Research

Related Articles

Consanguinity and primary immunodeficiencies.

Hum Hered. 2014;77(1-4):138-43

Authors: Al-Herz W, Aldhekri H, Barbouche MR, Rezaei N

Abstract
Primary immunodeficiencies (PIDs) are a heterogeneous group of genetic disorders caused by defects in the immune system that predispose patients to infections, autoimmune diseases, lymphoproliferation and malignancies. Most PIDs are inherited in an autosomal recessive pattern; therefore, they are more common in areas with high rates of consanguineous marriage. Reports about PIDs from these areas have demonstrated a peculiar prevalence of more severe forms of diseases compared to other regions, and patients born to consanguineous parents have increased rates of morbidity and mortality compared to other patients. Individuals at high risk of having a child with a PID who wish to have a healthy child have limited options, these include prenatal diagnosis and pre-implantation genetic diagnosis. However, these options require a collaborative team of specialists and may not always be implemented due to geographic, religious, financial or social factors. The recent introduction of newborn-screening programs for a number of T and B lymphocyte deficiencies will facilitate early diagnosis and therapeutic interventions, which may include hematopoietic stem cell transplantation and intravenous immunoglobulin treatment. There is a need for the implementation of strategies to increase public awareness of the health risks associated with consanguineous marriage. It should be stressed that genetic counseling should be an important component of the care of patients with PIDs as well as their families.

PMID: 25060276 [PubMed – indexed for MEDLINE]

Powered by WPeMatico

Related Articles

Dual-regulated lentiviral vector for gene therapy of X-linked chronic granulomatosis.

Mol Ther. 2014 Aug;22(8):1472-83

Authors: Chiriaco M, Farinelli G, Capo V, Zonari E, Scaramuzza S, Di Matteo G, Sergi LS, Migliavacca M, Hernandez RJ, Bombelli F, Giorda E, Kajaste-Rudnitski A, Trono D, Grez M, Rossi P, Finocchi A, Naldini L, Gentner B, Aiuti A

Abstract
Regulated transgene expression may improve the safety and efficacy of hematopoietic stem cell (HSC) gene therapy. Clinical trials for X-linked chronic granulomatous disease (X-CGD) employing gammaretroviral vectors were limited by insertional oncogenesis or lack of persistent engraftment. Our novel strategy, based on regulated lentiviral vectors (LV), targets gp91(phox) expression to the differentiated myeloid compartment while sparing HSC, to reduce the risk of genotoxicity and potential perturbation of reactive oxygen species levels. Targeting was obtained by a myeloid-specific promoter (MSP) and posttranscriptional, microRNA-mediated regulation. We optimized both components in human bone marrow (BM) HSC and their differentiated progeny in vitro and in a xenotransplantation model, and generated therapeutic gp91(phox) expressing LVs for CGD gene therapy. All vectors restored gp91(phox) expression and function in human X-CGD myeloid cell lines, primary monocytes, and differentiated myeloid cells. While unregulated LVs ectopically expressed gp91(phox) in CD34(+) cells, transcriptionally and posttranscriptionally regulated LVs substantially reduced this off-target expression. X-CGD mice transplanted with transduced HSC restored gp91(phox) expression, and MSP-driven vectors maintained regulation during BM development. Combining transcriptional (SP146.gp91-driven) and posttranscriptional (miR-126-restricted) targeting, we achieved high levels of myeloid-specific transgene expression, entirely sparing the CD34(+) HSC compartment. This dual-targeted LV construct represents a promising candidate for further clinical development.

PMID: 24869932 [PubMed – indexed for MEDLINE]

Powered by WPeMatico

Economic burden of common variable immunodeficiency: annual cost of disease.

Expert Rev Clin Immunol. 2015 Mar 25;:1-8

Authors: Sadeghi B, Abolhassani H, Naseri A, Rezaei N, Aghamohammadi A

Abstract
OBJECTIVES: In the context of the unknown economic burden imposed by primary immunodeficiency diseases, in this study, we sought to calculate the costs associated with the most prevalent symptomatic disease, common variable immunodeficiency (CVID).
METHODS: Direct, indirect and intangible costs were recorded for diagnosed CVID patients. Hidden Markov model was used to evaluate different disease-related factors and Monte Carlo method for estimation of uncertainty intervals.
RESULTS: The total estimated cost of diagnosed CVID is US$274,200/patient annually and early diagnosis of the disease can save US$6500. Hospital admission cost (US$25,000/patient) accounts for the most important expenditure parameter before diagnosis, but medication cost (US$40,600/patients) was the main factor after diagnosis primarily due to monthly administration of immunoglobulin.
CONCLUSION: The greatest cost-determining factor in our study was the cost of treatment, spent mostly on immunoglobulin replacement therapy of the patients. It was also observed that CVID patients’ costs are reduced after diagnosis due to appropriate management.

PMID: 25804338 [PubMed – as supplied by publisher]

Powered by WPeMatico

Seizure as the Presenting Manifestation in Griscelli Syndrome Type 2.

Pediatr Neurol. 2015 Jan 26;

Authors: Panigrahi I, Suthar R, Rawat A, Behera B

Abstract
BACKGROUND: Griscelli syndrome is an autosomal recessive disease that is characterized by hypopigmentation of the skin and hair, presence of large clumps of pigment in hair shafts, and accumulation of melanosomes in melanocytes; it resembles Chediak-Higashi syndrome. Griscelli syndrome type 2 is caused by mutations in the RAB27A gene and has predominant immunologic abnormalities.
METHOD: A retrospective case analysis highlighting neurological complications in an individual with Griscelli syndrome type 2.
RESULTS: We present a 1-year-old girl with Griscelli syndrome type 2 in an Asian Indian family, confirmed by mutation analysis of RAB27A gene. She presented with seizures and regression of developmental milestones following a brief febrile illness. Progressive neurological deterioration was associated with refractory status epilepticus. Neurological worsening may have resulted from the accelerated phase of the disease.
CONCLUSION: Griscelli syndrome type 2 is a rare primary immunodeficiency state with characteristic presentation in form of silvery hair, partial albinism, and immunological abnormalities. Predominant neurological presentation is rare, but it represents isolated central nervous system hemophagocytosis.

PMID: 25801174 [PubMed – as supplied by publisher]

Powered by WPeMatico

Study of naïve and memory cells in a cohort of Egyptian chronic granulomatous disease patients.

J Recept Signal Transduct Res. 2015 Mar 23;:1-6

Authors: El Hawary R, Meshaal S, Nagy D, Fikry I, Alkady R, Abd Elaziz D, Galal N, Boutros J, Elmarsafy A, Jan Farid R

Abstract
CONTEXT: Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder caused by inherited defects in the NADPH oxidase complex which may be involved in important pathways that connect innate and adaptive immunity.
OBJECTIVES: Characterize the naive and memory compartment of B and T lymphocytes in patients with CGD.
METHODS: Twenty CGD patients and twenty healthy controls matched for age and sex were enrolled in this study. Flow cytometric assessment of the naïve and memory compartments of peripheral blood lymphocytes was done using cell surface markers CD45RO, CD45RA, CD27, CD3 and CD19.
RESULTS: There were 15 (79%) autosomal recessive CGD patients (8 females (53%) and 7 males (47%), 100% positive parental consanguinity) and four (21%) X-linked CGD patients. On comparing the 3 groups; AR CGD, X-linked CGD and controls, there was a positive statistical significant difference for the percentage and absolute count of CD19 + CD27+ memory B cell (p = 0.028 and p = 0.047 respectively), CD45RA cells (with p values of p = 0.000 and 0.033, respectively), the naïve compartment CD3 + CD45RA+ cells percentage and absolute counts (p = 0.005, 0.01respectively), CD3 + CD27 + cells percentage and absolute counts (p = 0.001, 0.012 respectively), CD3 + CD45RA + CD27+ cells percentage and absolute counts (p = 0.015, 0.005, respectively). The significance was mainly attributed to the decrease in the X-linked group than control group.
CONCLUSION: There was an altered naïve and memory B profile in CGD patients, this may increase susceptibility of the patients to opportunistic infections and autoimmune disorders. T-cell alterations have to be interpreted cautiously especially in the presence of infections.

PMID: 25798665 [PubMed – as supplied by publisher]

Powered by WPeMatico

Fournier’s gangrene caused by Listeria monocytogenes as the primary organism.

Can J Infect Dis Med Microbiol. 2015 Jan-Feb;26(1):44-6

Authors: Asahata S, Hirai Y, Ainoda Y, Fujita T, Okada Y, Kikuchi K

Abstract
A 70-year-old man with a history of tongue cancer presented with Fournier’s gangrene caused by Listeria monocytogenes serotype 4b. Surgical debridement revealed undiagnosed rectal adenocarcinoma. The patient did not have an apparent dietary or travel history but reported daily consumption of sashimi (raw fish). Old age and immunodeficiency due to rectal adenocarcinoma may have supported the direct invasion of L monocytogenes from the tumour. The present article describes the first reported case of Fournier’s gangrene caused by L monocytogenes. The authors suggest that raw ready-to-eat seafood consumption be recognized as a risk factor for listeriosis, especially in cases of skin and soft tissue infection.

PMID: 25798155 [PubMed]

Powered by WPeMatico

DOCK8 primary immunodeficiency syndrome.

Lancet. 2015 Mar 19;

Authors: Purcell C, Cant A, Irvine AD

PMID: 25798541 [PubMed – as supplied by publisher]

Powered by WPeMatico

Quantitative defects in invariant NKT cells and TLR responses in patients with hyper-IgE syndrome.

Allergol Immunopathol (Madr). 2015 Mar 19;

Authors: Gutierrez-Hincapié S, Muskus-López CE, Montoya CJ, Trujillo-Vargas CM

Abstract
BACKGROUND: Autosomal dominant hyper-IgE syndrome (AD-HIES) is a primary immunodeficiency mainly caused by mutations in STAT3, a signalling molecule implicated in the development of appropriate immune responses. We aimed to characterise the innate immune response in AD-HIES.
METHODS: The frequency of innate immune cells in peripheral blood (PB) from seven AD-HIES patients and healthy controls were determined. CD80/CD86 surface expression and cytokine levels in supernatants from PBMC after stimulation with TLR-2, -4 and -9 agonists were also measured by flow cytometry. In addition, several SNPs within these TLR genes in genomic DNA samples from patients and controls were examined.
RESULTS: A significantly reduced number of PB iNKT cells was observed in the AD-HIES group. CpG-stimulated pDC and mDC from patients exhibited a lower increase in the expression of the costimulatory molecule CD80. We also observed an increase in the secretion of IL-12p70, TNF-alpha and IL-10 in PBMC from HIES patients after LTA or LPS stimuli. No association was found between the different SNPs detected and the HIES phenotype.
CONCLUSIONS: These findings demonstrate that important mediators of the innate immunity responses are affected in AD-HIES. More studies are necessary to investigate how the STAT3 function interferes with development of iNKT cells and TLR-mediated responses.

PMID: 25796310 [PubMed – as supplied by publisher]

Powered by WPeMatico

Related Articles

Myocardial ischemia and reperfusion leads to transient CD8 immune deficiency and accelerated immunosenescence in CMV-seropositive patients.

Circ Res. 2015 Jan 2;116(1):87-98

Authors: Hoffmann J, Shmeleva EV, Boag SE, Fiser K, Bagnall A, Murali S, Dimmick I, Pircher H, Martin-Ruiz C, Egred M, Keavney B, von Zglinicki T, Das R, Todryk S, Spyridopoulos I

Abstract
RATIONALE: There is mounting evidence of a higher incidence of coronary heart disease in cytomegalovirus-seropositive individuals.
OBJECTIVE: The aim of this study was to investigate whether acute myocardial infarction triggers an inflammatory T-cell response that might lead to accelerated immunosenescence in cytomegalovirus-seropositive patients.
METHODS AND RESULTS: Thirty-four patients with acute myocardial infarction undergoing primary percutaneous coronary intervention were longitudinally studied within 3 months after reperfusion (Cohort A). In addition, 54 patients with acute myocardial infarction and chronic myocardial infarction were analyzed in a cross-sectional study (Cohort B). Cytomegalovirus-seropositive patients demonstrated a greater fall in the concentration of terminally differentiated CD8 effector memory T cells (TEMRA) in peripheral blood during the first 30 minutes of reperfusion compared with cytomegalovirus-seronegative patients (-192 versus -63 cells/μL; P=0.008), correlating with the expression of programmed cell death-1 before primary percutaneous coronary intervention (r=0.8; P=0.0002). A significant proportion of TEMRA cells remained depleted for ≥3 months in cytomegalovirus-seropositive patients. Using high-throughput 13-parameter flow cytometry and human leukocyte antigen class I cytomegalovirus-specific dextramers, we confirmed an acute and persistent depletion of terminally differentiated TEMRA and cytomegalovirus-specific CD8(+) cells in cytomegalovirus-seropositive patients. Long-term reconstitution of the TEMRA pool in chronic cytomegalovirus-seropositive postmyocardial infarction patients was associated with signs of terminal differentiation including an increase in killer cell lectin-like receptor subfamily G member 1 and shorter telomere length in CD8(+) T cells (2225 versus 3397 bp; P<0.001).
CONCLUSIONS: Myocardial ischemia and reperfusion in cytomegalovirus-seropositive patients undergoing primary percutaneous coronary intervention leads to acute loss of antigen-specific, terminally differentiated CD8 T cells, possibly through programmed cell death-1-dependent programmed cell death. Our results suggest that acute myocardial infarction and reperfusion accelerate immunosenescence in cytomegalovirus-seropositive patients.

PMID: 25385851 [PubMed – indexed for MEDLINE]

Powered by WPeMatico

B-cell reconstitution after lentiviral vector-mediated gene therapy in patients with Wiskott-Aldrich syndrome.

J Allergy Clin Immunol. 2015 Mar 16;

Authors: Castiello MC, Scaramuzza S, Pala F, Ferrua F, Uva P, Brigida I, Sereni L, van der Burg M, Ottaviano G, Albert MH, Roncarolo MG, Naldini L, Aiuti A, Villa A, Bosticardo M

Abstract
BACKGROUND: Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and susceptibility to autoimmunity and lymphomas. Hematopoietic stem cell transplantation is the treatment of choice; however, administration of WAS gene-corrected autologous hematopoietic stem cells has been demonstrated as a feasible alternative therapeutic approach.
OBJECTIVE: Because B-cell homeostasis is perturbed in patients with WAS and restoration of immune competence is one of the main therapeutic goals, we have evaluated reconstitution of the B-cell compartment in 4 patients who received autologous hematopoietic stem cells transduced with lentiviral vector after a reduced-intensity conditioning regimen combined with anti-CD20 administration.
METHODS: We evaluated B-cell counts, B-cell subset distribution, B cell-activating factor and immunoglobulin levels, and autoantibody production before and after gene therapy (GT). WAS gene transfer in B cells was assessed by measuring vector copy numbers and expression of Wiskott-Aldrich syndrome protein.
RESULTS: After lentiviral vector-mediated GT, the number of transduced B cells progressively increased in the peripheral blood of all patients. Lentiviral vector-transduced progenitor cells were able to repopulate the B-cell compartment with a normal distribution of B-cell subsets both in bone marrow and the periphery, showing a WAS protein expression profile similar to that of healthy donors. In addition, after GT, we observed a normalized frequency of autoimmune-associated CD19(+)CD21(-)CD35(-) and CD21(low) B cells and a reduction in B cell-activating factor levels. Immunoglobulin serum levels and autoantibody production improved in all treated patients.
CONCLUSIONS: We provide evidence that lentiviral vector-mediated GT induces transgene expression in the B-cell compartment, resulting in ameliorated B-cell development and functionality and contributing to immunologic improvement in patients with WAS.

PMID: 25792466 [PubMed – as supplied by publisher]

Powered by WPeMatico