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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]

Early-onset autoimmune disease as a manifestation of primary immunodeficiency.

May 23, 2015 By Manish Butte

Early-onset autoimmune disease as a manifestation of primary immunodeficiency.

Front Immunol. 2015;6:185

Authors: Carneiro-Sampaio M, Coutinho A

Abstract
Autoimmune disorders (AID) have been increasingly observed in association with primary immunodeficiencies (PIDs). Here, we discuss the interface between PID and AID, focusing on autoimmune manifestations early in life, which can be diagnostic clues for underlying PIDs. Inflammatory bowel disease in infants and children has been associated with IL-10 and IL-10R deficiencies, chronic granulomatous disease, immunedysregulation-polyendocrinopathy-enteropathy-X-linked syndrome (IPEX), autoinflammatory disorders, and others. Some PIDs have been identified as underlying defects in juvenile systemic lupus erythematosus: C1q-, IgA-, IgM deficiencies, alterations of the IFN-α pathway (in Aicardi-Goutières syndrome due to TREX1 mutation). IPEX (due to FOXP3 mutation leading to Treg cell deficiency), usually appearing in the first months of life, was recently observed in miscarried fetuses with hydrops who presented with CD3+ infiltrating lymphocytes in the pancreas. Hemophagocytic lymphohistiocytosis due to perforin deficiency was also identified as a cause of fetal hydrops. In conclusion, PID should be suspected in any infant with signs of autoimmunity after excluding transferred maternal effects, or in children with multiple and/or severe AID.

PMID: 25999944 [PubMed]

Autoimmunity in patients with selective IgA deficiency.

May 23, 2015 By Manish Butte

Autoimmunity in patients with selective IgA deficiency.

J Investig Allergol Clin Immunol. 2015;25(2):112-9

Authors: Abolhassani H, Gharib B, Shahinpour S, Masoom SN, Havaei A, Mirminachi B, Arandi N, Torabi-Sagvand B, Khazaei HA, Mohammadi J, Rezaei N, Aghamohammadi A

Abstract
BACKGROUND AND OBJECTIVE: Selective immunoglobulin A deficiency (SIgAD) is the most common primary antibody deticiency. Patients with SIgAD have a greater risk of concomitant autoimmune disorders than healthy individuals. The exact mechanism underlying the relationship between autoimmunity and SIgAD is not fully understood. The aim of this study was to evaluate potential associations between autoimmunity and specific clinical or immunological findings in patients with SIgAD.
METHODS: The study population comprised 57 symptomatic patients (65% males) with confirmed SIgAD who were referred to our center. Demographic data and history of autoimmunity were recorded both for patients and for their relatives. Comprehensive clinical and laboratory examinations were performed to investigate autoimmune complications in all the patients.
RESULTS: Autoimmune disorders were documented in 17 cases (29.8%; 9 males and 8 females). The most common manifestations were thyroiditis, vitiligo, and hemolytic anemia (3 cases each). Ten patients (17.5%) had a family history of autoimmunity. Significant associations were detected between autoimmunity and increased duration of follow-up (P = .003), serum level of IgM (P = .01), regulatory T-cell count (P = .03), and class-switched memory B-cell count (P = .01). Four cases of autoimmune SIgAD (23.5%) progressed to common variable immunodeficiency during the follow-up period (P = .006).
CONCLUSIONS: Autoimmune disorders, autoimmune cytopenia, and Ig subclass deficiency can lead to severe clinical manifestations in patients with SIgAD. Therefore, immunologists and pediatricians should be aware of these conditions.

PMID: 25997304 [PubMed – in process]

Primary hepatic leiomyoma: unusual cause of an intrahepatic mass.

May 21, 2015 By Manish Butte

Primary hepatic leiomyoma: unusual cause of an intrahepatic mass.

Ann Transl Med. 2015 Apr;3(5):73

Authors: Vyas S, Psica A, Watkins J, Yu D, Davidson B

Abstract
Leiomyomas are benign lesions arising from the smooth muscle layer. They are most commonly detected either within the gastrointestinal or genitourinary tracts. Primary hepatic leiomyoma (PHL) is a rare pathology. It is an isolated pathology within the liver, without evidence of any other coexisting leiomyomas. Very few cases have been described in literature. PHL may occur in healthy individuals although an association with immunodeficiency and Epstein-Barr virus (EBV) infection has been observed. Majority of the reported cases have been in females. A 20-year-old female patient presented with abdominal symptoms. MRI confirmed an 8 cm mass, with very low signal intensity on T2 images and peripheral rim enhancement on gadolinium. A laparoscopic left lateral sectorectomy was performed. Final histopathology confirmed the presence of benign lesion with spindle cell and smooth muscle proliferation and a fibro-vascular stroma compatible with a leiomyoma. There was no evidence of any leiomyomatous lesion elsewhere in the body. A rare diagnosis of PHL was therefore established. Acknowledging the rare incidence of this lesion, we report the same and review the relevant literature. PHL is usually a retrospective diagnosis, confirmed on histo-pathology assessment of the resected specimen. Liver resection is required in these patients due to the presence of symptoms, in the presence of a solid mass lesion within the liver. Surgery is thus definitive, diagnostic cum therapeutic.

PMID: 25992372 [PubMed]

Developmental trajectories in 22q11.2 deletion syndrome.

May 20, 2015 By Manish Butte

Developmental trajectories in 22q11.2 deletion syndrome.

Am J Med Genet C Semin Med Genet. 2015 May 18;

Authors: Swillen A, McDonald-McGinn D

Abstract
Chromosome 22q11.2 deletion syndrome (22q11.2DS), a neurogenetic condition, is the most common microdeletion syndrome affecting 1 in 2,000-4,000 live births and involving haploinsufficiency of ∼50 genes resulting in a multisystem disorder. Phenotypic expression is highly variable and ranges from severe life-threatening conditions to only a few associated features. Most common medical problems include: congenital heart disease, in particular conotruncal anomalies; palatal abnormalities, most frequently velopharyngeal incompetence (VPI); immunodeficiency; hypocalcemia due to hypoparathyroidism; genitourinary anomalies; severe feeding/gastrointestinal differences; and subtle dysmorphic facial features. The neurocognitive profile is also highly variable, both between individuals and during the course of development. From infancy onward, motor delays (often with hypotonia) and speech/language deficits are commonly observed. During the preschool and primary school ages, learning difficulties are very common. The majority of patients with 22q11.2DS have an intellectual level that falls in the borderline range (IQ 70-84), and about one-third have mild to moderate intellectual disability. More severe levels of intellectual disability are uncommon in children and adolescents but are more frequent in adults. Individuals with 22q11.2DS are at an increased risk for developing several psychiatric disorders including attention deficit with hyperactivity disorder (ADHD), autism spectrum disorder (ASD), anxiety and mood disorders, and psychotic disorders and schizophrenia. In this review, we will focus on the developmental phenotypic transitions regarding cognitive development in 22q11.2DS from early preschool to adulthood, and on the changing behavioral/psychiatric phenotype across age, on a background of frequently complex medical conditions. © 2015 Wiley Periodicals, Inc.

PMID: 25989227 [PubMed – as supplied by publisher]

Bone marrow transcriptome and epigenome profiles of equine common variable immunodeficiency patients unveil block of B lymphocyte differentiation.

May 20, 2015 By Manish Butte

Bone marrow transcriptome and epigenome profiles of equine common variable immunodeficiency patients unveil block of B lymphocyte differentiation.

Clin Immunol. 2015 May 16;

Authors: Tallmadge RL, Shen L, Tseng CT, Miller SC, Barry J, Felippe MJ

Abstract
Common variable immunodeficiency (CVID) is a late-onset humoral deficiency characterized by B lymphocyte dysfunction or loss, decreased immunoglobulin production, and recurrent bacterial infections. CVID is the most frequent human primary immunodeficiency but still presents challenges in the understanding of its etiology and treatment. CVID in equine patients manifests with a natural impairment of B lymphocyte differentiation, and is a unique model to identify genetic and epigenetic mechanisms of disease. Bone marrow transcriptome analyses revealed decreased expression of genes indicative of the pro-B cell differentiation stage, importantly PAX5 (p≤0.023). We hypothesized that aberrant epigenetic regulation caused PAX5 gene silencing, resulting in the late-onset and non-familial manifestation of CVID. A significant increase in PAX5 enhancer region methylation was identified in equine CVID patients by genome-wide reduced-representation bisulfite sequencing and bisulfite PCR sequencing (p=0.000). Thus, we demonstrate that integrating transcriptomics and epigenetics in CVID enlightens potential mechanisms of dysfunctional B lymphopoiesis or function.

PMID: 25988861 [PubMed – as supplied by publisher]