Manish Butte

B-cell activation with CD40L or CpG measures the function of B-cell subsets and identifies specific defects in immunodeficient patients.

Eur J Immunol. 2016 Nov 1;:

Authors: Marasco E, Farroni C, Cascioli S, Marcellini V, Scarsella M, Giorda E, Mortari EP, Leonardi L, Scarselli A, Valentini D, Cancrini C, Duse M, Grimsholm O, Carsetti R

Abstract
Around 65% of primary immunodeficiencies are antibody deficiencies. Functional tests are useful tools to study B-cell functions in vitro. However, no accepted guidelines for performing and evaluating functional tests have been issued yet. Here, we report our experience on the study of B-cell functions in infancy and throughout childhood. We show that T-independent stimulation with CpG measures proliferation and differentiation potential of memory B cells. Switched memory B cells respond better than IgM memory B cells. On the other hand, CD40L, a T-dependent stimulus, does not induce plasma cell differentiation, but causes proliferation of naïve and memory B cells. During childhood, the production of plasmablasts in response to CpG increases with age mirroring the development of memory B cells. The response to CD40L does not change with age. In patients with selective IgA deficiency (SIgAD), we observed that switched memory B cells are reduced due to the absence of IgA memory B cells. In agreement, IgA plasma cells are not generated in response to CpG. Unexpectedly, B cells from SIgAD patients show a reduced proliferative response to CD40L. Our results demonstrate that functional tests are an important tool to assess the functions of the humoral immune system. This article is protected by copyright. All rights reserved.

PMID: 27800605 [PubMed – as supplied by publisher]

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Evaluation of ColdZyme® Mouth Spray on prevention of upper respiratory tract infections in a boy with primary immunodeficiency: a case report.

J Med Case Rep. 2016 Oct 31;10(1):302

Authors: Clarsund M, Blom U, Gardulf A

Abstract
BACKGROUND: Primary immunodeficiencies include a variety of disorders that render patients more susceptible to infections. If left untreated, these infections may be fatal. Patients with primary antibody deficiencies are therefore given prophylactic immunoglobulin G replacement therapy. ColdZyme® Mouth Spray is a medical device intended to reduce the probability of catching a cold and/or can help shorten the duration of a cold, if used at an early stage of the infection, by forming a thin protective barrier on the pharyngeal mucous membrane. This is the first report of this kind in the literature.
CASE PRESENTATION: The parents of a 12-year-old white boy diagnosed as having common variable immunodeficiency voluntarily started to let their son use ColdZyme® Mouth Spray to reduce common cold infections if possible. Prior to using ColdZyme® Mouth Spray, he had recurrent microbial infections of his ears, sinuses, nose, bronchi, and lungs. He also frequently exhibited continuous rhinorrhea, fungal growth in his oral cavity, and gingivitis with wounds in his gums. As a consequence, his and his family’s health-related quality of life was severely compromised. He commenced a twice-daily treatment (morning and evening) with ColdZyme® Mouth Spray; the weekly administration of immunoglobulin G (Hizentra®) for replacement therapy was continued throughout this period. Data were retrieved by using a daily diary about infections and symptoms. His guardians had recorded infection symptoms since he was diagnosed as having common variable immunodeficiency 10 years earlier to follow the effect of the immunoglobulin G treatment. Shortly after commencement of ColdZyme® Mouth Spray treatment, he experienced a marked improvement in symptoms and health-related quality of life. His continuous rhinorrhea disappeared, breathing through his nose was easier, oral fungal infection decreased, and wounds in his gum tissue healed for the first time in several years.
CONCLUSIONS: We observed that when ColdZyme® Mouth Spray was used to reduce common cold viral infection in a patient with common variable immunodeficiency on immunoglobulin G replacement therapy, secondary microbial and fungal infections in his oral cavity and oropharynx were also reduced. A controlled study is warranted to confirm the observed results.

PMID: 27799071 [PubMed – in process]

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Latin American Challenges with the Diagnosis and Treatment of Primary Immunodeficiency Diseases.

Expert Rev Clin Immunol. 2016 Oct 31;

Authors: Costa-Carvalho B, González-Serrano M, Espinosa-Padilla S, Segundo G

Abstract
INTRODUCTION: Diagnosis of primary immunodeficiency diseases (PID) is still a challenge in many countries in Latin America (LA), especially those that face social and economic problems. The creation of a society was fundamental to combine efforts that resulted in an effective educational program, establishment of a registry and a network to improve diagnosis. Areas covered: The focus of this article is to portray the scenario of PID in LA covering different aspects from different countries. For this, a questionnaire was sent to countries that participate in the Latin American Society for Immunodeficiencies (LASID) registry, with questions related to PID challenges in LA. We realized that today the greatest challenge is the availability of laboratory tests to investigate newly described PIDs. Expert commentary: Despite being faced with many difficulties, the Latin America Society for Immunodeficiencies is supporting clinical immunologists throughout the continent, which has resulted in a greater awareness of these diseases and an increase in the number of diagnosis.

PMID: 27797286 [PubMed – as supplied by publisher]

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Skin Necrosis Following Subcutaneous Immunoglobulin (SCIg).

J Clin Immunol. 2016 Oct 28;

Authors: Carne E, Ponsford M, El-Shanawany T, Jolles S

PMID: 27796699 [PubMed – as supplied by publisher]

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Primary immunodeficiency disease and hematology.

Rinsho Ketsueki. 2016;57(10):2275-2284

Authors: Kanegane H

Abstract
Primary immunodeficiency disease (PID) is an inborn error of the immune system, and is characterized by not only susceptibility to infection but also frequent combination with autoimmune diseases and malignancies. PID is principally caused by a germline mutation, and some PID patients develop hematological abnormalities. In some patients, PID is associated with hemophagocytosis-induced cytopenia, neutropenia, thrombocytopenia, and autoimmune cytopenia. In addition, a subset of PID patients presented with myeloid dysplasia. In contrast, hematological and malignant diseases are mainly associated with somatic mutations. However, recent advances in genetic analysis revealed that defects of the same gene might cause PID and hematological disease. Therefore, PID and hematological diseases are not exclusive but rather complementary, and clinicians should remain open to investigating these diseases.

PMID: 27795540 [PubMed – in process]

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[Hyper-IgE syndrome. Lessons from function and defects of STAT-3 or DOCK-8].

Rev Alerg Mex. 2016 Oct-Dec;63(4):385-396

Authors: Alcántara-Montiel JC, Vega-Torres BI

Abstract
In the classification of primary immunodeficiencies, hyper-IgE syndrome, identified with OMIM code # 147060 in the Online Mendelian Inheritance in Man catalog, belongs to the group of syndromes associated with combined immunodeficiencies. It is characterized by elevated levels of IgE, eosinophilia, recurrent skin abscesses, pneumonia, lung parenchyma lesions, recurrent infections, rashes in newborns, eczema, sinusitis, otitis, and mucocutaneous candidiasis. Hyper-IgE syndrome can be transmitted by autosomal dominant or autosomal recessive modes of inheritance. Hyper-IgE syndrome in its dominant form includes non-immunological manifestations like characteristic facies, pathological dentition, scoliosis, bone disorders, and joint hyperextensibility. The reported cause of the dominant form is the loss of function of the signal transducer and activator of transcription 3 (STAT-3, with MIM # 102582). Mutations in dedicator of cytokines 8 (DOCK-8) is the most common cause of the autosomal recessive form of hyper-IgE syndrome.

PMID: 27795219 [PubMed – in process]

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[Clinic of humoral primary immunodeficiencies in adults. Experience in a tertiary hospital].

Rev Alerg Mex. 2016 Oct-Dec;63(4):334-341

Authors: Cambray-Gutiérrez JC, Herrera-Sánchez DA, Blancas-Galicia L, O’Farrill-Romanillos PM

Abstract
BACKGROUND: Primary immunodeficiencies (PID) are characterized by alteration of the components of the immune system. Humoral deficiencies represent 50%. The most common are selective IgA deficiency, Bruton agammaglobulinemia, and common variable immunodeficiency (CVID).
OBJECTIVE: To describe the epidemiological and clinical characteristics of adults with humoral PID, cared for in a Primary Humoral Immunodeficiencies Clinic.
METHODS: A descriptive cross-sectional study that included a year of analysis, including 35 patients with humoral PID, 31 with CVID, and 4 with Bruton agammaglobulinemia. Data were analyzed with descriptive statistics.
RESULTS: Of 35 patients studied, 31 had CVID (88.5%) and 4 (11.5%) Bruton agammaglobulinemia; 21 were men and 14 women. The age at onset of symptoms was 22.7 years, and the delay in diagnosis was 7.2 years. 11.4% of CVID patients died during the study; 4 had malignancies, 22.8% autoimmune diseases, and 48.5% gastrointestinal disorders. Patients with Bruton agammaglobulinemia presented no comorbidities.
CONCLUSIONS: Unlike reports in the literature, in the study group, CVID was the most common cause of humoral PID, predominantly in men; the most common gastrointestinal disorder was intestinal functional disorder.

PMID: 27795213 [PubMed – in process]

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Novel AICDA mutation in a case of autosomal recessive hyper-IgM syndrome, growth hormone deficiency and autoimmunity.

Allergol Immunopathol (Madr). 2016 Oct 24;:

Authors: Fazel A, Kashef S, Aleyasin S, Harsini S, Karamizadeh Z, Zoghi S, Flores SK, Boztug K, Rezaei N

Abstract
BACKGROUND: The Hyper-immunoglobulin M syndromes (HIGM) are a heterogeneous group of genetic disorders, which have been rarely reported to be associated with growth hormone deficiency (GHD).
METHODS AND RESULTS: A nine-year-old girl with recurrent urinary tract infections, diarrhoea, sinopulmonary infections, and failure to thrive since the age of six months had normal CD3+, CD4+, CD8+T lymphocytes, and CD19+B lymphocytes and natural killer (NK) cells, but extremely elevated IgM and significantly decreased IgG and IgA. In view of the patient’s short stature, growth hormone evaluation was carried out and growth hormone deficiency established. The patient underwent Ig replacement therapy and received growth hormone therapy in addition to antibiotics and responded well. Furthermore, the patient developed benign cervical lymphadenopathy, as well as elevated erythrocyte sedimentation rate, positive autoantibodies to SSA-Ro, and severely dry eyes, which partially responded to both the punctate occlusion and systemic corticosteroids, at the age of seven years. Sequencing analysis of the exons from activation-induced cytidine deaminase (AICDA) gene revealed that the patient was homozygous for a single T to C transversion at position 455 in exon 4, which replaces a Valine with an Alanine.
CONCLUSIONS: To our knowledge, this is a new AICDA mutation, which has not been reported previously in HIGM. The mutation analysis could improve diagnosis of HIGM patients and also elaborating on the spectrum of AICDA mutations.

PMID: 27789066 [PubMed – as supplied by publisher]

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Mammographically dense human breast tissue stimulates MCF10DCIS.com progression to invasive lesions and metastasis.

Breast Cancer Res. 2016 Oct 25;18(1):106

Authors: Huo CW, Waltham M, Khoo C, Fox SB, Hill P, Chen S, Chew GL, Price JT, Nguyen CH, Williams ED, Henderson M, Thompson EW, Britt KL

Abstract
BACKGROUND: High mammographic density (HMD) not only confers a significantly increased risk of breast cancer (BC) but also is associated with BCs of more advanced stages. However, it is unclear whether BC progression and metastasis are stimulated by HMD. We investigated whether patient-derived HMD breast tissue could stimulate the progression of MCF10DCIS.com cells compared with patient-matched low mammographic density (LMD) tissue.
METHODS: Sterile breast specimens were obtained immediately after prophylactic mastectomy from high-risk women (n = 10). HMD and LMD regions of each specimen were resected under radiological guidance. Human MCF10DCIS.com cells, a model of ductal carcinoma in situ (DCIS), were implanted into silicone biochambers in the groins of severe combined immunodeficiency mice, either alone or with matched LMD or HMD tissue (1:1), and maintained for 6 weeks. We assessed biochamber weight as a measure of primary tumour growth, histological grade of the biochamber material, circulating tumour cells and metastatic burden by luciferase and histology. All statistical tests were two-sided.
RESULTS: HMD breast tissue led to increased primary tumour take, increased biochamber weight and increased proportions of high-grade DCIS and grade 3 invasive BCs compared with LMD. This correlated with an increased metastatic burden in the mice co-implanted with HMD tissue.
CONCLUSIONS: Our study is the first to explore the direct effect of HMD and LMD human breast tissue on the progression and dissemination of BC cells in vivo. The results suggest that HMD status should be a consideration in decision-making for management of patients with DCIS lesions.

PMID: 27776557 [PubMed – in process]

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Duration of antibody response following vaccination against feline immunodeficiency virus.

J Feline Med Surg. 2016 Oct 21;:

Authors: Westman ME, Malik R, Hall E, Harris M, Hosie MJ, Norris JM

Abstract
OBJECTIVES: Recently, two point-of-care (PoC) feline immunodeficiency virus (FIV) antibody test kits (Witness and Anigen Rapid) were reported as being able to differentiate FIV-vaccinated from FIV-infected cats at a single time point, irrespective of the gap between testing and last vaccination (0-7 years). The aim of the current study was to investigate systematically anti-FIV antibody production over time in response to the recommended primary FIV vaccination series.
METHODS: First, residual plasma from the original study was tested using a laboratory-based ELISA to determine whether negative results with PoC testing were due to reduced as opposed to absent antibodies to gp40. Second, a prospective study was performed using immunologically naive client-owned kittens and cats given a primary FIV vaccination series using a commercially available inactivated whole cell/inactivated whole virus vaccine (Fel-O-Vax FIV, three subcutaneous injections at 4 week intervals) and tested systematically (up to 11 times) over 6 months, using four commercially available PoC FIV antibody kits (SNAP FIV/FeLV Combo [detects antibodies to p15/p24], Witness FeLV/FIV [gp40], Anigen Rapid FIV/FeLV [p24/gp40] and VetScan FeLV/FIV Rapid [p24]).
RESULTS: The laboratory-based ELISA showed cats from the original study vaccinated within the previous 0-15 months had detectable levels of antibodies to gp40, despite testing negative with two kits that use gp40 as a capture antigen (Witness and Anigen Rapid kits). The prospective study showed that antibody testing with SNAP Combo and VetScan Rapid was positive in all cats 2 weeks after the second primary FIV vaccination, and remained positive for the duration of the study (12/12 and 10/12 cats positive, respectively). Antibody testing with Witness and Anigen Rapid was also positive in a high proportion of cats 2 weeks after the second primary FIV vaccination (8/12 and 7/12, respectively), but antibody levels declined below the level of detection in most cats (10/12) by 1 month after the third (final) primary FIV vaccination. All cats tested negative using Witness and Anigen Rapid 6 months after the third primary FIV vaccination.
CONCLUSIONS AND RELEVANCE: This study has shown that a primary course of FIV vaccination does not interfere with FIV antibody testing in cats using Witness and Anigen Rapid, provided primary vaccination has not occurred within the previous 6 months. Consequently, Witness and Anigen Rapid antibody test kits can be used reliably to determine FIV infection status at the time of annual booster FIV vaccination to help detect ‘vaccine breakthroughs’ and in cats that have not received a primary course of FIV vaccination within the preceding 6 months. The duration of antibody response following annual booster FIV vaccination and the resulting effect on antibody testing using PoC kits needs to be determined by further research. The mechanism(s) for the variation in FIV antibody test kit performance remains unclear.

PMID: 27770018 [PubMed – as supplied by publisher]

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