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ICON: The Early Diagnosis of Congenital Immunodeficiencies.

March 17, 2014 By Manish Butte

ICON: The Early Diagnosis of Congenital Immunodeficiencies.

J Clin Immunol. 2014 Mar 12;

Authors: Routes J, Abinun M, Al-Herz W, Bustamante J, Condino-Neto A, De La Morena MT, Etzioni A, Gambineri E, Haddad E, Kobrynski L, Le Deist F, Nonoyama S, Oliveira JB, Perez E, Picard C, Rezaei N, Sleasman J, Sullivan KE, Torgerson T

Abstract
Primary immunodeficiencies are intrinsic defects in the immune system that result in a predisposition to infection and are frequently accompanied by a propensity to autoimmunity and/or immunedysregulation. Primary immunodeficiencies can be divided into innate immunodeficiencies, phagocytic deficiencies, complement deficiencies, disorders of T cells and B cells (combined immunodeficiencies), antibody deficiencies and immunodeficiencies associated with syndromes. Diseases of immune dysregulation and autoinflammatory disorder are many times also included although the immunodeficiency in these disorders are often secondary to the autoimmunity or immune dysregulation and/or secondary immunosuppression used to control these disorders. Congenital primary immunodeficiencies typically manifest early in life although delayed onset are increasingly recognized. The early diagnosis of congenital immunodeficiencies is essential for optimal management and improved outcomes. In this International Consensus (ICON) document, we provide the salient features of the most common congenital immunodeficiencies.

PMID: 24619621 [PubMed – as supplied by publisher]

Lentiviral vectors for the treatment of primary immunodeficiencies.

March 17, 2014 By Manish Butte

Lentiviral vectors for the treatment of primary immunodeficiencies.

J Inherit Metab Dis. 2014 Mar 12;

Authors: Farinelli G, Capo V, Scaramuzza S, Aiuti A

Abstract
In the last years important progress has been made in the treatment of several primary immunodeficiency disorders (PIDs) with gene therapy. Hematopoietic stem cell (HSC) gene therapy indeed represents a valid alternative to conventional transplantation when a compatible donor is not available and recent success confirmed the great potential of this approach. First clinical trials performed with gamma retroviral vectors were promising and guaranteed clinical benefits to the patients. On the other hand, the outcome of severe adverse events as the development of hematological abnormalities highlighted the necessity to develop a safer platform to deliver the therapeutic gene. Self-inactivating (SIN) lentiviral vectors (LVVs) were studied to overcome this hurdle through their preferable integration pattern into the host genome. In this review, we describe the recent advancements achieved both in vitro and at preclinical level with LVVs for the treatment of Wiskott-Aldrich syndrome (WAS), chronic granulomatous disease (CGD), ADA deficiency (ADA-SCID), Artemis deficiency, RAG1/2 deficiency, X-linked severe combined immunodeficiency (γchain deficiency, SCIDX1), X-linked lymphoproliferative disease (XLP) and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome.

PMID: 24619149 [PubMed – as supplied by publisher]

α- and β-Papillomavirus infection in a young patient with an unclassified primary T-cell immunodeficiency and multiple mucosal and cutaneous lesions.

March 17, 2014 By Manish Butte

α- and β-Papillomavirus infection in a young patient with an unclassified primary T-cell immunodeficiency and multiple mucosal and cutaneous lesions.

J Am Acad Dermatol. 2014 Mar 4;

Authors: Landini MM, Borgogna C, Peretti A, Colombo E, Zavattaro E, Boldorini R, Miglio U, Doorbar J, Ravanini P, Kumar R, Moratto D, Badolato R, De Andrea M, Gariglio M

Abstract
BACKGROUND: Correlating human papillomavirus (HPV) type with the clinical and histopathological features of skin lesions (from genital and nongenital sites) can present a diagnostic challenge.
OBJECTIVE: In this study, HPV infection patterns were correlated with pathology and clinical presentation in lesional and nonlesional body sites from a young patient with a primary T-cell immunodeficiency.
METHODS: HPV infection was evaluated at both DNA and protein levels by polymerase chain reaction and immunohistochemistry.
RESULTS: The patient’s genital lesions were caused exclusively by α-genotypes (high-risk type HPV-51 in the anal and low-risk type HPV-72 in the penile condylomas). The opposite was true for the skin lesions, which were infected by β-genotypes alone (HPV-8 and HPV-24). HPV-24 was the predominant type in terms of viral load, and the only one found in productive areas of infection. The patient had already developed high-grade dysplasia in the anal condyloma-like lesions, and showed areas of early-stage dysplasia in the lesions caused by the β-genotype HPV-24.
LIMITATIONS: The basic origin of the immunodeficiency is not yet defined.
CONCLUSION: These findings provide proof of principle that both α- and β-genotypes can cause overt dysplastic lesions when immunosurveillance is lost, which is not restricted to epidermodysplasia verruciformis.

PMID: 24612648 [PubMed – as supplied by publisher]

Genetic defects and the role of helper T-cells in the pathogenesis of common variable immunodeficiency.

March 17, 2014 By Manish Butte

Genetic defects and the role of helper T-cells in the pathogenesis of common variable immunodeficiency.

Adv Biomed Res. 2014;3:2

Authors: Yazdani R, Hakemi MG, Sherkat R, Homayouni V, Farahani R

Abstract
Common variable immunodeficfiiency (CVID) is a primary immunodeficiency syndrome representing a heterogeneous set of disorders resulting mostly in antibody deficiency and recurrent infections. However, inflammatory and autoimmune disorders and some kinds of malignancies are frequently reported as a part of the syndrome. Although it is one of the most widespread primary immunodeficiency, only recently some genetic defects in CVID have been identified. Mutations have been detected in inducible T-cell costimulator (ICOS), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), B-cell activating factor-receptor (BAFF-R), B-cell receptor complex (CD19, CD21 and CD81) and CD20. On the other hand, recent studies have shown a decrease in T-helper-17 cells frequency and their characteristic cytokines in CVID patients and this emphasis on the vital role of the T-cells in immunopathogenesis of the CVID. Furthermore, in the context of autoimmune diseases accompanying CVID, interleukin 9 has recently attracted a plenty of considerations. However, the list of defects is expanding as exact immunologic pathways and genetic disorders in CVID are not yet defined. In this review, we have a special focus on the immunopathogenesis of CVID, recent advances in understanding the underlying etiology and genetics for patients.

PMID: 24600593 [PubMed]

Cytokine-Mediated Regulation of Plasma Cell Generation: IL-21 Takes Center Stage.

March 17, 2014 By Manish Butte

Cytokine-Mediated Regulation of Plasma Cell Generation: IL-21 Takes Center Stage.

Front Immunol. 2014;5:65

Authors: Moens L, Tangye SG

Abstract
During our life, we are surrounded by continuous threats from a diverse range of invading pathogens. Our immune system has evolved multiple mechanisms to efficiently deal with these threats so as to prevent them from causing disease. Terminal differentiation of mature B cells into plasma cells (PC) – the antibody (Ab) secreting cells of the immune system – is critical for the generation of protective and long-lived humoral immune responses. Indeed, efficient production of antigen (Ag)-specific Ab by activated B cells underlies the success of most currently available vaccines. The mature B-cell pool is composed of several subsets, distinguished from one according to size, surface marker expression, location, and Ag exposure, and they all have the capacity to differentiate into PCs. For a B-cell to acquire the capacity to produce Abs, it must undergo an extensive differentiation process driven by changes in gene expression. Two broad categories of Ags exist that cause B-cell activation and differentiation: T cell dependent (TD) or T cell independent (TI). In addition to the B-cell subset and nature of the Ag, it is important to consider the cytokine environment that can also influence how B-cell differentiation is achieved. Thus, while many cytokines can induce Ab-secretion by B cells after activation with mimics of TD and TI stimuli in vitro, they can have different efficacies and specificities, and can often preferentially induce production of one particular Ig isotype over another. Here, we will provide an overview of in vitro studies (mouse and human origin) that evaluated the role of different cytokines in inducing the differentiation of distinct B-cell subsets to the PC lineage. We will place particular emphasis on IL-21, which has emerged as the most potent inducer of terminal B-cell differentiation in humans. We will also focus on the role of IL-21 and defects in B-cell function and how these contribute to human immunopathologies such as primary immunodeficiencies and B-cell mediated autoimmune conditions.

PMID: 24600453 [PubMed – as supplied by publisher]

Diagnostic accuracy of nitric oxide measurements to detect Primary Ciliary Dyskinesia.

March 17, 2014 By Manish Butte

Diagnostic accuracy of nitric oxide measurements to detect Primary Ciliary Dyskinesia.

Eur J Clin Invest. 2014 Mar 5;

Authors: Boon M, Meyts I, Proesmans M, Vermeulen FL, Jorissen M, De Boeck K

Abstract
BACKGROUND: Primary Ciliary Dyskinesia (PCD) is an orphan disease characterized by recurrent respiratory infections and an increased prevalence of situs inversus and male infertility. Low nasal Nitric Oxide (nNO) is used as a new test to diagnose PCD. The test sensitivity is good, but specificity has not been studied widely. Therefore, we evaluated the diagnostic accuracy of low nNO to diagnose PCD in a large cohort, including healthy patients and different disease controls.
MATERIALS AND METHODS: nNO was measured during plateau exhalation against resistance (nNOplat ) and during tidal breathing (nNOtid ). Moreover, we measured fractional exhaled NO (FENO). We included 226 patients: 38 with PCD, 49 healthy controls and 139 disease controls (cystic fibrosis, humoral immunodeficiency and asthma).
RESULTS: The nNOplat cut-off value of 300 ppb provided the best sensitivity (89.5%) and specificity (87.3%) to detect PCD. There was overlap between PCD and disease controls: 16.5% of disease controls had a false positive result. nNOtid correlated with nNOplat (r 0.912), but values differed (p 0.0001). The nNOtid cut-off of 200 ppb had a sensitivity of 89.5% and a specificity of 80.6% to detect PCD. The FENO cut-off of 10 ppb had an acceptable sensitivity (89.5%), but a low specificity (58.3%). Positive and negative likelihood ratios were suboptimal for all tests.
CONCLUSIONS: nNOplat , nNOtid and FENO measurements overlap between PCD and disease controls. Sensitivity is comparable for the 3 tests. Applying composite scores slightly improves diagnostic accuracy. Given the less than 90% test sensitivity, PCD should be considered in patients with intermediate results. This article is protected by copyright. All rights reserved.

PMID: 24597492 [PubMed – as supplied by publisher]

STAT3 is a central regulator of lymphocyte differentiation and function.

March 17, 2014 By Manish Butte

STAT3 is a central regulator of lymphocyte differentiation and function.

Curr Opin Immunol. 2014 Mar 1;28C:49-57

Authors: Kane A, Deenick EK, Ma CS, Cook MC, Uzel G, Tangye SG

Abstract
Signalling in lymphocytes through cytokine receptors is critical for their development, activation and differentiation into effector cells that mediate protection against pathogens and provide the host with protective immunological memory. The essential role of cytokine signalling has been established not only by the generation and examination of gene-targeted mice, but also ‘Experiments of Nature’ whereby monogenic mutations cause primary immunodeficient conditions characterised by impaired immunity to infectious diseases due to compromised lymphocyte function. Mutations in STAT3 cause autosomal dominant hyper-IgE syndrome. Here, we will review how the study of STAT3-deficient individuals has revealed non-redundant functions of STAT3 and specific cytokines in human lymphocyte biology, and have delineated mechanisms underlying the distinct clinical features of autosomal dominant hyper-IgE syndrome.

PMID: 24594518 [PubMed – as supplied by publisher]

NK cell development and function – Plasticity and redundancy unleashed.

March 17, 2014 By Manish Butte

NK cell development and function – Plasticity and redundancy unleashed.

Semin Immunol. 2014 Mar 1;

Authors: Cichocki F, Sitnicka E, Bryceson YT

Abstract
Bone marrow-derived natural killer (NK) cells constitute the major subset of cytotoxic lymphocytes in peripheral blood. They provide innate defense against intracellular infection or malignancy and contribute to immune homeostasis. Large numbers of NK cells are also present in tissues, including the liver and uterus, where they can mediate immunosurveillance but also play important roles in tissue remodeling and vascularization. Here, we review the pathways involved in NK cell lineage commitment and differentiation, discussing relationships to other lymphocyte populations and highlighting genetic determinants. Characterizing NK cells from distinct tissues and during infections have revealed subset specializations, reflecting inherent cellular plasticity. In this context, we discuss how different environmental and inflammatory stimuli may shape NK cells. Particular emphasis is placed on genes identified as being critical for NK cell development, differentiation, and function from studies of model organisms or associations with disease. Such studies are also revealing important cellular redundancies. Here, we provide a view of the genetic framework constraining NK cell development and function, pinpointing molecules required for these processes but also underscoring plasticity and redundancy that may underlie robust immunological function. With this view, built in redundancy may highlight the importance of NK cells to immunity.

PMID: 24594002 [PubMed – as supplied by publisher]

Advances in basic and clinical immunology in 2013.

March 17, 2014 By Manish Butte

Advances in basic and clinical immunology in 2013.

J Allergy Clin Immunol. 2014 Feb 28;

Authors: Chinen J, Notarangelo LD, Shearer WT

Abstract
A significant number of contributions to our understanding of primary immunodeficiencies (PIDs) in pathogenesis, diagnosis, and treatment were published in the Journal in 2013. For example, deficiency of mast cell degranulation caused by signal transducer and activator of transcription 3 deficiency was demonstrated to contribute to the difference in the frequency of severe allergic reactions in patients with autosomal dominant hyper-IgE syndrome compared with that seen in atopic subjects with similar high IgE serum levels. High levels of nonglycosylated IgA were found in patients with Wiskott-Aldrich syndrome, and these abnormal antibodies might contribute to the nephropathy seen in these patients. New described genes causing immunodeficiency included caspase recruitment domain 11 (CARD11), mucosa-associated lymphoid tissue 1 (MALT1) for combined immunodeficiencies, and tetratricopeptide repeat domain 7A (TTC7A) for mutations associated with multiple atresia with combined immunodeficiency. Other observations expand the spectrum of clinical presentation of specific gene defects (eg, adult-onset idiopathic T-cell lymphopenia and early-onset autoimmunity might be due to hypomorphic mutations of the recombination-activating genes). Newborn screening in California established the incidence of severe combined immunodeficiency at 1 in 66,250 live births. The use of hematopoietic stem cell transplantation for PIDs was reviewed, with recommendations to give priority to research oriented to establish the best regimens to improve the safety and efficacy of bone marrow transplantation. These represent only a fraction of significant research done in patients with PIDs that has accelerated the quality of care of these patients. Genetic analysis of patients has demonstrated multiple phenotypic expressions of immune deficiency in patients with nearly identical genotypes, suggesting that additional genetic factors, possibly gene dosage, or environmental factors are responsible for this diversity.

PMID: 24589342 [PubMed – as supplied by publisher]

Oral cavity and oropharyngeal squamous cell carcinoma in young adults: a review of the literature.

March 17, 2014 By Manish Butte

Oral cavity and oropharyngeal squamous cell carcinoma in young adults: a review of the literature.

Radiol Oncol. 2014 Mar;48(1):1-10

Authors: Majchrzak E, Szybiak B, Wegner A, Pienkowski P, Pazdrowski J, Luczewski L, Sowka M, Golusinski P, Malicki J, Golusinski W

Abstract
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a disease of middle-aged to elderly adults. However, an increased incidence of HNSCC in young people under 45 years of age has been reported recently. In the present review, we focused on the epidemiology and aetiology of HNSCC in adults under 45 years of age.
METHODS: We reviewed literature related to HNSCC in adult patients less than 45 years of age and discussed current treatment options and prognosis.
RESULTS: HNSCC in young adults is associated with a higher incidence rate in nonsmokers, lower female-to-male ratio, a higher percentage of oral cavity and oropharynx tumours, and fewer second primary tumours. However, aside from traditional risk factors of tobacco and alcohol exposure, the causes of these cancers in young adults remain unclear. Agents that might contribute to risk include infection with high-risk human papillomavirus subtypes as well as genetic factors or immunodeficiency status. The expected increase in incidence and mortality of the young with HNSCC may become a major public health concern if current trends persist, particularly lifestyle habits that may contribute to this disease.
CONCLUSIONS: Given the younger age and potential long-term adverse sequelae of traditional HNSCC treatments, young adults should be treated on a case-by-case basis and post-therapy quality of life must be considered in any treatment-decision making process.

PMID: 24587773 [PubMed – as supplied by publisher]