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PIK3R1 Mutation Associated with Hyper IgM (APDS2 Syndrome): A Case Report and Review of the Literature.

Endocr Metab Immune Disord Drug Targets. 2019 Feb 24;:

Authors: Yazdani R, Hamidi Z, Babaha F, Azizi G, Fekrvand S, Abolhassani H, Aghamohammadi A

Abstract
BACKGROUND AND OBJECTIVE: APDS [Activated phosphoinositide 3-kinase (PI3K) δ Syndrome] is a newly found special form of primary immunodeficiency caused by mutations in genes encoding PI3Kδ subunits and over-activation of the PI3K signaling pathway. Gain-of-function and loss-of-function mutations in PIK3CD (encoding P110δ) and PIK3R1 (encoding p85α, p55α and p50α) lead to APDS1 and APDS2, respectively. The subsequent irregular PI3K downstream signaling cascade is associated with abnormalities in B cells and T cells and the consequent heterogeneous clinical manifestations including respiratory tract infections, autoimmunity, lymphoproliferation and not to mention primary antibody deficiency. In this study, we report a 12-year-old girl with a mutation in the PIK3R1 gene who manifested immunological phenotypes resembling hyper IgM syndrome along with a review of the literature of the previously reported patients.
METHODS: Whole exome sequencing was performed to detect the underlying genetic mutation in this patient.
RESULTS: A de novo heterozygous splice site mutation in the hot spot of the PIK3R1 gene within the intron 10 was found (c.1425+1G>A).
CONCLUSION: Further investigations are required for evaluation of the underlying genetic defects and the possible associations between genetic underpinning and heterogeneous severity and features of the disease.

PMID: 30799802 [PubMed – as supplied by publisher]

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Health-Related Quality of Life in Children and Adults with Primary Immunodeficiencies: A Systematic Review and Meta-analysis.

J Allergy Clin Immunol Pract. 2019 Feb 20;:

Authors: Peshko D, Titova E, Korsunskiy I, Kondrikova E, Pulvirenti F, Quinti I, Blyuss O, Galvin AD, Munblit D

Abstract
BACKGROUND: Primary immunodeficiency disorders (PID) is a group of diseases that has been found to have an adverse impact on Quality of Life (QoL) and health related quality of life (HRQL).
OBJECTIVE: To systematically assess available evidence on PID patients HRQL.
METHODS: We performed a literature search of all studies reporting HRQL assessments in patients with PID published in English from inception to 11 April 2017 using MEDLINE and EMBASE.
RESULTS: Out of 1699 articles, 37 met the inclusion criteria. HRQL was assessed by using a variety of generic instruments. CHQ-PF50 and SF-36 were the most frequently used (for children and adults, respectively). No PID-specific HRQL instruments were used for children. HRQL is significantly lower in PID adults (mean score difference -24.46, 95%CI, -34.57; -14.34) and children (-10.06, -12.95; -7.17) compared to the reference population and lower than in patients with other chronic conditions. There is a general agreement between child- and parent-reported data, although parents report child school-related HRQL as more impaired than children (6.19, 0.38; 11.99). Most studies were of low to moderate quality and had methodological limitations.
CONCLUSION: Available evidence suggests that PID patients have a lower HRQL than healthy individuals and patients with other chronic conditions, including diabetes mellitus and juvenile idiopathic arthritis. No disease-specific instruments are available for children and few options are available for adults. This finding highlights the need for developing PID-specific instruments which would allow for a more sensitive evaluation of PID impact on patient health and psychological wellbeing, school/work and social activities.

PMID: 30797077 [PubMed – as supplied by publisher]

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Primary immunodeficiency and autoimmunity: A comprehensive review.

J Autoimmun. 2019 Feb 19;:

Authors: Amaya-Uribe L, Rojas M, Azizi G, Anaya JM, Gershwin ME

Abstract
The primary immunodeficiency diseases (PIDs) include many genetic disorders that affect different components of the innate and adaptive responses. The number of distinct genetic PIDs has increased exponentially with improved methods of detection and advanced laboratory methodology. Patients with PIDs have an increased susceptibility to infectious diseases and non-infectious complications including allergies, malignancies and autoimmune diseases (ADs), the latter being the first manifestation of PIDs in several cases. There are two types of PIDS. Monogenic immunodeficiencies due to mutations in genes involved in immunological tolerance that increase the predisposition to develop autoimmunity including polyautoimmunity, and polygenic immunodeficiencies characterized by a heterogeneous clinical presentation that can be explained by a complex pathophysiology and which may have a multifactorial etiology. The high prevalence of ADs in PIDs demonstrates the intricate relationships between the mechanisms of these two conditions. Defects in central and peripheral tolerance, including mutations in AIRE and T regulatory cells respectively, are thought to be crucial in the development of ADs in these patients. In fact, pathology that leads to PID often also impacts the Treg/Th17 balance that may ease the appearance of a proinflammatory environment, increasing the odds for the development of autoimmunity. Furthermore, the influence of chronic and recurrent infections through molecular mimicry, bystander activation and super antigens activation are supposed to be pivotal for the development of autoimmunity. These multiple mechanisms are associated with diverse clinical subphenotypes that hinders an accurate diagnosis in clinical settings, and in some cases, may delay the selection of suitable pharmacological therapies. Herein, a comprehensively appraisal of the common mechanisms among these conditions, together with clinical pearls for treatment and diagnosis is presented.

PMID: 30795880 [PubMed – as supplied by publisher]

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Lung disease in STAT3-Hyper-IgE-Syndrome requires intense therapy.

Allergy. 2019 Feb 21;:

Authors: Kröner C, Neumann J, Ley-Zaporozhan J, Hagl B, Meixner I, Spielberger BD, Dückers G, Belohradsky BH, Niehues T, Borte M, Rosenecker J, Kappler M, Nährig S, Reu S, Griese M, Renner ED

Abstract
BACKGROUND: Pulmonary complications are responsible for high morbidity and mortality rates in patients with the rare immunodeficiency disorder STAT3 hyper-IgE syndrome (STAT3-HIES). The aim of this study was to expand knowledge about lung disease in STAT3-HIES.
METHODS: The course of pulmonary disease, radiological and histopathological interrelations, therapeutic management, and the outcome of 14 STAT3-HIES patients were assessed.
RESULTS: The patients’ quality of life was compromised most by pulmonary disease. All 14 patients showed first signs of lung disease at a median onset of 1.5 years of age. Lung function revealed a mixed obstructive-restrictive impairment with reduced FEV1 and FVC in 75% of the patients. The severity of lung function impairment was associated with Aspergillus fumigatus infection and prior lung surgery. Severe lung tissue damage, with reduced numbers of ABCA3 positive type II pneumocytes, was observed in the histological assessment of two deceased patients. Imaging studies of all patients above 6 years of age showed severe airway and parenchyma destruction. Lung surgeries frequently led to complications, including fistula formation. Long-term antifungal and antibacterial treatment proved to be beneficial, as were inhalation therapy, chest physiotherapy, and exercise. Regular immunoglobulin replacement therapy tended to stabilize lung function.
CONCLUSIONS: Due to its severity, pulmonary disease in STAT3-HIES patients requires strict monitoring and intensive therapy. This article is protected by copyright. All rights reserved.

PMID: 30793327 [PubMed – as supplied by publisher]

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Diminished Ovarian Reserve Chemotherapy-Induced Mouse Model: A Tool for the Preclinical Assessment of New Therapies for Ovarian Damage.

Reprod Sci. 2019 Feb 21;:1933719119831784

Authors: Buigues A, Marchante M, Herraiz S, Pellicer A

Abstract
Diminished ovarian reserve (DOR) and primary ovarian insufficiency (POI) are primary factors leading to infertility. However, there is a lack of appropriate animal models of DOR usable for assessing new therapeutic strategies. In this study, we aimed to evaluate whether chemotherapy treatment in mice could reproduce features similar of that observed in women with DOR. Twenty-one Nonobese diabetic/severe combined immunodeficiency (NOD/SCID) female mice were allocated to 3 groups (n = 7/group): control, single dose of vehicle (Dimethyl Sulfoxide [DMSO]); DOR, single reduced chemotherapy dose; and POI, single standard chemotherapy dose. After 21 days, mice underwent ovarian hyperstimulation and mating. Part of the animals were harvested to analyze ovarian reserve, ovulation and fertilization rates, and morphology, apoptosis, and vascularization of the ovarian stroma. The remaining mice underwent multiple matings to assess pregnancy rates and litter sizes. The DOR and POI mice showed an impaired estrous cyclicity and a decrease in ovarian mass, number of follicles, Metaphase II (MII) oocytes, and embryos as well as in ovarian stroma vascularization. Mice in both models showed also an increase in the percentage of morphologically abnormal follicles, stromal degeneration, and apoptosis. Similar to that observed in DOR and POI patients, these impairments were less severe in DOR than in POI mice. None of the POI females were able to achieve a pregnancy. Meanwhile, DOR females achieved several consecutive pregnancies, although litter size was decreased when compared to controls. In conclusion, a mouse model which displayed most of the ovarian characteristics and fertility outcomes of women with DOR has been established using a single dose of chemotherapy.

PMID: 30791852 [PubMed – as supplied by publisher]

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Antibodies as biomarker candidates for response and survival to checkpoint inhibitors in melanoma patients.

J Immunother Cancer. 2019 Feb 20;7(1):50

Authors: Fässler M, Diem S, Mangana J, Hasan Ali O, Berner F, Bomze D, Ring S, Niederer R, Del Carmen Gil Cruz C, Pérez Shibayama CI, Krolik M, Siano M, Joerger M, Recher M, Risch L, Güsewell S, Risch M, Speiser DE, Ludewig B, Levesque MP, Dummer R, Flatz L

Abstract
BACKGROUND: Long-term survival of stage IV melanoma patients has improved significantly with the development of immune checkpoint inhibitors (CIs). Reliable biomarkers to predict response and clinical outcome are needed.
METHODS: We investigated the role of melanoma-associated antibodies as predictive markers for CI therapy in two independent cohorts. In cohort 1, a prospective study, we measured specific antibodies before treatment, after one week and after six to nine weeks of treatment. Cohort 2 consisted of serum samples prior to CI therapy initiation. ELISA assays were performed to quantify specific IgG directed against melanocyte differentiation antigens tyrosinase-related proteins 1 and 2 (TRP1/TYRP1 and TRP2/TYRP2), glycoprotein 100 (gp100), MelanA/MART1, and the cancer-testis antigen NY-ESO-1. Response was defined as either complete or partial remission on CT scan according to RECIST 1.1.
RESULTS: In cohort 1, baseline levels of these antibodies were higher in the responder group, although statistical significance was only reached for NY-ESO-1 (p = 0.007). In cohort 2, significantly higher antibody baseline levels for MelanA/MART1 (p = 0.003) and gp100 (p = 0.029) were found. After pooling the results from both cohorts, higher levels of MelanA/MART1 (p = 0.013), TRP1/TYRP1 (p = 0.048), TRP2/TYRP2 (p = 0.047) and NY-ESO-1 (p = 0.005) specific antibodies at baseline were independently associated with response.
CONCLUSIONS: Melanoma-associated antibodies may be candidate biomarkers for response and survival in metastatic melanoma patients being treated with CIs. These markers may be used to complement patient assessment, in combination with PD-L1 status, tumor-infiltrating lymphocytes and tumor mutational burden, with the aim to predict outcome of CI treatment in patients with metastatic melanoma.
TRIAL REGISTRATION: Ethikkommission Ostschweiz, EKOS 16/079 https://ongoingprojects.swissethics.ch/runningProjects_list.php?q=%28BASECID~contains~2016-00998%29&orderby=dBASECID .

PMID: 30786924 [PubMed – in process]

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Human inborn errors of the actin cytoskeleton affecting immunity: way beyond WAS and WIP.

Immunol Cell Biol. 2019 Feb 18;:

Authors: Tangye SG, Bucciol G, de Las Casas JM, Pillay B, Ma CS, Moens L, Meyts I

Abstract
Inherited defects in genes encoding for proteins that are involved in the assembly and dynamics of the actin skeleton have increasingly been identified in patients presenting with primary immunodeficiencies. In this review, we summarize a subset of the recently described conditions, emphasizing the clinical features as well as the immunophenotype and pathophysiology. This article is protected by copyright. All rights reserved.

PMID: 30779216 [PubMed – as supplied by publisher]

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Clinical, Immunological, and Molecular Findings in 57 Patients With Severe Combined Immunodeficiency (SCID) From India.

Front Immunol. 2019;10:23

Authors: Aluri J, Desai M, Gupta M, Dalvi A, Terance A, Rosenzweig SD, Stoddard JL, Niemela JE, Tamankar V, Mhatre S, Bargir U, Kulkarni M, Shah N, Aggarwal A, Lashkari HP, Krishna V, Govindaraj G, Kalra M, Madkaikar M

Abstract
Severe combined immunodeficiency (SCID) represents one of the most severe forms of primary immunodeficiency (PID) disorders characterized by impaired cellular and humoral immune responses. Here, we report the clinical, immunological, and molecular findings in 57 patients diagnosed with SCID from India. Majority of our patients (89%) presented within 6 months of age. The most common clinical manifestations observed were recurrent pneumonia (66%), failure to thrive (60%), chronic diarrhea (35%), gastrointestinal infection (21%), and oral candidiasis (21%). Hematopoietic Stem Cell Transplantation (HSCT) is the only curative therapy available for treating these patients. Four patients underwent HSCT in our cohort but had a poor survival outcome. Lymphopenia (absolute lymphocyte counts/μL <2,500) was noted in 63% of the patients. Based on immunophenotypic pattern, majority of the cases were T-B- SCID (39%) followed by T-B+ SCID (28%). MHC class II deficiency accounted for 10.5% of our patient group. A total of 49 patients were molecularly characterized in this study and 32 novel variants were identified in our cohort. The spectrum of genetic defects in our cohort revealed a wide genetic heterogeneity with the major genetic cause being RAG1/2 gene defect (n = 12) followed by IL2RG (n = 9) and JAK3 defects (n = 9). Rare forms of SCID like Purine nucleoside phosphorylase (PNP) deficiency, reticular dysgenesis, DNA-Protein Kinase (DNA-PKcs) deficiency, six cases of MHC class II deficiency and two ZAP70 deficiency were also identified in our cohort. Fourteen percent of the defects still remained uncharacterized despite the application of next generation sequencing. With the exception of MHC class II deficiency and ZAP70 deficiency, all SCID patients had extremely low T cell receptor excision (TRECs) (<18 copies/μL).

PMID: 30778343 [PubMed – in process]

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