Research

Deficient Production of Reactive Oxygen Species Leads to Severe Chronic DSS-Induced Colitis in Ncf1/p47phox-Mutant Mice.

June 1, 2014 By Manish Butte

Deficient Production of Reactive Oxygen Species Leads to Severe Chronic DSS-Induced Colitis in Ncf1/p47phox-Mutant Mice.

PLoS One. 2014;9(5):e97532

Authors: Rodrigues-Sousa T, Ladeirinha AF, Santiago AR, Carvalheiro H, Raposo B, Alarcão A, Cabrita A, Holmdahl R, Carvalho L, Souto-Carneiro MM

Abstract
BACKGROUND: Colitis is a common clinical complication in chronic granulomatous disease (CGD), a primary immunodeficiency caused by impaired oxidative burst. Existing experimental data from NADPH-oxidase knockout mice propose contradictory roles for the involvement of reactive oxygen species in colitis chronicity and severity. Since genetically controlled mice with a point-mutation in the Ncf1 gene are susceptible to chronic inflammation and autoimmunity, we tested whether they presented increased predisposition to develop chronic colitis.
METHODS: Colitis was induced in Ncf1-mutant and wild-type mice by a 1st 7-days cycle of dextran sulfate sodium (DSS), intercalated by a 7-days resting period followed by a 2nd 7-days DSS-cycle. Cytokines were quantified locally in the colon inflammatory infiltrates and in the serum. Leukocyte infiltration and morphological alterations of the colon mucosa were assessed by immunohistochemistry.
RESULTS: Clinical scores demonstrated a more severe colitis in Ncf1-mutant mice than controls, with no recovery during the resting period and a severe chronic colitis after the 2nd cycle, confirmed by histopathology and presence of infiltrating neutrophils, macrophages, plasmocytes and lymphocytes in the colon. Severe colitis was mediated by increased local expression of cytokines (IL-6, IL-10, TNF-α, IFN-γ and IL-17A) and phosphorylation of Leucine-rich repeat kinase 2 (LRRK2). Serological cytokine titers of those inflammatory cytokines were more elevated in Ncf1-mutant than control mice, and were accompanied by systemic changes in functional subsets of monocytes, CD4+T and B cells.
CONCLUSION: This suggests that an ineffective oxidative burst leads to severe chronic colitis through local accumulation of peroxynitrites, pro-inflammatory cytokines and lymphocytes and systemic immune deregulation similar to CGD.

PMID: 24873968 [PubMed – in process]

[Clinical study on cytomegalovirus infection after hematopoietic stem cell transplantation in 26 patients with primary immunodeficiency diseases].

May 30, 2014 By Manish Butte

[Clinical study on cytomegalovirus infection after hematopoietic stem cell transplantation in 26 patients with primary immunodeficiency diseases].

Zhonghua Xue Ye Xue Za Zhi. 2014 May 14;35(5):424-7

Authors: Que M, Xiao J, Guan X, Xian Y, Su Y, Wen X, Li Y, Wang Y, Xiao L, Yu J

Abstract
OBJECTIVE: To explore the risk factors, and control measures of cytomegalovirus (CMV) infection after hematopoietic stem cell transplantion (HSCT) in children with primary immunodeficiency diseases(PID).
METHODS: We retrospectively analyzed results of 26 patients with PID-Wiskott-Aldrich syndrome (WAS, n=20), severe combined immunodeficiency (SCID, n=1) , X-linked chronic granulomatous disease (XCGD, n=2) and X-linked hyper-immunoglobulin M (IgM) syndrome (XHIM, n=3)-who underwent HSCT from June 2007 to December 2012in our center. Serologic studies (ELISA) and weekly CMV infection surveillance (quantitative PCR, qPCR) were routinely performed before and after HSCT. Ganciclovir or forcarnet was used for pre-emptive and curative therapy.
RESULTS: All 26 patients were male with the median age at HSCT of 27 months (range 7-77 months). At a median follow up of 24 months (range 5-66 months), the 5-year overall survival rate was (75.0±9.0) %. CMV infection occurred in 42.3% (11 of 26) of the patients, two of them developed CMV interstitial pneumonia (CMVIP). Univariate analysis revealed that the incidence of pre-transplant CMV infection between with and without CMV activation groups after HSCT was significantly different (62.5% vs 10.0%, P=0.010). Additional variables not associated with CMV infection were stem-cell sources, donor type, HLA disparity and acute GVHD (all P values>0.05).
CONCLUSION: CMV infection was a major complication of HSCT. Sensitive monitoring, early diagnosis, timely treatment may improve the survival rate for these PID undergoing HSCT.

PMID: 24857213 [PubMed – in process]

[Survival analysis of hematopoietic stem cell transplantation in children with primary immunodeficiency in Spain.]

May 30, 2014 By Manish Butte

[Survival analysis of hematopoietic stem cell transplantation in children with primary immunodeficiency in Spain.]

An Pediatr (Barc). 2014 May 22;

Authors: Hladun R, Badell I, González M, Martínez AM, Sánchez de Toledo J, Olivé MT, González ME, Elorza I, Díaz de Heredia C, por el Grupo Español de Trasplante de Médula Ósea en Niños (GETMON)

Abstract
INTRODUCTION: Children with primary immunodeficiency have severe life-threatening infections and a higher prevalence of autoimmune problems, allergy and lymphoproliferative disorders. Allogenic hematopoietic stem cell transplantation has been the only potentially curative option.
PATIENTS AND METHODS: Patients with primary immunodeficiency underwent allogenic stem cell transplantation in the period 1985-2011, and registered in the Spanish Working Party for Bone Marrow Transplantation in Children.
RESULTS: One hundred and fifty nine patients underwent 173 allogenic stem cell transplantations, of whom 97 had severe combined immunodeficiency, 30 with immune dysregulation disorders, 25 Wiskott-Aldrich syndrome, and 21 phagocyte disorders. The median patient age at diagnosis was 6 months (range: 17 days – 168 months) and the median patient age at transplant was 12 months (range: 1 month – 189 months). The donors were 30 (19%) identical siblings, 40 (25%) alternative family donors, and 89 (56%) unrelated donors. The source of stem cells was bone marrow in 68 (43%), cord blood in 52 (33%), and peripheral blood in 39 (24%). Ninety eight (61.6%) are alive, 57 (35.9%) died. Event-free survival at 10 years was 63%, with 90% for children transplanted from identical siblings, 36% for those transplanted from alternative family donors, and 66% for those transplanted from unrelated donors.
CONCLUSIONS: The best results have been obtained with identical siblings, but other options may be considered.

PMID: 24857430 [PubMed – as supplied by publisher]

Primary immunodeficiency disorders: general classification, new molecular insights, and practical approach to diagnosis and treatment.

May 30, 2014 By Manish Butte

Primary immunodeficiency disorders: general classification, new molecular insights, and practical approach to diagnosis and treatment.

Ann Allergy Asthma Immunol. 2014 Jun;112(6):489-495

Authors: Ochs HD, Hagin D

PMID: 24860921 [PubMed – as supplied by publisher]

Dietary gluten and the development of type 1 diabetes.

May 30, 2014 By Manish Butte

Dietary gluten and the development of type 1 diabetes.

Diabetologia. 2014 May 29;

Authors: Antvorskov JC, Josefsen K, Engkilde K, Funda DP, Buschard K

Abstract
Gluten proteins differ from other cereal proteins as they are partly resistant to enzymatic processing in the intestine, resulting in a continuous exposure of the proteins to the intestinal immune system. In addition to being a disease-initiating factor in coeliac disease (CD), gluten intake might affect type 1 diabetes development. Studies in animal models of type 1 diabetes have documented that the pathogenesis is influenced by diet. Thus, a gluten-free diet largely prevents diabetes in NOD mice while a cereal-based diet promotes diabetes development. In infants, amount, timing and mode of introduction have been shown to affect the diabetogenic potential of gluten, and some studies now suggest that a gluten-free diet may preserve beta cell function. Other studies have not found this effect. There is evidence that the intestinal immune system plays a primary role in the pathogenesis of type 1 diabetes, as diabetogenic T cells are initially primed in the gut, islet-infiltrating T cells express gut-associated homing receptors, and mesenteric lymphocytes transfer diabetes from NOD mice to NOD/severe combined immunodeficiency (SCID) mice. Thus, gluten may affect diabetes development by influencing proportional changes in immune cell populations or by modifying the cytokine/chemokine pattern towards an inflammatory profile. This supports an important role for gluten intake in the pathogenesis of type 1 diabetes and further studies should be initiated to clarify whether a gluten-free diet could prevent disease in susceptible individuals or be used with newly diagnosed patients to stop disease progression.

PMID: 24871322 [PubMed – as supplied by publisher]

Implications to payers of switch from hospital-based intravenous immunoglobulin to home-based subcutaneous immunoglobulin therapy in patients with primary and secondary immunodeficiencies in Canada.

May 30, 2014 By Manish Butte

Implications to payers of switch from hospital-based intravenous immunoglobulin to home-based subcutaneous immunoglobulin therapy in patients with primary and secondary immunodeficiencies in Canada.

Allergy Asthma Clin Immunol. 2014;10(1):23

Authors: Gerth WC, Betschel SD, Zbrozek AS

Abstract
BACKGROUND: Switching primary/secondary immunodeficiency (PID/SID) patients from intravenous immunoglobulin (IVIg) to home-based subcutaneous immunoglobulin (SCIg) therapy reduces nurse time. A nurse shortage in Canada provides an important context to estimate the net economic benefit, the number of patients needed to switch to SCIg to recoup one full-time equivalent (FTE), and potential population-wide savings of reduced nurse time to a payer.
METHODS: The net economic benefit was estimated by multiplying the hourly compensation for nurses in Canada by the hours required for each administration route. The number needed to switch to SCIg to gain one nurse FTE was estimated by dividing the work hours in a year by the average annual savings in nursing time in a PID population in Canada. The prevalence of treated PID/SID in Canada was calculated using provincial IgG audit data to extrapolate the potential population-wide savings of switching patients to SCIg therapy.
FINDINGS: The net economic gain from switching one patient to home-based SCIg care would be C$2,603 (Canadian Dollars) in year 1 and C$2,948 each year thereafter. Switching 37 IVIg patients to SCIg would gain one nurse FTE. Switching 50% of the estimated 5,486 PID and SID patients in Canada receiving IVIg therapy to SCIg has the potential to save 223.3 nurse FTEs (C$23.2 million in labor costs).
CONCLUSIONS: A shift from IVIg to less labor-intensive SCIg has the potential to help alleviate nurse shortages and reduce overall health care costs in Canada. Health care professionals might consider advocating for home-based SCIg therapy for PID/SID patients when clinically appropriate.

PMID: 24872821 [PubMed]

Zebrafish as a model for understanding the evolution of the vertebrate immune system and human primary immunodeficiency.

May 30, 2014 By Manish Butte

Zebrafish as a model for understanding the evolution of the vertebrate immune system and human primary immunodeficiency.

Exp Hematol. 2014 May 10;

Authors: Iwanami N

Abstract
Zebrafish is an important vertebrate model that provides the opportunity for the combination of genetic interrogation with advanced live imaging in the analysis of complex developmental and physiological processes. Among the many advances that have been achieved using the zebrafish model, it has had a great impact on immunology. Here, I discuss recent work focusing on the genetic underpinnings of the development and function of lymphocytes in fish. Lymphocytes play critical roles in vertebrate-specific acquired immune systems of jawless and jawed fish. The unique opportunities afforded by the ability to carry out forward genetic screens and the rapidly evolving armamentarium of reverse genetics in fish usher in a new immunological research that complements the traditional models of chicken and mouse. Recent work has greatly increased our understanding of the molecular components of the zebrafish immune system, identifying evolutionarily conserved and fish-specific functions of immune-related genes. Interestingly, some of the genes whose mutations underlie the phenotypes in immunodeficient zebrafish were also identified in immunodeficient human patients. In addition, due to the generally conserved structure and function of immune facilities, the zebrafish also provides a versatile model to examine the functional consequences of genetic variants in immune-relevant genes in the human population. Thus, we propose that genetic approaches using the zebrafish hold great potential for a better understanding of molecular mechanisms of human primary immunodeficiencies and the evolution of vertebrate immune systems.

PMID: 24824573 [PubMed – as supplied by publisher]

Allergic diseases in children with primary immunodeficiencies.

May 30, 2014 By Manish Butte

Allergic diseases in children with primary immunodeficiencies.

Turk J Pediatr. 2014 Jan-Feb;56(1):41-7

Authors: Ozcan C, Metin A, Erkoçoğlu M, Kocabaş CN

Abstract
The aim of this study was to evaluate and compare the frequency of atopy and allergic disease in all groups of primary immunodeficiency (PID) patients. The study was done on 318 patients with PID between the ages of 6 months and 18 years. The patients and their parents were questioned regarding their histories of asthma and allergic disease. Within the study group, 82.4% of the patients had antibody deficiency, 10.4% combined immunodeficiency, 6.6% phagocyte number or function defect, and 0.6% complement deficiency. Patients with selective immunoglobulin (Ig)A deficiency had a more significant history of ever wheezing compared to those with IgG subclass deficiency (p=0.022). The frequency of current wheezing was higher in patients with antibody deficiency than in patients with combined immunodeficiency (p=0.049). In conclusion, patients with antibody deficiency, especially those with selective IgA deficiency, should be evaluated regarding asthma and allergic diseases if recurring respiratory symptoms are present.

PMID: 24827946 [PubMed – in process]

Lymphadenitis caused by infection with an isoniazid- and rifampin-resistant strain of Mycobacterium bovis BCG in an infant with IFN-γ/IL-12 pathway defect.

May 30, 2014 By Manish Butte

Lymphadenitis caused by infection with an isoniazid- and rifampin-resistant strain of Mycobacterium bovis BCG in an infant with IFN-γ/IL-12 pathway defect.

J Bras Pneumol. 2014 Apr;40(2):188-92

Authors: Diniz LM, Guimarães T, Oliveira Md, Pinto JA, Miranda SS

Abstract
We report a rare case in a female infant (age, 3.5 months) with primary immunodeficiency (IFN-γ/IL-12 pathway defect) who presented with suppurative lymphadenitis after Mycobacterium bovis BCG vaccination. The strain of M. bovis BCG identified was found to be resistant to isoniazid and rifampin. The patient was treated with a special pharmacological regimen involving isoniazid (in a limited, strategic manner), ethambutol, streptomycin, and IFN-γ, after which there was complete resolution of the lesions.

PMID: 24831405 [PubMed – in process]

Gene Expression Profiling in Peripheral Blood Mononuclear Cells of Patients with Common Variable Immunodeficiency: Modulation of Adaptive Immune Response following Intravenous Immunoglobulin Therapy.

May 30, 2014 By Manish Butte

Gene Expression Profiling in Peripheral Blood Mononuclear Cells of Patients with Common Variable Immunodeficiency: Modulation of Adaptive Immune Response following Intravenous Immunoglobulin Therapy.

PLoS One. 2014;9(5):e97571

Authors: Dolcino M, Patuzzo G, Barbieri A, Tinazzi E, Rizzi M, Beri R, Argentino G, Ottria A, Lunardi C, Puccetti A

Abstract
BACKGROUND: Regular intravenous immunoglobulin treatment is used to replace antibody deficiency in primary immunodeficiency diseases; however the therapeutic effect seems to be related not only to antibody replacement but also to an active role in the modulation of the immune response. Common variable immunodeficiency is the most frequent primary immunodeficiency seen in clinical practice.
METHODS: We have studied the effect of intravenous immunoglobulin replacement in patients with common variable immunodeficiency by evaluating the gene-expression profiles from Affimetrix HG-U133A. Some of the gene array results were validated by real time RT-PCR and by the measurement of circulating cytokines and chemokines by ELISA. Moreover we performed FACS analysis of blood mononuclear cells from the patients enrolled in the study.
RESULTS: A series of genes involved in innate and acquired immune responses were markedly up- or down-modulated before therapy. Such genes included CD14, CD36, LEPR, IRF-5, RGS-1, CD38, TNFRSF25, IL-4, CXCR4, CCR3, IL-8. Most of these modulated genes showed an expression similar to that of normal controls after immunoglobulin replacement. Real time RT-PCR of selected genes and serum levels of IL-4, CXCR4 before and after therapy changed accordingly to gene array results. Interestingly, serum levels of IL-8 remained unchanged, as the corresponding gene, before and after treatment. FACS analysis showed a marked decrease of CD8+T cells and an increase of CD4+T cells following treatment. Moreover we observed a marked increase of CD23-CD27-IgM-IgG- B cells (centrocytes).
CONCLUSIONS: Our results are in accordance with previous reports and provide further support to the hypothesis that the benefits of intravenous immunoglobulin therapy are not only related to antibody replacement but also to its ability to modulate the immune response in common variable immunodeficiency.

PMID: 24831519 [PubMed – in process]