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Immunoglobulin class-switch recombination deficiencies.

June 24, 2015 By Manish Butte

Immunoglobulin class-switch recombination deficiencies.

Arthritis Res Ther. 2012;14(4):218

Authors: Durandy A, Kracker S

Abstract
Immunoglobulin class-switch recombination deficiencies (Ig-CSR-Ds) are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE) production. Depending on the molecular defect in question, the Ig-CSR-D may be combined with an impairment in somatic hypermutation (SHM). Some of the mechanisms underlying Ig-CSR and SHM have been described by studying natural mutants in humans. This approach has revealed that T cell-B cell interaction (resulting in CD40-mediated signaling), intrinsic B-cell mechanisms (activation-induced cytidine deaminase-induced DNA damage), and complex DNA repair machineries (including uracil-N-glycosylase and mismatch repair pathways) are all involved in class-switch recombination and SHM. However, several of the mechanisms required for full antibody maturation have yet to be defined. Elucidation of the molecular defects underlying the diverse set of Ig-CSR-Ds is essential for understanding Ig diversification and has prompted better definition of the clinical spectrum of diseases and the development of increasingly accurate diagnostic and therapeutic approaches.

PMID: 22894609 [PubMed – indexed for MEDLINE]

Aetiology and clinical characteristics of patients with bronchiectasis in a Chinese Han population: A prospective study.

June 23, 2015 By Manish Butte

Aetiology and clinical characteristics of patients with bronchiectasis in a Chinese Han population: A prospective study.

Respirology. 2015 Jun 19;

Authors: Qi Q, Wang W, Li T, Zhang Y, Li Y

Abstract
BACKGROUND AND OBJECTIVE: Bronchiectasis is a chronic respiratory disease with diverse causes that may differ in clinical features and thus treatment options. However, few large-scale studies on the aetiology of bronchiectasis are currently available. This study aims to determine aetiology and clinical features of bronchiectasis in a Chinese Han population.
METHODS: This prospective study enrolled adult patients diagnosed with bronchiectasis as confirmed by high-resolution computed tomography at five general hospitals in Shandong from January 2010 to August 2014. Causes of bronchiectasis were sought by analysis of clinical history and auxiliary examinations (including serum immunoglobulin determination, saccharin test, Aspergillus skin prick test, autoantibody detection and electronic bronchoscopy).
RESULTS: A total of 476 adult patients with bronchiectasis were included, and all patients were of Chinese Han ethnicity. Idiopathic (66.0%) was the most common cause, followed by post-tuberculosis (16.0%). Other uncommon causes included post-infective (3.8%), immunodeficiency (3.8%), allergic bronchopulmonary aspergillosis (4.0%), rheumatic diseases (4.4%) and primary ciliary dyskinesia (0.9%). Patients with post-tuberculosis bronchiectasis had a higher frequency of upper lobe involvement (P < 0.05). Cylindrical bronchiectasis was the most common type of all causes, with varicose bronchiectasis occurring more frequently in post-tuberculosis bronchiectasis and allergic bronchopulmonary aspergillosis (P < 0.05). However, patients with different causes did not differ in lung function and sputum isolation rate of Pseudomonas aeruginosa (P > 0.05).
CONCLUSIONS: In a Chinese Han population in Shandong, idiopathic bronchiectasis is the most common form of bronchiectasis followed by post-tuberculosis bronchiectasis. Patients with different causes differ in distribution and pattern of bronchiectasis on computed tomography.

PMID: 26096854 [PubMed – as supplied by publisher]

Genetics of common variable immunodeficiency: role of transmembrane activator and calcium modulator and cyclophilin ligand interactor.

June 23, 2015 By Manish Butte

Genetics of common variable immunodeficiency: role of transmembrane activator and calcium modulator and cyclophilin ligand interactor.

Int J Immunogenet. 2015 Jun 19;

Authors: Sathkumara HD, De Silva NR, Handunnetti S, De Silva AD

Abstract
Common variable immunodeficiency (CVID) is the most common clinically manifested primary immunodeficiency, which represents a heterogeneous group of hypogammaglobulinemias of largely unknown molecular defects. The hallmark of the disease is the elevated susceptibility to recurrent infections of respiratory and gastrointestinal tract, mainly due to encapsulated bacteria while a significant proportion of patients with CVID develop autoimmune and lymphoproliferative complications. The primary cause of CVID is still not known. However, a number of distinct genetic defects including in inducible co-stimulator (ICOS), B-cell-activating factor receptor (BAFFR) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) have been identified in a minority of patients with CVID. Mutations in tumour necrosis factor receptor superfamily (TNFRSF) member, TACI, are more frequently found to be associated to the disease in about 10% of patients with CVID, but may require additional immunologic defects for complete expression of the phenotype, as unaffected heterozygotes have also been described. Clinically, patients with TACI mutations could present with the complete spectrum of complications seen in CVID. Recent animal studies have provided substantial information on TACI signalling, yet it still offers an outstanding opportunity for further exploration of the aetiology, as a large part of it remains poorly understood. In this review, we aim at giving an insight into the genetics underlying the CVID and particularly at outlining the role of TACI and its relative contribution to the development of CVID-like phenotypes in human.

PMID: 26096648 [PubMed – as supplied by publisher]

Update on Vaccine-Derived Polioviruses – Worldwide, January 2014-March 2015.

June 19, 2015 By Manish Butte

Update on Vaccine-Derived Polioviruses – Worldwide, January 2014-March 2015.

MMWR Morb Mortal Wkly Rep. 2015 Jun 19;64(23):640-646

Authors: Diop OM, Burns CC, Sutter RW, Wassilak SG, Kew OM

Abstract
Since the World Health Assembly’s 1988 resolution to eradicate poliomyelitis, one of the main tools of the World Health Organization (WHO) Global Polio Eradication Initiative (GPEI) has been the live, attenuated oral poliovirus vaccine (OPV). OPV might require several doses to induce immunity but provides long-term protection against paralytic disease. Through effective use of OPV, GPEI has brought polio to the threshold of eradication. Wild poliovirus type 2 (WPV2) was eliminated in 1999, WPV3 has not been detected since November 2012, and WPV1 circulation appears to be restricted to parts of Pakistan and Afghanistan. However, continued use of OPV carries two key risks. The first, vaccine-associated paralytic poliomyelitis (VAPP) has been recognized since the early 1960s. VAPP is a very rare event that occurs sporadically when an administered dose of OPV reverts to neurovirulence and causes paralysis in the vaccine recipient or a nonimmune contact. VAPP can occur among immunologically normal vaccine recipients and their contacts as well as among persons who have primary immunodeficiencies (PIDs) manifested by defects in antibody production; it is not associated with outbreaks. The second, the emergence of genetically divergent, neurovirulent vaccine-derived polioviruses (VDPVs) was recognized more recently. Circulating VDPVs (cVDPVs) resemble WPVs and, in areas with low OPV coverage, can cause polio outbreaks. Immunodeficiency-associated VDPVs (iVDPVs) can replicate and be excreted for years in some persons with PIDs; GPEI maintains a registry of iVDPV cases. Ambiguous VDPVs (aVDPVs) are isolates that cannot be classified definitively. This report updates previous surveillance summaries and describes VDPVs detected worldwide during January 2014-March 2015. Those include new cVDPV outbreaks in Madagascar and South Sudan, and sharply reduced type 2 cVDPV (cVDPV2) circulation in Nigeria and Pakistan during the latter half of 2014. Eight newly identified persons in six countries were found to excrete iVDPVs, and a patient in the United Kingdom was still excreting iVDPV2 in 2014 after more than 28 years. Ambiguous VDPVs were found among immunocompetent persons and environmental samples in 16 countries. Because the large majority of VDPV case-isolates are type 2, WHO has developed a plan for coordinated worldwide withdrawal of trivalent (types 1, 2, and 3) OPV (tOPV) and replacement with bivalent (types 1 and 3) OPV (bOPV) in April 2016, preceded by introduction of at least 1 dose of injectable inactivated poliovirus vaccine (IPV) into routine immunization schedules worldwide to maintain immunity to type 2 viruses.

PMID: 26086635 [PubMed – as supplied by publisher]

Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naïve-to-memory B-cell transition.

June 18, 2015 By Manish Butte

Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naïve-to-memory B-cell transition.

Nat Commun. 2015;6:7335

Authors: Rodríguez-Cortez VC, Del Pino-Molina L, Rodríguez-Ubreva J, Ciudad L, Gómez-Cabrero D, Company C, Urquiza JM, Tegnér J, Rodríguez-Gallego C, López-Granados E, Ballestar E

Abstract
Common variable immunodeficiency (CVID), the most frequent primary immunodeficiency characterized by loss of B-cell function, depends partly on genetic defects, and epigenetic changes are thought to contribute to its aetiology. Here we perform a high-throughput DNA methylation analysis of this disorder using a pair of CVID-discordant MZ twins and show predominant gain of DNA methylation in CVID B cells with respect to those from the healthy sibling in critical B lymphocyte genes, such as PIK3CD, BCL2L1, RPS6KB2, TCF3 and KCNN4. Individual analysis confirms hypermethylation of these genes. Analysis in naive, unswitched and switched memory B cells in a CVID patient cohort shows impaired ability to demethylate and upregulate these genes in transitioning from naive to memory cells in CVID. Our results not only indicate a role for epigenetic alterations in CVID but also identify relevant DNA methylation changes in B cells that could explain the clinical manifestations of CVID individuals.

PMID: 26081581 [PubMed – in process]

Neutrophil functional disorder in childhood.

June 17, 2015 By Manish Butte

Neutrophil functional disorder in childhood.

Prilozi. 2015;36(1):183-90

Authors: Mironska K

Abstract
(Full text is available at http://www.manu.edu.mk/prilozi). Neutrophil functional disorders thought to be uncommon, yet important as a cause of morbidity and mortality in infants and children. During the first years of life, when the immune system is still not completely mature, when the viral infections are frequent and antibiotic overuse can damage and alter the immune response, the inadequate nutrition followed with iron deficient anemia and malnutrition can lead the child`s organism in state of immunodeficiency. Sometimes is difficult to distinguish at the beginning weather the cause of patient suffering from frequent infections is existing of primary immunodeficiency disorder or the cause of the immunodeficiency state is just from exogenous factors. Fortunately, primary immune deficiencies are rare diseases and only 6-7% of all of them, due to the neutrophilic functional disorders. Unfortunately, many exogenous and environmental factors have influence to the immune system, and the percentage of secondary caused neutrophilic functional disorders is much higher and should be considered when children are investigated for immunodeficiency. So, when to suspect neutrophil functional disorder? The hallmarks for diseases related to the neutrophilic functional disorders are discussed in this article. Key words: neutrophil, phagocytosis, NBT test, Neutrophil function, Neutrophil functional disorder, malnutration.

PMID: 26076788 [PubMed – in process]

Hematopoietic stem cell transplant for hyper-IgM syndrome due to CD40L defects: A single-center experience.

June 16, 2015 By Manish Butte

Hematopoietic stem cell transplant for hyper-IgM syndrome due to CD40L defects: A single-center experience.

Pediatr Transplant. 2015 Jun 13;

Authors: Al-Saud B, Al-Mousa H, Al-Ahmari A, Al-Ghonaium A, Ayas M, Alhissi S, Al-Muhsen S, Al-Seraihy A, Arnaout R, Al-Dhekri H, Hawwari A

Abstract
HIGMI is a disease with a high risk for morbidity and mortality. HSCT has been shown to be a curative option. This study retrospectively reviewed and analyzed data from five patients who received HSCT at King Faisal Specialist Hospital & Research Centre (KFSH&RC) in Riyadh, Saudi Arabia, between 2005 and 2013. Five patients with HIGMI syndrome underwent HSCT at a median age of 41 months (range, 9-72 months). The median time from diagnosis to transplantation was 30 months (range, 5-58 months). For all five patients, the donors were HLA-identical siblings. In three patients, the conditioning regimen was composed of BU and CY. Fludarabine and melphalan with either ATG or alemtuzumab was used in two patients. For GVHD prophylaxis, cyclosporine was used in two patients, and the combination of cyclosporine and MTX was used in three patients. The survival rate was 100%, with a median follow-up of 69 months (range, 13-100 months). All patients engrafted. Two patients developed acute GVHD. Four patients showed complete immune recovery with positive CD40L expression in activated T cells and discontinued IVIG replacement. HSCT in early stage from an HLA-matched sibling donor is potentially effective at curing the disease.

PMID: 26073206 [PubMed – as supplied by publisher]

A novel treatment in X-linked agammaglobulinaemia – hyperbaric oxygen therapy in refractory chronic wounds.

June 16, 2015 By Manish Butte

A novel treatment in X-linked agammaglobulinaemia – hyperbaric oxygen therapy in refractory chronic wounds.

J Clin Immunol. 2014 Oct;34(7):784-7

Authors: Steele CL, Cridge C, Edgar JD

Abstract
Chronic wounds are a rare complication of X-linked agammaglobulinaemia (XLA). Fastidious organisms such as helicobacter bills have been reported in XLA with chronic wounds but sterile chronic wounds also occur. Hyperbaric Oxygen Therapy has been used in chronic wounds but has not previously been reported in primary antibody deficiencies. We present a case of a chronic wound in a patient with XLA refractory to antimicrobial therapy that made a remarkable recovery following Hyperbaric Oxygen Therapy.

PMID: 25091287 [PubMed – indexed for MEDLINE]

Inborn errors of metabolism underlying primary immunodeficiencies.

June 16, 2015 By Manish Butte

Inborn errors of metabolism underlying primary immunodeficiencies.

J Clin Immunol. 2014 Oct;34(7):753-71

Authors: Parvaneh N, Quartier P, Rostami P, Casanova JL, de Lonlay P

Abstract
A number of inborn errors of metabolism (IEM) have been shown to result in predominantly immunologic phenotypes, manifesting in part as inborn errors of immunity. These phenotypes are mostly caused by defects that affect the (i) quality or quantity of essential structural building blocks (e.g., nucleic acids, and amino acids), (ii) cellular energy economy (e.g., glucose metabolism), (iii) post-translational protein modification (e.g., glycosylation) or (iv) mitochondrial function. Presenting as multisystemic defects, they also affect innate or adaptive immunity, or both, and display various types of immune dysregulation. Specific and potentially curative therapies are available for some of these diseases, whereas targeted treatments capable of inducing clinical remission are available for others. We will herein review the pathogenesis, diagnosis, and treatment of primary immunodeficiencies (PIDs) due to underlying metabolic disorders.

PMID: 25081841 [PubMed – indexed for MEDLINE]

Adequate patient's outcome achieved with short immunoglobulin replacement intervals in severe antibody deficiencies.

June 16, 2015 By Manish Butte

Adequate patient’s outcome achieved with short immunoglobulin replacement intervals in severe antibody deficiencies.

J Clin Immunol. 2014 Oct;34(7):813-9

Authors: Milito C, Pulvirenti F, Pesce AM, Digiulio MA, Pandolfi F, Visentini M, Quinti I

Abstract
PURPOSE: The optimal immune globulin replacement dosages required over time to minimize infection risks in patients with Primary Antibody Deficiencies are not definitely established. As with many interventions, there may be specific subgroups of patients who are more likely to benefit from treatment with higher or lower dosages. The aim of the study was to verify the efficacy of a rationale for individualized immune globulin utilization and to elucidate the effects of care on patient outcome.
METHODS: Single centre interventional study on 108 patients with Primary Antibody Deficiencies. The objective was to determine for each patient the best interval between immune globulins administration in order to: • Keep IgG trough levels >500 mg/dL, • Minimize of major infections (pneumonias and infections requiring hospitalization), • Minimize of adverse events (AE).
RESULTS: Ninthly eight per cent of patients achieved the objective of the study. Patients who had low switched memory B cells and low IgA serum levels and/or are affected by bronchiectasis and/or enteropathy and/or continued to experience adverse events despite pre-medications, achieved the study objective by shortening the administration intervals to 2-weeks or to 1-week without the need to increase the monthly cumulative immunoglobulin dosage and its relative cost. The adverse events were reduced by administrating low Ig dosages in a single setting. Patients without risk factors achieved the study objective with immune globulin replacement administered with the widely used interval of 3 or 4 weeks.
CONCLUSIONS: The exact timing and optimal immunoglobulin prophylaxis regimen might be tailored according to clinical and immunological markers.

PMID: 25047154 [PubMed – indexed for MEDLINE]