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[Is familial screening useful in selective immunoglobulin A deficiency?]

June 3, 2015 By Manish Butte

[Is familial screening useful in selective immunoglobulin A deficiency?]

An Pediatr (Barc). 2015 May 29;

Authors: Soler-Palacín P, Cobos-Carrascosa E, Martín-Nalda A, Caracseghi F, Hernández M, Figueras-Nadal C

Abstract
INTRODUCTION: Selective immunoglobulin A deficiency (SIgAD), the most common primary immunodeficiency, is often asymptomatic. High rates of familial clustering have been described in SIgAD, but the causative genetic defect and mechanism of inheritance are unknown.
OBJECTIVES: To determine whether familial SIgAD cases show more severe clinical and immunological characteristics than sporadic ones; to investigate the utility of screening first-degree relatives (FDRs) of these patients, and to determine whether symptoms in affected family members are important enough to justify screening.
PATIENTS AND METHODS: Descriptive, cross-sectional study (October 2010-September 2011) of all patients with SIgAD and followed up in our center. Demographic, clinical, and analytical data were reviewed. A familial case was defined as an SIgAD patient with at least one affected FDR.
RESULTS: Of the 130 participants, 42 were SIgAD patients and 88 FDR. There were 13 (31%) familial cases and and 14 (16%) affected FDRs. Six family members had to be analyzed in order to detect one affected one. There were no clinical differences between familial and sporadic SIgAD cases. The percentages of intestinal disease (p=001, OR=9.57, 95%CI 2.59-35.3), hospitalizations (p=045, OR=4.01; 95%CI 1.10-14.67], and need for chronic treatment (p=006, OR=5.5; 95%CI 1.57-19.54) were higher in affected FDRs than in unaffected ones.
CONCLUSIONS: The symptoms were not more severe in familial than sporadic SIgAD cases. Nonetheless, the elevated prevalence of affected FDRs with significant morbidity may justify routine screening of close family members of these patients.

PMID: 26033741 [PubMed – as supplied by publisher]

The Swiss National Registry for Primary Immunodeficiencies: Report on the first 6 years' activity 2008-2014.

June 3, 2015 By Manish Butte

The Swiss National Registry for Primary Immunodeficiencies: Report on the first 6 years’ activity 2008-2014.

Clin Exp Immunol. 2015 Jun 1;

Authors: Marschall K, Hoernes M, Bitzenhofer-Grüber M, Jandus P, Duppenthaler A, Wuillemin WA, Rischewski J, Boyman O, Heininger U, Hauser T, Steiner U, Posfay-Barbe K, Seebach J, Recher M, Hess C, Helbling A, Reichenbach J, Swiss PID Registry Working Group

Abstract
The Swiss National Registry for Primary Immunodeficiency Disorders (PID) was established in 2008, constituting a nationwide network of paediatric and adult departments involved in the care for patients with PID at university medical centres, affiliated teaching hospitals and medical institutions. The registry collects anonymised clinical and genetic information on PID patients and is set up within the framework of the European database for PID, run by the European Society of Immunodeficiency Diseases. To date, a total of n=348 patients are registered in Switzerland indicating an estimated minimal prevalence of 4.2 patients per 100,000 inhabitants. Distribution of different PID categories, age and gender are similar to the European cohort of currently 19,091 registered patients: “Predominantly Antibody Disorders” are the most common diseases observed (n=217/348, 62%), followed by “Phagocytic Disorders” (n=31/348, 9%). As expected “Predominantly Antibody Disorders” are more prevalent in adults than in children (78% vs. 31%). Within this category “Common Variable Immunodeficiency Disorder” (CVID) is the most prevalent PID (n=98/217, 45%), followed by “Other Hypogammaglobulinemias” (i.e. a group of non-classified Hypogammaglobulinemias) (n=54/217, 25%). Amongst “Phagocytic Disorders”, “Chronic Granulomatous Disease” is the most prevalent PID (n=27/31, 87%). The diagnostic delay between onset of symptoms and diagnosis is high with a median of 6 years for CVID and more than 3 years for “Other Hypogammaglobulinemias”. This article is protected by copyright. All rights reserved.

PMID: 26031847 [PubMed – as supplied by publisher]

Immunoglobulins and their use in children.

June 3, 2015 By Manish Butte

Immunoglobulins and their use in children.

Adv Clin Exp Med. 2015 Jan-Feb;24(1):153-9

Authors: Łaguna P, Gołębiowska-Staroszczyk S, Trzaska M, Grabarczyk M, Matysiak M

Abstract
Immunoglobulin preparations are one of the products of the human plasma fractionation, where the plasma is obtained, in accordance with WHO guidelines from at least 1,000 donors. These preparations contain all IgG subclasses with various antigen characteristics. In clinical practice these drugs are used as replacement therapy in patients with primary and secondary immunodeficiencies as well as immunomodulatory therapy in many autoimmune diseases and systemic inflammatory diseases. Here we present characteristics of i.v. polyvalent, human immunoglobulin preparations available on the Polish market and the possibilities of their use in clinical practice, in children with hematological diseases. Considering the very low consumption of immunoglobulin preparations in our country as compared to other European countries, we would like to draw the attention of medical professionals, especially pediatricians and haematologists, to the benefits that stem from the use of these drugs in the therapy of children with haematological diseases. Our work will also facilitate the choice of an optimal polyvalent human immunoglobulin preparation for a particular patient.

PMID: 25923100 [PubMed – indexed for MEDLINE]

The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis.

May 30, 2015 By Manish Butte

The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis.

Haematologica. 2015 May 28;

Authors: Bode SF, Ammann S, Al-Herz W, Bataneant M, Dvorak CC, Gehring S, Gennery A, Gilmour KC, Gonzalez-Granado LI, GroB-Wieltsch U, Ifversen M, Lingman-Framme J, Matthes-Martin S, Mesters R, Meyts I, van Montfrans JM, Pachlopnik Schmid J, Pai SY, Soler-Palacin P, Schuermann U, Schuster V, Seidel MG, Speckmann C, Stepensky P, Sykora KW, Tesi B, Vraetz T, Waruiru C, Bryceson YT, Moshous D, Lehmberg K, Jordan MB, Ehl S

Abstract
Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. This includes patients with primary immunodeficiencies, in whom pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistiocytosis. Twelve patients had severe combined immunodeficiency with <100/ml T-cells, 18 had partial T-cell deficiencies; episodes of hemophagocytic lymphohistiocytosis were mostly associated with viral infections. Twenty-two patients had chronic granulomatous disease with hemophagocytic episodes mainly associated with bacterial infections. Compared to patients with cytotoxicity defects, patients with T-cell deficiencies had lower soluble CD25 and higher ferritin. Other criteria for hemophagocytoc lymphohistiocytosis were not discriminative. Thus, (i) a hemophagocytic inflammatory syndrome fulfilling criteria for hemophagocytic lymphohistiocytosis can be the initial manifestation of primary immunodeficiencies. (ii) this syndrome can develop despite severe deficiency of T- and NK-cells, implicating that pathophysiology is distinct and not appropriately described as Lympho-Histiocytosis in these patients (iii) current criteria for hemophagocytoc lymphohistiocytosis are insufficient to differentiate hemophagocytic inflammatory syndromes with different pathogenesis. This is important because of implications for therapy, in particular for protocols targeting T-cells.

PMID: 26022711 [PubMed – as supplied by publisher]

Disseminated bronchiectasis in an adult with common variable immunodeficiency.

May 29, 2015 By Manish Butte

Disseminated bronchiectasis in an adult with common variable immunodeficiency.

Colomb Med (Cali). 2015 Jan-Mar;46(1):47-50

Authors: Zea-Vera AF, Agudelo-Rojas OL

Abstract
Primary immunodeficiencies (PID) are traditionally considered childhood diseases; however, adults account for 35% of all patients with PID. Antibody deficiencies, especially Common Variable Immunodeficiency (CVID), which have their peak incidence in adulthood, require a high suspicion index. Even though the estimated frequency of CVID is not high (1:25,000), high rates of under diagnosis and under reporting are very likely. The delay in diagnosis increases the morbidity and mortality; therefore, adult physicians should be able to suspect, identify and initiate management of individuals with PID. Here we report the case of a 37 year-old man presenting to the emergency room with dyspnea, fever and cough; he developed respiratory failure requiring mechanical ventilation. He complained of recurring pneumonia associated with widespread bronchiectasis since he was 18 years old. Serum immunoglobulins quantification showed severe hypogammaglobulinemia (total IgG <140 mg/dL; total IgA, 2.9 mg/dL; and total IgM <5 mg/dL). Treatment with Human Intravenous Immunoglobulin (IVIG) 10% was started, and with antibiotic treatment for severe pneumonia (during 14 days) was also prescribed. His clinical evolution has been favorable after one year follow-up. Common Variable Immunodeficiency (CVID) diagnosis was made.

PMID: 26019385 [PubMed – in process]

A Novel In-Frame Deletion in the Leucine Zipper Domain of C/EBPε Leads to Neutrophil-Specific Granule Deficiency.

May 29, 2015 By Manish Butte

A Novel In-Frame Deletion in the Leucine Zipper Domain of C/EBPε Leads to Neutrophil-Specific Granule Deficiency.

J Immunol. 2015 May 27;

Authors: Wada T, Akagi T, Muraoka M, Toma T, Kaji K, Agematsu K, Koeffler HP, Yokota T, Yachie A

Abstract
Neutrophil-specific granule deficiency (SGD) is a rare autosomal recessive primary immunodeficiency characterized by neutrophil dysfunction, bilobed neutrophil nuclei and lack of neutrophil-specific granules. Defects in a myeloid-specific transcription factor, CCAAT/enhancer binding protein-ε (C/EBPε), have been identified in two cases in which homozygous frameshift mutations led to loss of the leucine zipper domain. In this study, we report a 55-y-old woman affected with SGD caused by a novel homozygous 2-aa deletion (ΔRS) in the leucine zipper domain of the C/EBPε gene. The patient showed characteristic neutrophil abnormalities and recurrent skin infections; however, there was no history of deep organ infections. Biochemical analysis revealed that, in contrast to the two frameshift mutations, the ΔRS mutant maintained normal cellular localization, DNA-binding activity, and dimerization, and all three mutants exhibited marked reduction in transcriptional activity. The ΔRS mutant was defective in its association with Gata1 and PU.1, as well as aberrant cooperative transcriptional activation of eosinophil major basic protein. Thus, the ΔRS likely impairs protein-protein interaction with other transcription factors, resulting in a loss of transcriptional activation. These results further support the importance of the leucine zipper domain of C/EBPε for its essential function, and indicate that multiple molecular mechanisms lead to SGD.

PMID: 26019275 [PubMed – as supplied by publisher]

Comparing Genomic Profiles of Women With and Without Fibromyalgia.

May 28, 2015 By Manish Butte

Comparing Genomic Profiles of Women With and Without Fibromyalgia.

Biol Res Nurs. 2015 May 26;

Authors: Lukkahatai N, Walitt B, Espina A, Wang D, Saligan LN

Abstract
BACKGROUND: Fibromyalgia syndrome (FMS), a chronic musculoskeletal condition characterized by diffuse pain, fatigue, sleep impairment, and cognitive dysfunction, is associated with significant functional disability. Its underlying biological mechanisms are unknown. This study investigated differentially expressed genes between women with FMS and healthy volunteers.
METHODS: Women who met the 1990 or 2010 American College of Rheumatology fibromyalgia criteria were compared to age- and race-matched pain-free healthy women. Peripheral blood samples were collected, and a full genome microarray gene expression analysis was performed. One-way analysis of variance was used to identify differentially expressed genes using the filtering criterion of 1% false discovery rate. Analysis of canonical pathways associated with these genes was performed. Confirmatory quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay verified microarray results. Independent t-tests compared gene and protein expression between groups.
RESULT: Participants were 54 women with FMS and 25 controls. Expression arrays from a subset of women with FMS (n = 29) and controls (n = 20) showed upregulation of 12 genes (>1.8-fold change, p < .05) in the FMS sample. Differentially expressed genes were related to B-cell development, primary immunodeficiency signaling, and mitotic roles of polo-like kinase. CENPK and HSP90AA1 were the most differentially expressed genes (p < .01).
CONCLUSION: Activity of interrelated pathways related to immune response, and homeostasis appears to be relevant to the experience of FMS. Replication and exploration of the relationship between gene expression and symptom severity will help determine clinical relevance of these findings.

PMID: 26015072 [PubMed – as supplied by publisher]

An unusual case of neonatal stridor.

May 27, 2015 By Manish Butte

An unusual case of neonatal stridor.

J Coll Physicians Surg Pak. 2015 May;25(5):376-7

Authors: Nirupam N, Maheshwari A, Ram Kumar TV, Aneja S

Abstract
A25-day baby neonate presented with fever and stridor. He had severe respiratory distress at admission. The systemic examination was unremarkable. The roentgenogram of soft tissues of neck revealed widening of superior mediastinum. Computed tomography of neck and upper chest revealed multiple abscesses in the retropharyngeal space, parapharyngeal space, and superior mediastinum. The child improved on aggressive antibiotic treatment protocol. It raises awareness among paediatricians to consider this diagnosis when confronting neonate with fever and stridor. An early diagnosis and aggressive appropriate management will reduce mortality and morbidity associated with this life-threatening condition. Athorough search for a primary source of infection should be done. Neonate should be screened for primary and secondary immunodeficiency disorders before discharge.

PMID: 26008668 [PubMed – in process]

Rescue of DNA-PK Signaling and T-Cell Differentiation by Targeted Genome Editing in a prkdc Deficient iPSC Disease Model.

May 23, 2015 By Manish Butte

Rescue of DNA-PK Signaling and T-Cell Differentiation by Targeted Genome Editing in a prkdc Deficient iPSC Disease Model.

PLoS Genet. 2015 May;11(5):e1005239

Authors: Rahman SH, Kuehle J, Reimann C, Mlambo T, Alzubi J, Maeder ML, Riedel H, Fisch P, Cantz T, Rudolph C, Mussolino C, Joung JK, Schambach A, Cathomen T

Abstract
In vitro disease modeling based on induced pluripotent stem cells (iPSCs) provides a powerful system to study cellular pathophysiology, especially in combination with targeted genome editing and protocols to differentiate iPSCs into affected cell types. In this study, we established zinc-finger nuclease-mediated genome editing in primary fibroblasts and iPSCs generated from a mouse model for radiosensitive severe combined immunodeficiency (RS-SCID), a rare disorder characterized by cellular sensitivity to radiation and the absence of lymphocytes due to impaired DNA-dependent protein kinase (DNA-PK) activity. Our results demonstrate that gene editing in RS-SCID fibroblasts rescued DNA-PK dependent signaling to overcome radiosensitivity. Furthermore, in vitro T-cell differentiation from iPSCs was employed to model the stage-specific T-cell maturation block induced by the disease causing mutation. Genetic correction of the RS-SCID iPSCs restored T-lymphocyte maturation, polyclonal V(D)J recombination of the T-cell receptor followed by successful beta-selection. In conclusion, we provide proof that iPSC-based in vitro T-cell differentiation is a valuable paradigm for SCID disease modeling, which can be utilized to investigate disorders of T-cell development and to validate gene therapy strategies for T-cell deficiencies. Moreover, this study emphasizes the significance of designer nucleases as a tool for generating isogenic disease models and their future role in producing autologous, genetically corrected transplants for various clinical applications.

PMID: 26000857 [PubMed – as supplied by publisher]

Surface Plasmon Resonance Analysis Shows an IgG-Isotype-Specific Defect in ABO Blood Group Antibody Formation in Patients with Common Variable Immunodeficiency.

May 23, 2015 By Manish Butte

Surface Plasmon Resonance Analysis Shows an IgG-Isotype-Specific Defect in ABO Blood Group Antibody Formation in Patients with Common Variable Immunodeficiency.

Front Immunol. 2015;6:211

Authors: Fischer MB, Wolfram W, Binder CJ, Böhmig GA, Wahrmann M, Eibl MM, Wolf HM

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is the most common clinically severe primary immunodeficiency and comprises a heterogeneous group of patients with recurrent severe bacterial infections due to the failure to produce IgG antibodies after exposure to infectious agents and immunization. Diagnostic recommendations for antibody failure include assessment of isoagglutinins. We have readdressed this four decades old but still accepted recommendation with up to date methodology.
METHODS: Anti-A/B IgM- and IgG-antibodies were measured by Diamed-ID Micro Typing, surface plasmon resonance (SPR) using the Biacore(®) device and flow cytometry.
RESULTS: When Diamed-ID Micro Typing was used, CVID patients (n = 34) showed IgG- and IgM-isoagglutinins that were comparable to healthy volunteers (n = 28), while all XLA patients (n = 8) had none. Anti-A/B IgM-antibodies were present in more than 2/3 of the CVID patients and showed binding kinetics comparable to anti-A/B IgM-antibodies from healthy individuals. A correlation could be found in CVID patients between levels of anti-A/B IgM-antibodies and levels of serum IgM and PnP-IgM-antibodies. In contrast in CVID patients as a group ABO antibodies were significantly decreased when assessed by SPR, which correlated with levels of switched memory, non-switched memory and naïve B cells, but all CVID patients had low/undetectable anti-A/B IgG-antibodies.
CONCLUSION: These results indicate that conventional isoagglutinin assessment and assessment of anti-A/B IgM antibodies are not suited for the diagnosis of impaired antibody production in CVID. Examination of anti-A/B IgG antibodies by SPR provides a useful method for the diagnosis of IgG antibody failure in all CVID patients studied, thus indicating an important additional rationale to start immunoglobulin replacement therapy early in these patients, before post-infectious sequelae develop.

PMID: 25999949 [PubMed]