225 patients (184 [92%] male; mean age, 63.9 years; range, 30-92 years) who underwent total laryngectomy and had negative final margins, 127 patients underwent primary total laryngectomy and 98 underwent salvage total laryngectomy, with mean (SEM) follow-up of 29.3 (1.8) months. Initial frozen margins were positive in 40 of 225 patients (18%); positive initial margins occurred in 21 of 127 patients who underwent primary total laryngectomy (17%) and in 19 of 98 patients who underwent salvage total laryngectomy (19%). On multivariable analysis, only salvage laryngectomy was associated with significantly worse disease-free survival (hazard ratio [HR], 3.35; 95% CI, 1.76-6.36). Among 98 patients who underwent salvage total laryngectomy, positive lymph nodes, lymphovascular invasion, extracapsular nodal extension, and adjuvant therapy were associated with worse disease-free survival on univariable analysis, but no factors remained significant on multivariable analysis. Among 127 patients who underwent primary total laryngectomy, positive nodes, lymphovascular invasion, extracapsular nodal extension, and positive initial margins were associated with worse disease-free survival; however, only positive initial margins were associated with significantly worse disease-free survival on multivariable analysis (HR, 5.01; 95% CI, 1.55-16.2).
Conclusions and Relevance: In this study, positive initial margins were associated with worse disease-free survival among patients who underwent primary total laryngectomy despite negative margins on final pathologic examination. This finding may indicate aggressive tumor behavior in the context of primary laryngeal squamous cell carcinoma.

PMID: 30054637 [PubMed - as supplied by publisher]

https://ift.tt/2LJ2UJr

Association of the Anterolateral Thigh Osteomyocutaneous Flap With Femur Structural Integrity and Assessment of Prophylactic Fixation.

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Association of the Anterolateral Thigh Osteomyocutaneous Flap With Femur Structural Integrity and Assessment of Prophylactic Fixation.

JAMA Otolaryngol Head Neck Surg. 2018 Jul 26;:

Authors: Worley ML, Patterson TM, Graboyes EM, Wu Y, Brody RM, Hornig J, Walton Z

Abstract
Importance: The chimeric anterolateral thigh osteomyocutaneous (ALTO) free flap is a recently described microvascular option for head and neck osseous defects associated with complex soft-tissue requirements. To date, the association of ALTO flap harvest with femur structural integrity and the need for routine prophylactic fixation following harvest has been incompletely described.
Objective: To investigate the association of ALTO flap harvest, with and without prophylactic fixation, on femur structural integrity as measured by 4-point bend and torsional biomechanical testing.
Design and Setting: At a research laboratory, 24 synthetic fourth-generation composite femurs with validated biomechanical properties underwent 10-cm-long, 30% circumferential osteotomies at the proximal middle third of the femur; 6 femurs served as controls. Osteotomized femurs with and without fixation underwent torsional and 4-point bend biomechanical testing. Femur fixation consisted of intramedullary nail and distal interlock screw placement.
Main Outcomes and Measures: Force and torque to fracture (expressed in kilonewtons [kN] and Newton meters [N∙m], respectively) were compared between controls, osteotomized femurs without fixation, and osteotomized femurs with fixation. Additional outcome measures included femur stiffness and fracture patterns.
Results: On posterior to anterior (PA) 4-point bend testing, force to fracture of osteotomized femurs was 22% of controls (mean difference, 8.3 kN; 95% CI, 6.6-10.0 kN). On torsional testing the torque to fracture of osteotomized femurs was 12% of controls (mean difference, 351.1 N∙m; 95% CI, 307.1-395.1 N∙m). Following fixation there was a 67% improvement in PA force to fracture and a 37% improvement in torque to fracture. However, osteotomized femurs with fixation continued to have a reduced PA force to fracture at 37% of controls (mean difference, 6.8 kN; 95% CI, 4.5-9.2 kN) and torque to fracture at 16% of controls (mean difference, 333.7 N∙m; 95% CI, 306.8-360.6 N∙m). On torsional testing, all osteotomized femurs developed similar spiral fractures through a corner of the distal osteotomy site. This fracture pattern changed after prophylactic fixation with femurs developing nondisplaced fractures through the proximal osteotomy site. There were no underlying hardware failures during testing of osteotomized femurs with fixation.
Conclusions and Relevance: Anterolateral thigh osteomyocutaneous flap harvest results in significant changes in the structural integrity of the femur. Postoperative stabilization should be strongly considered, with future research directed at investigating the clinical significance of residual biomechanical changes following femur fixation.

PMID: 30054621 [PubMed - as supplied by publisher]

https://ift.tt/2NUVfoV

Nodular Mass in the Upper Lip.

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Nodular Mass in the Upper Lip.

JAMA Otolaryngol Head Neck Surg. 2018 Jul 26;:

Authors: Nam J, Jung EA, Jeong J

PMID: 30054613 [PubMed - as supplied by publisher]

https://ift.tt/2LAB17j

Pleomorphic Adenoma of the Nasolacrimal Duct.

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Pleomorphic Adenoma of the Nasolacrimal Duct.

JAMA Otolaryngol Head Neck Surg. 2018 Jul 26;:

Authors: Haft SJ, Jafari A, Lowenthal BM, Korn BS, DeConde AS

PMID: 30054608 [PubMed - as supplied by publisher]

https://ift.tt/2vdUYpb

Management of Hoarseness.

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Management of Hoarseness.

JAMA Otolaryngol Head Neck Surg. 2018 Jul 26;:

Authors: Francis DO

PMID: 30054603 [PubMed - as supplied by publisher]

https://ift.tt/2LvOVYi

Sinonasal computed tomography in pediatric cystic fibrosis: do we know the indications?

Publication date: Available online 29 July 2018

Source: International Journal of Pediatric Otorhinolaryngology

Author(s): Michelle Manzini, Cláudia Schweiger, Denise Manica, Letícia Rocha Machado, Paula de Souza Dias Lopes, Leo Sekine, Carlo Sasso Faccin, Otávio BejzmanPiltcher, Paulo José CauduroMarostica

Abstract

Objectives

To investigated the correlation between sinonasal computed tomography (SNCT) findings and sinonasal symptoms, genotype, chronic colonization by Pseudomonas aeruginosa, forced expiratory volume in the first second (FEV1), body mass index (BMI), Shwachman-Kulczycki (SK) score, and Bhalla score in patients with cystic fibrosis.

Methods

We retrospectively reviewed the medical records of 61 patients aged 2-16 years who received care at the Pediatric Cystic Fibrosis Center of our institution over a 10-year period. SNCT findings were graded using the Lund-Mackay scoring system. For patients who had SNCT scans performed at two different time points, the findings from both examinations were compared.

Results

Patients with chronic P. aeruginosa colonization and patients with atelectasis had higher Lund-Mackay scores (p=0.04 and p=0.01, respectively). There was no difference in Lund-Mackay scores between sinonasal symptomatic and asymptomatic patients (p=0.45). Among patients who had two SNCT scans available (n=11), those with no evidence of bronchiectasis on chest CT had decreased Lund-Mackay scores compared to those with evidence of bronchiectasis, who had an increase in their scores (p=0.03). Variations in the Bhalla score were positively and variations in the SK score were negatively correlated with variations in the Lund-Mackay score (r=0.74, p=0.01; and r=−0.85, p<0.01).

Conclusions

Associations between SNCT findings, chronic P. aeruginosa colonization, SK score, and chest CT findings were demonstrated. Further studies with larger sample sizes are needed to evaluate patient follow-up and assess the benefits of the sinonasal treatment strategy adopted for patients who exhibit pulmonary deterioration despite controlling for other factors associated with exacerbation.

https://ift.tt/2vevHv7

Indirubin ameliorates imiquimod-induced psoriasis-like skin lesions in mice by inhibiting inflammatory responses mediated by IL-17A-producing γδ T cells

Publication date: September 2018

Source: Molecular Immunology, Volume 101

Author(s): Xiang-jiang Xie, Ting-ting Di, Yan Wang, Ming-xing Wang, Yu-jiao Meng, Yan Lin, Xiao-long Xu, Ping Li, Jing-xia Zhao

Abstract

Objectives

Indirubin (IR) is a bisindole compound extracted from the leaves of Chinese herb Indigo Naturalis. Indigo Naturalis has been widely used in traditional Chinese medicine to treat inflammatory and autoimmune diseases. Psoriasis is a chronic immune-mediated inflammatory skin disease in which γδ T cells play an important role. This study aims to determine the immunoregulatory effects and the underlying mechanisms of Indirubin in psoriasis-related inflammatory responses.

Methods

BALB/c mice with imiquimod (IMQ)-induced psoriasis-like dermatitis were treated with saline (Model), 1 mg/kg methotrexate (MTX) that serves as a positive control, or 12.5, 25 and 50 mg/kg Indirubin(IR) intragastrically. Keratinocytes proliferation, inflammatory cells infiltration, the expression of inflammatory cytokines and Jak/Stat pathway-related proteins in the skin lesion were examined. The abundance of γδ T cells in lymph nodes and spleen was determined by flow cytometry. The IL-17 expression and secretion, and the activation of Jak3/Stat3 pathways in in vitro cultured γδ T cell were tested.

Results

Indirubin ameliorated keratinocyte proliferation, reduced the infiltration of CD3⁺ T cells, IL-17 A-producing γδ T cells, and CD11b⁺ neutrophils, inhibited the mRNA expression of Il1, Il6, Il23, Il17a and Il22, and the protein expression of Jak/Stat pathway-related molecules in the skin lesion. Indirubin also reduced the abundance of γδ T cell and CCR6⁺ γδ T cells (the major IL-17 A producer) in spleen and lymph nodes. In cultured γδ T cells, Indirubin inhibited the mRNA expression of Il17a and Ifng, and the secretion of IL-17 A, while suppressed the activation of Jak3/Stat3 pathways.

Conclusion

Indirubin alleviates IMQ-induced psoriasis-like dermatitis mainly through reducing the inflammatory responses mediated by IL-17 A-producing γδ T cells involving Jak3/Stat3 activation. Our results highlighted the novel mechanisms by which Indirubin ameliorates psoriasis-related inflammatory responses, supporting its therapeutic potential.

https://ift.tt/2K4MO8b

Antibodies targeting circulating protective molecules in lupus nephritis: Interest as serological biomarkers

Publication date: Available online 29 July 2018

Source: Autoimmunity Reviews

Author(s): Chantal Dumestre-Pérard, Giovanna Clavarino, Sophie Colliard, Jean-Yves Cesbron, Nicole M. Thielens

Abstract

Lupus nephritis (LN) is one of the most frequent and severe manifestations of systemic lupus erythematosus (SLE), considered as the major predictor of poor prognosis. An early diagnosis of LN is a real challenge in the management of SLE and has an important implication in guiding treatments. In clinical practice, conventional parameters still lack sensitivity and specificity for detecting ongoing disease activity in lupus kidneys and early relapse of nephritis. LN is characterized by glomerular kidney injury, essentially due to deposition of immune complexes involving autoantibodies against cellular components and circulating proteins. One of the possible mechanisms of induction of autoantibodies in SLE is a defect in apoptotic cells clearance and subsequent release of intracellular autoantigens. Autoantibodies against soluble protective molecules involved in the uptake of dying cells, including complement proteins and pentraxins, have been described. In this review, we present the main autoantibodies found in LN, with a focus on the antibodies against these protective molecules. We also discuss their pathogenic role and conclude with their potential interest as serological biomarkers in LN.

https://ift.tt/2AhKNWp