Research

Bronchus Associated Lymphoid Tissue Lymphoma Presenting with Immunodeficiency and Multiple Pulmonary Nodules.

Case Rep Pulmonol. 2017;2017:4804378

Authors: Borekci S, Ozbalak M, Ersen E, Akı H, Cem Ar M, Umut S

Abstract
Bronchus Associated Lymphoid Tissue Lymphoma (BALTOMA) is a rare subgroup of pulmonary non-Hodgkin’s lymphomas (NHLs) comprising less than 1% of all cases. It constitutes 3.6% of all extranodal lymphomas and only 0.5-1% of primary pulmonary malignancies. They are usually low grade B-cell lymphomas and are considered to originate from the mucosa associated lymphoid tissue (MALT) of the bronchi. Here, we represent a rare case of BALTOMA presenting with immunodeficiency and multiple pulmonary nodules.

PMID: 28386504 [PubMed]

Powered by WPeMatico

Host virus and pneumococcus-specific immune responses in high-count monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia: implications for disease progression.

Haematologica. 2017 Apr 06;:

Authors: Criado I, Muñoz-Criado S, Rodríguez-Caballero A, Nieto WG, Romero A, Fernández-Navarro P, Alcoceba M, Contreras T, González M, Orfao A, Almeida J, Primary Health Care Group of Salamanca for the Study of MBL

Abstract
Patients diagnosed with chronic lymphocytic leukemia display a high incidence of infections due to an associated immunodeficiency that includes hypogammaglobulinemia. A higher risk of infections has also been recently reported for high-count monoclonal B-cell lymphocytosis, while no information is available in low-count monoclonal B-cell lymphocytosis. Here, we evaluated the status of the humoral immune system in patients with chronic lymphocytic leukemia (n=58), as well as in low- (n=71) and high-count (n=29) monoclonal B-cell lymphocytosis vs. healthy donors (n=91). Total free plasma immunoglobulin titers and specific levels of antibodies against cytomegalovirus, Epstein-Barr Virus, Influenza and S.pneumoniae were measured by nephelometry and ELISA-based techniques, respectively. Overall, our results show that both chronic lymphocytic leukemia and high-count monoclonal B-cell lymphocytosis patients, but not low-count monoclonal B-cell lymphocytosis subjects, present with relatively high levels of antibodies specific for the latent viruses investigated, associated with progressively lower levels of S.pneumoniae-specific immunoglobulins. These findings probably reflect asymptomatic chronic reactivation of humoral immune responses against host viruses associated with expanded virus-specific antibody levels and progressively decreased protection against other microorganisms, denoting a severe humoral immunodeficiency state not reflected by the overall plasma immunoglobulin levels. Alternatively, these results could reflect a potential role of ubiquitous viruses in the pathogenesis of the disease. Further analyses are necessary to establish the relevance of such asymptomatic humoral immune responses against host viruses in the expansion of the tumor B-cell clone and progression from monoclonal B-cell lymphocytosis to chronic lymphocytic leukemia.

PMID: 28385786 [PubMed – as supplied by publisher]

Powered by WPeMatico

In vitro T lymphocyte proliferation by carboxyfluorescein diacetate succinimidyl ester method is helpful in diagnosing and managing primary immunodeficiencies.

J Clin Lab Anal. 2017 Apr 06;:

Authors: Azarsiz E, Karaca N, Ergun B, Durmuscan M, Kutukculer N, Aksu G

Abstract
BACKGROUND: Functional studies besides routine laboratory tests for the definitive diagnosis of T lymphocyte disorders with isolated T or combined T/B-cell immunodeficiencies are important. We hereby summarized our experience with a carboxyfluorescein diacetate succinimidyl ester (CFSE)-based assay for the assessment of mitogenic T-cell proliferation responses in primary immunodeficiency (PID) patients who have not been diagnosed yet or genetically analyzed, but classified as probably having T-cell defects.
METHODS: Unclassified patients (n=46) and controls (n=25) were evaluated for T-cell disorders with CFSE-based assay.
RESULTS: CD3(+) blast cells after PHA-L stimulation were significantly lower in patients (31.1±28.8) than controls (67.9±8.79; P<.001). Nine patients with low and four patients with normal CD3 values had severely decreased blastic transformation. The proliferation response decreased mostly in combined immunodeficiency group. Sixteen of them had impaired proliferation responses. Appropriate molecular genetical analyses were planned after thorough evaluation of each patient.
CONCLUSIONS: In vitro lymphocyte cell proliferation analysis by CFSE method is a reliable and practical choice for the assessment of mitogenic T lymphocyte responses in yet unclassified PID patients for targeting further genetical analyses.

PMID: 28383134 [PubMed – as supplied by publisher]

Powered by WPeMatico

Treatment of Pediatric Acute Graft-versus-Host Disease-Lessons from Primary Immunodeficiency?

Front Immunol. 2017;8:328

Authors: Flinn AM, Gennery AR

Abstract
Allogeneic hematopoietic stem cell transplant (HSCT) is used to treat increasing numbers of malignant and non-malignant disorders. Despite significant advances in improved human leukocyte antigens-typing techniques, less toxic conditioning regimens and better supportive care, resulting in improved clinical outcomes, acute graft-versus-host disease (aGvHD) continues to be a major obstacle and, although it principally involves the skin, gastrointestinal tract, and liver, the thymus is also a primary target. An important aim following HSCT is to achieve complete and durable immunoreconstitution with a diverse T-cell receptor (TCR) repertoire to recognize a broad range of pathogens providing adequate long-term adaptive T-lymphocyte immunity, essential to reduce the risk of infection, disease relapse, and secondary malignancies. Reconstitution of adaptive T-lymphocyte immunity is a lengthy and complex process which requires a functioning and structurally intact thymus responsible for the production of new naïve T-lymphocytes with a broad TCR repertoire. Damage to the thymic microenvironment, secondary to aGvHD and the effect of corticosteroid treatment, disturbs normal signaling required for thymocyte development, resulting in impaired T-lymphopoiesis and reduced thymic export. Primary immunodeficiencies, in which failure of central or peripheral tolerance is a major feature, because of intrinsic defects in hematopoietic stem cells leading to abnormal T-lymphocyte development, or defects in thymic stroma, can give insights into critical processes important for recovery from aGvHD. Extracorporeal photopheresis is a potential alternative therapy for aGvHD, which acts in an immunomodulatory fashion, through the generation of regulatory T-lymphocytes (Tregs), alteration of cytokine patterns and modulation of dendritic cells. Promoting normal central and peripheral immune tolerance, with selective downregulation of immune stimulation, could reduce aGvHD, and enable a reduction in other immunosuppression, facilitating thymic recovery, restoration of normal T-lymphocyte ontogeny, and complete immunoreconstitution with improved clinical outcome as the ability to fight infections improves and risk of secondary malignancy or relapse diminishes.

PMID: 28377772 [PubMed – in process]

Powered by WPeMatico

Specific polysaccharide antibody deficiency revealed by severe bacterial infections in adulthood: a report on eleven cases.

Clin Infect Dis. 2017 Apr 01;:

Authors: Lopez B, Boucher A, Bahuaud M, Mortuaire G, Melliez H, Launay D, Terriou L, Wemeau-Stervinou L, Wallaert B, Faure K, Wallet F, Hachulla E, Hatron PY, Dubucquoi S, Batteux F, Labalette M, Lefèvre G

Abstract
We report on 11 cases of specific polysaccharide antibody deficiency (SPAD) revealed in adulthood by severe infections with encapsulated bacteria. Given that immunoglobulin replacement therapy can effectively prevent the recurrence of bacterial infections in this context, SPAD should be considered once other antibody deficiencies have been ruled out.

PMID: 28379361 [PubMed – as supplied by publisher]

Powered by WPeMatico

Identification and characterization of a nationwide Danish adult common variable immunodeficiency cohort.

Scand J Immunol. 2017 Apr 02;:

Authors: Westh L, Mogensen TH, Dalgaard LS, Bernth Jensen JM, Katzenstein T, Hansen AE, Larsen OD, Terpling S, Nielsen TL, Larsen CS

Abstract
In this study we identified all adults living in Denmark diagnosed with common variable immunodeficiency (CVID) and characterized them according to clinical presentation and EUROclass classification. Using a retrospective, cross-sectional design, possible CVID patients were identified in the Danish National Patient Register and Centers in Denmark treating patients with primary immunodeficiencies. The CVID diagnosis was verified by review of medical records. One-hundred-seventy-nine adults with CVID were identified. This corresponds to a prevalence of 1:26,000. The median age at onset of symptoms was 29 years with no sex difference. The median age at diagnosis was 40 years. Males were diagnosed earlier with a peak in the fourth decade of life, whereas females were diagnosed later with a peak in the sixth decade. The median diagnostic delay was seven years. Recurrent sinopulmonary infections were seen in 92.7% of the patients. The prevalence of non-infectious complications was similar to that of previously reported cohorts: bronchiectasis (35.8%), splenomegaly (22.4%), lymphadenopathy (26.3%), granulomatous inflammation (3.9%), and idiopathic thrombocytopenic purpura (14.5%). Non-infectious complications were strongly associated with B cell phenotype, with all having a reduced number of isotype switched memory B cells. One-hundred-seventy (95%) were treated with immunoglobulin replacement therapy; primarily administered subcutaneously. According to international guidelines diagnostic evaluation was inadequate in most cases. This study emphasizes the need for improved diagnostic criteria and more awareness of CVID as a differential diagnosis. Diagnosis and management of CVID patients is a challenge requiring specialists with experience in the field of PID. This article is protected by copyright. All rights reserved.

PMID: 28370285 [PubMed – as supplied by publisher]

Powered by WPeMatico

Complement factor 5 (C5) p.A252T mutation is prevalent in, but not restricted to, Sub-Saharan Africa: Implications for the susceptibility to meningococcal disease.

Clin Exp Immunol. 2017 Apr 01;:

Authors: Franco-Jarava C, Comas D, Orren A, Hernández-González M, Colobran R

Abstract
Complement C5 deficiency (C5D) is a rare primary immunodeficiency associated with recurrent infections, particularly meningitis by Neisseria species. To date, studies to elucidate the molecular basis of hereditary C5D have included less than 40 families, and most C5 mutations (13/17) have been found in single families. However, the recently described C5 p.A252T mutation is reported to be associated with approximately 7% of meningococcal disease cases in South Africa. This finding raises the question of whether the mutation may be prevalent in other parts of Africa or other continental regions. The aim of this study was to investigate the prevalence of C5 p.A252T in Africa and other regions and discuss the implications for prophylaxis against meningococcal disease. In total, 2710 samples from healthy donors within various populations worldwide were analysed by qPCR assay to detect the C5 p.A252T mutation. Eleven samples were found to be heterozygous for p.A252T, and 9 of these samples were from Sub-Saharan African populations (allele frequency 0.94%). Interestingly, two other heterozygous samples were from individuals in populations outside Africa (Israel and Pakistan). These findings, together with data from genomic variation databases, indicate a 0.5% to 2% prevalence of the C5 p.A252T mutation in heterozygosity in Sub-Saharan Africa. Therefore, this mutation may have a relevant role in meningococcal disease susceptibility in this geographical area. This article is protected by copyright. All rights reserved.

PMID: 28369827 [PubMed – as supplied by publisher]

Powered by WPeMatico

A 3-Year-Old Girl with Recurrent Infections and Autoimmunity due to a STAT1 Gain-of-Function Mutation: The Expanding Clinical Presentation of Primary Immunodeficiencies.

Front Pediatr. 2017;5:55

Authors: Aldave Becerra JC, Cachay Rojas E

Abstract
We report a 3-year-old Peruvian girl, born to non-consanguineous parents. At the age of 8 months, she had a severe pneumonia complicated with empyema that required thoracic drainage and mechanical ventilation. Although no microorganisms were isolated, the patient recovered with broad-spectrum antibiotics. Since that date, she has presented multiple episodes of pneumonia and recurrent episodes of bronchospasm. At 1 year 5 months of age, the patient began with recurrent episodes of oropharyngeal, vaginal, and skin candidiasis, which improved transiently after using oral azole drugs. At 2.5 years of age, she was admitted with lupus-like syndrome, including serositis, hemolytic anemia, thrombocytopenia, and positive antinuclear (1:80) and dsDNA (1:10) autoantibodies. Available immunologic testing was not contributory. Imaging studies revealed bilateral ethmoidal sinusitis and mild hepatomegaly. Bone marrow analysis did not showed evidence of leukemia or myelodysplasia, while renal biopsy concluded mild mesangial proliferation. Genetic studies revealed a pathogenic heterozygous signal transducer and activator of transcription 1 gain-of-function mutation (WT/P293L). The clinical status and lung function of the patient has worsened progressively. She has not achieved an optimal response to therapy, including high-dose intravenous immunoglobulin, GM-CSF, prophylactic antibiotics and antifungal drugs, so we plan to perform hematopoietic stem cell transplantation.

PMID: 28367431 [PubMed – in process]

Powered by WPeMatico

Strains responsible for invasive meningococcal disease in patients with terminal complement pathway deficiencies.

J Infect Dis. 2017 Mar 25;:

Authors: Rosain J, Hong E, Fieschi C, Vieira Martins P, El Sissy C, Deghmane AE, Ouachée M, Thomas C, Launay D, de Pontual L, Suarez F, Moshous D, Picard C, Taha MK, Frémeaux-Bacchi V

Abstract
Background.: Patients with terminal complement pathway deficiencies (TPD) are susceptible to recurrent invasive meningococcal disease (IMD). Neisseria meningitidis (Nm) strains infecting these patients are poorly documented in the literature.
Methods.: We identified patients with TPD and available Nm strains isolated during IMD. We investigated the genetic basis of the different TPD and the characteristics of the Nm strains.
Results.: We included n=56 patients with C5 (n=8), C6 (n=20), C7 (n=18), C8 (n=9) or C9 (n=1) deficiency. Genetic study was performed in 47 patients and 30 pathogenic variants were identified in the genes coding for C5 (n=4), C6 (n=5), C7 (n=12), C8 (n=7) and C9 (n=2). We characterized 61 Nm strains responsible for IMD in the 56 patients with TPD. The most frequent strains belonged to group Y (n=27; 44%), B (n=18; 30%) and W (n=8; 13%). Hyperinvasive clonal complexes (cc) (cc11, cc32, cc41/44 or cc269) were responsible for 21% of IMD cases. The cc23 predominates and represented 26% of all invasive isolates. Eleven out the 15 cc identified fit to 12 different cc belonging to carriage strains.
Conclusions.: Unusual meningococcal strains with low level of virulence similar to carriage strains are most frequently responsible for IMD in patients with TPD.

PMID: 28368462 [PubMed – as supplied by publisher]

Powered by WPeMatico

ASGCT 20(th) Anniversary Special Issue of Molecular Therapy: Evolving Gene Therapy in Primary Immunodeficiency.

Mol Ther. 2017 Mar 30;:

Authors: Thrasher AJ, Williams DA

Abstract
Prior to the first successful bone marrow transplant in 1968, patients born with severe combined immunodeficiency (SCID) invariably died. Today, with a widening availability of newborn screening, major improvements in the application of allogeneic procedures, and the emergence of successful hematopoietic stem and progenitor cell (HSC/P) gene therapy, the majority of these children can be identified and cured. Here, we trace key steps in the development of clinical gene therapy for SCID and other primary immunodeficiencies (PIDs), and review the prospects for adoption of new targets and technologies.

PMID: 28366768 [PubMed – as supplied by publisher]

Powered by WPeMatico