Blog

Gene Therapy for Primary Immunodeficiencies: Current Status and Future Prospects.

May 30, 2014 By Manish Butte

Gene Therapy for Primary Immunodeficiencies: Current Status and Future Prospects.

Drugs. 2014 May 22;

Authors: Qasim W, Gennery AR

Abstract
Gene therapy using autologous haematopoietic stem cells offers a valuable treatment option for patients with primary immunodeficiencies who do not have access to an HLA-matched donor, although such treatments have not been without their problems. This review details gene therapy trials for X-linked and adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD). X-linked SCID was chosen for gene therapy because of previous ‘natural’ genetic correction through a reversion event in a single lymphoid precursor, demonstrating limited thymopoiesis and restricted T-lymphocyte receptor repertoire, showing selective advantage of progenitors possessing the wild-type gene. In early studies, patients were treated with long terminal repeats-intact gamma-retroviral vectors, without additional chemotherapy. Early results demonstrated gene-transduced cells, sustained thymopoiesis, and a diverse T-lymphocyte repertoire with normal function. Serious adverse effects were subsequently reported in 5 of 20 patients, with T-lymphocyte leukaemia developing, secondary to the viral vector integrating adjacent to a known oncogene. New trials using self-inactivating gamma-retroviral vectors are progressing. Trials for ADA-SCID using gamma-retroviral vectors have been successful, with no similar serious adverse effects reported; trials using lentiviral vectors are in progress. Patients with WAS and CGD treated with early gamma-retroviral vectors have developed similar lymphoproliferative adverse effects to those seen in X-SCID-current trials are using new-generation vectors. Targeted gene insertion using homologous recombination of corrected gene sequences by cellular DNA repair pathways following targeted DNA breakage will improve efficacy and safety of gene therapy. A number of new techniques are discussed.

PMID: 24848753 [PubMed – as supplied by publisher]

Transcriptional regulation of Munc13-4 expression in cytotoxic lymphocytes is disrupted by an intronic mutation associated with a primary immunodeficiency.

May 30, 2014 By Manish Butte

Transcriptional regulation of Munc13-4 expression in cytotoxic lymphocytes is disrupted by an intronic mutation associated with a primary immunodeficiency.

J Exp Med. 2014 May 19;

Authors: Cichocki F, Schlums H, Li H, Stache V, Holmes T, Lenvik TR, Chiang SC, Miller JS, Meeths M, Anderson SK, Bryceson YT

Abstract
Autosomal recessive mutations in UNC13D, the gene that encodes Munc13-4, are associated with familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Munc13-4 expression is obligatory for exocytosis of lytic granules, facilitating cytotoxicity by T cells and natural killer (NK) cells. The mechanisms regulating Munc13-4 expression are unknown. Here, we report that Munc13-4 is highly expressed in differentiated human NK cells and effector CD8(+) T lymphocytes. A UNC13D c.118-308C>T mutation, causative of FHL3, disrupted binding of the ETS family member ELF1 to a conserved intronic sequence. This mutation impairs UNC13D intron 1 recruitment of STAT4 and the chromatin remodeling complex component BRG1, diminishing active histone modifications at the locus. The intronic sequence acted as an overall enhancer of Munc13-4 expression in cytotoxic lymphocytes in addition to representing an alternative promoter encoding a novel Munc13-4 isoform. Mechanistically, T cell receptor engagement facilitated STAT4-dependent Munc13-4 expression in naive CD8(+) T lymphocytes. Collectively, our data demonstrates how chromatin remodeling within an evolutionarily conserved regulatory element in intron 1 of UNC13D regulates the induction of Munc13-4 expression in cytotoxic lymphocytes and suggests that an alternative Munc13-4 isoform is required for lymphocyte cytotoxicity. Thus, mutations associated with primary immunodeficiencies may cause disease by disrupting transcription factor binding.

PMID: 24842371 [PubMed – as supplied by publisher]

Vaccine use in primary immunodeficiency disorders.

May 30, 2014 By Manish Butte

Vaccine use in primary immunodeficiency disorders.

Vaccine. 2014 May 13;

Authors: Principi N, Esposito S

Abstract
Primary immunodeficiency disorders (PIDs) are a heterogeneous group of rare, congenital and genetically determined conditions caused by one or more defects of innate and/or adaptive immunity. In subjects suffering from PIDs, an unusually increased susceptibility to infections is demonstrated. As infections condition the final prognosis of most PIDs, clearly defined prophylactic practices are essential. In most cases, intravenously or subcutaneously administered immunoglobulin remains the mainstay of treatment, although antibiotics and antifungals can be added under some conditions, particularly when the infections are highly recurrent despite immunoglobulin replacement. Vaccines could also play a role, but their administration leads to different results depending on the type of PID: in some cases, immune response is not impaired, and vaccines can evoke the same protection as that usually induced in healthy subjects; in others, the immunodeficiency significantly interferes with antigen stimulation of the immune system and, depending on the type and degree of impairment, little or no protection is evoked. Moreover, particularly when live vaccines are given, significant vaccine-related adverse events can occur, including the emergence of disease from vaccine strains. The main aim of this paper is to discuss what is currently known about how and when vaccines can be used in patients with PIDs in order to facilitate physician choices and assure the best possible patient protection.

PMID: 24837766 [PubMed – as supplied by publisher]

Spinal deformity caused by hyperimmunoglobulin E syndrome.

May 30, 2014 By Manish Butte

Spinal deformity caused by hyperimmunoglobulin E syndrome.

J Neurosurg Spine. 2014 May 16;:1-4

Authors: Araya N, Inose H, Kato T, Saito M, Sumiya S, Yamada T, Yoshii T, Kawabata S, Okawa A

Abstract
Hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency syndrome characterized by recurrent staphylococcal infections in the skin and lungs, with an incidence of less than one case per million persons. Skeletal and connective tissue abnormalities, such as scoliosis, osteoporosis, pathological fractures, and hyperextensive joints, are other manifestations of HIES. However, only one report documents the use of implants to treat spinal deformity caused by HIES, which was discovered following corrective surgery resulting in postoperative infection. In this case report, the authors describe a 16-year-old male with low-back pain and infections of the soft tissue. Radiological findings showed deteriorated kyphotic deformity due to the pathological compression fracture of T-11 with intensive conservative treatment. Anterior and posterior fixation surgery was performed. Thereafter, the patient showed no signs of infection. An investigation was conducted to avoid any postoperative infection.

PMID: 24836661 [PubMed – as supplied by publisher]

Improving current immunoglobulin therapy for patients with primary immunodeficiency: quality of life and views on treatment.

May 30, 2014 By Manish Butte

Improving current immunoglobulin therapy for patients with primary immunodeficiency: quality of life and views on treatment.

Patient Prefer Adherence. 2014;8:621-9

Authors: Espanol T, Prevot J, Drabwell J, Sondhi S, Olding L

Abstract
BACKGROUND: Subcutaneous or intravenous immunoglobulin replacement is the mainstay of treatment for most patients with primary immunodeficiency disease (PID). The purpose of this study was to gain an understanding of how existing PID therapies affect patient lives and to identify desired improvements to immunoglobulin treatments.
METHODS: An online questionnaire was made available through the International Patient Organisation for Primary Immunodeficiencies to patients with PID and their caregivers regarding current treatment satisfaction, living with PID, and patient preferences using a conjoint approach. Health-related quality of life was canvassed via questionnaires using the Short Form 12 Health Survey and EuroQoL 5 Dimensions.
RESULTS: A total of 300 responded to the survey (72% patients with PID and 28% caregivers) from across 21 countries, mostly the UK, Sweden, Canada, France, Germany, and Spain. Fifty-three percent and 45% of patients received intravenous and subcutaneous therapy, respectively. Most respondents (76%) were satisfied with their current treatment, reflecting the benefits that immunoglobulin therapy provides for patient health and well-being. However, patients remained below the physical and mental well-being norms for health-related quality of life as determined by the questionnaire. All respondents expressed a desire for 4-weekly infusions, the ability to administer these at home, self-administration, shorter duration of administration, and fewer needle sticks.
CONCLUSION: The results of this survey highlight the importance of providing access to different treatment options and modes of administration to ensure individual patient needs are best met.

PMID: 24833896 [PubMed]

Epiphora as the presenting sign of relapsed non-Hodgkin lymphoma in a child with Bruton agammaglobulinemia.

May 30, 2014 By Manish Butte

Epiphora as the presenting sign of relapsed non-Hodgkin lymphoma in a child with Bruton agammaglobulinemia.

Eur J Ophthalmol. 2014 May 8;:0

Authors: Gokce G, Ceylan OM, Uysal Y, Yildizoglu U, Atas E, Kurt B

Abstract
PURPOSE: Primary or secondary infiltration of the lacrimal drainage system by a lymphoid neoplasm is rare in children. Primary immunodeficiencies are characterized by occurrence of unusual malignancies at unexpected locations in the pediatric age group.
METHODS: Case report.
RESULTS: A 12-year-old boy with a history of Bruton agammaglobulinemia and non-Hodgkin lymphoma (NHL) that primarily originated in the perianal region was referred to our oculoplastics department for persistent epiphora. Computed tomography scan and nasal endoscopy revealed relapse of NHL in the inferior portion of the nasolacrimal duct. Complete remission was achieved with chemotherapy.
CONCLUSIONS: Epiphora could be the initial manifestation of a relapse or a recurrence of an underlying malignancy in the pediatric population with predisposing immunodeficiency.

PMID: 24832039 [PubMed – as supplied by publisher]

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]

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]

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]

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]