Research

Clinical, Immunological, Molecular Analyses and Outcomes of Iranian Patients with LRBA Deficiency: A Longitudinal Study.

Pediatr Allergy Immunol. 2017 May 17;:

Authors: Azizi G, Abolhassani H, Mahdaviani SA, Chavoshzadeh Z, Eshghi P, Yazdani R, Kiaee F, Shaghaghi M, Mohammadi J, Rezaei N, Hammarström L, Aghamohammadi A

Abstract
BACKGROUND: LPS-responsive beige-like anchor protein (LRBA) deficiency is a combined immunodeficiency caused by mutation in LRBA gene. The patients have a variety of clinical symptoms including hypogammaglobulinemia, recurrent infections, autoimmunity and enteropathy.
METHODS: A total of 17 LRBA-deficient patients were enrolled in this longitudinal study. For all patients, demographic information, clinical records, laboratory and molecular data were collected.
RESULTS: Hypogammaglobulinemia were reported in 14 (82.4%), CD4(+) T cell deficiency in five (29.4%), NK cell deficiency in three (21.4%) and CD19(+) B cell deficiency in 11 (64.7%) patients. All patients had history of infectious complications; pneumonia was the most common (76.5%) occurring infection. A history of lymphoproliferative disorders was observed in 14 (82.3%), enteropathy in 13 (76.5%), allergic symptoms in six (35.5%), neurological problems in four (23.5) and autoimmunity (mostly autoimmune cytopenia) in 13 (76.5%) patients. Sirolimus treatment improved enteropathy of patients with remarkable success. The 20-year overall survival rate declined to 70.6%.
CONCLUSION: LRBA deficiency has a very broad and variable phenotype and should be considered, especially in children with early onset hypogammaglobulinemia, severe autoimmune manifestations, enteropathy, lymphoproliferation, and recurrent respiratory tract infections. This article is protected by copyright. All rights reserved.

PMID: 28512785 [PubMed – as supplied by publisher]

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Serial sonographic findings during progression from acute pyelonephritis to renal abscess: a rare case report.

CEN Case Rep. 2016 Sep 24;:

Authors: Sato M, Suzuki S, Shimada S, Yamamoto S, Taketazu G, Mukai T, Taketazu M, Sakata H, Oki J

Abstract
Renal abscess, accumulation of infective fluid in the kidney, is a rare pathology. Currently, no reports of the serial imaging changes of acute pyelonephritis (APN) progressing to renal abscess exist. We report clinical and serial sonographic findings of a patient with hyper-immunoglobulin E syndrome, a primary immunodeficiency, who developed APN that progressed to renal abscess. Renal ultrasonography revealed that echogenicity of infectious lesions dramatically changed from isoechoic to hyperechoic and to hypoechoic during progression. These findings are useful for differential diagnosis of APN, acute focal bacterial nephritis, and renal abscess.

PMID: 28509119 [PubMed – as supplied by publisher]

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Clinical and Molecular Heterogeneity of RTEL1 Deficiency.

Front Immunol. 2017;8:449

Authors: Speckmann C, Sahoo SS, Rizzi M, Hirabayashi S, Karow A, Serwas NK, Hoemberg M, Damatova N, Schindler D, Vannier JB, Boulton SJ, Pannicke U, Göhring G, Thomay K, Verdu-Amoros JJ, Hauch H, Woessmann W, Escherich G, Laack E, Rindle L, Seidl M, Rensing-Ehl A, Lausch E, Jandrasits C, Strahm B, Schwarz K, Ehl SR, Niemeyer C, Boztug K, Wlodarski MW

Abstract
Typical features of dyskeratosis congenita (DC) resulting from excessive telomere shortening include bone marrow failure (BMF), mucosal fragility, and pulmonary or liver fibrosis. In more severe cases, immune deficiency and recurring infections can add to disease severity. RTEL1 deficiency has recently been described as a major genetic etiology, but the molecular basis and clinical consequences of RTEL1-associated DC are incompletely characterized. We report our observations in a cohort of six patients: five with novel biallelic RTEL1 mutations p.Trp456Cys, p.Ile425Thr, p.Cys1244ProfsX17, p.Pro884_Gln885ins53X13, and one with novel heterozygous mutation p.Val796AlafsX4. The most unifying features were hypocellular BMF in 6/6 and B-/NK-cell lymphopenia in 5/6 patients. In addition, three patients with homozygous mutations p.Trp456Cys or p.Ile425Thr also suffered from immunodeficiency, cerebellar hypoplasia, and enteropathy, consistent with Hoyeraal-Hreidarsson syndrome. Chromosomal breakage resembling a homologous recombination defect was detected in patient-derived fibroblasts but not in hematopoietic compartment. Notably, in both cellular compartments, differential expression of 1243aa and 1219/1300aa RTEL1 isoforms was observed. In fibroblasts, response to ionizing irradiation and non-homologous end joining were not impaired. Telomeric circles did not accumulate in patient-derived primary cells and lymphoblastoid cell lines, implying alternative pathomechanisms for telomeric loss. Overall, RTEL1-deficient cells exhibited a phenotype of replicative exhaustion, spontaneous apoptosis and senescence. Specifically, CD34(+) cells failed to expand in vitro, B-cell development was compromised, and T-cells did not proliferate in long-term culture. Finally, we report on the natural history and outcome of our patients. While two patients died from infections, hematopoietic stem cell transplantation (HSCT) resulted in sustained engraftment in two patients. Whether chemotherapy negatively impacts on the course and onset of other DC-related symptoms remains open at present. Early-onset lung disease occurred in one of our patients after HSCT. In conclusion, RTEL deficiency can show a heterogeneous clinical picture ranging from mild hypocellular BMF with B/NK cell lymphopenia to early-onset, very severe, and rapidly progressing cellular deficiency.

PMID: 28507545 [PubMed – in process]

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The heterogeneity of systemic inflammation in bronchiectasis.

Respir Med. 2017 Jun;127:33-39

Authors: Saleh AD, Chalmers JD, De Soyza A, Fardon TC, Koustas SO, Scott J, Simpson AJ, Brown JS, Hurst JR

Abstract
BACKGROUND: Systemic inflammation in bronchiectasis is poorly studied in relation to aetiology and severity. We hypothesized that molecular patterns of inflammation may define particular aetiology and severity groups in bronchiectasis.
METHOD: We assayed blood concentrations of 31 proteins from 90 bronchiectasis patients (derivation cohort) and conducted PCA to examine relationships between these markers, disease aetiology and severity. Key results were validated in two separate cohorts of 97 and 79 patients from other centres.
RESULTS: There was significant heterogeneity in protein concentrations across the derivation population. Increasing severity of bronchiectasis (BSI) was associated with increasing fibrinogen (rho = 0.34, p = 0.001 -validated in a second cohort), and higher fibrinogen was associated with worse lung function, Pseudomonas colonisation and impaired health-status. There were generally similar patterns of inflammation in patients with idiopathic and post-infectious disease. However, patients with primary immunodeficiency had exaggerated IL-17 responses, validated in a second cohort (n = 79, immunodeficient 12.82 pg/ml versus idiopathic/post-infectious 4.95 pg/ml, p = 0.001), and thus IL-17 discriminated primary immunodeficiency from other aetiologies (AUC 0.769 (95%CI 0.661-0.877)).
CONCLUSION: Bronchiectasis is associated with heterogeneity of systemic inflammatory proteins not adequately explained by differences in disease aetiology or severity. More severe disease is associated with enhanced acute-phase responses. Plasma fibrinogen was associated with bronchiectasis severity in two cohorts, Pseudomonas colonisation and health status, and offers potential as a useful biomarker.

PMID: 28502416 [PubMed – in process]

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Toward an Inclusive, Congruent, and Precise Definition of Autoinflammatory Diseases.

Front Immunol. 2017;8:497

Authors: Wekell P, Berg S, Karlsson A, Fasth A

Abstract
Autoinflammatory disease was introduced as a concept in 1999, demarcating an entirely new group of diseases in clinical, immunological, and conceptual terms. During recent years, the preconditions for the definition of autoinflammatory conditions have changed. This includes the recent discovery of a number of monogenic autoinflammatory conditions with complex phenotypes that combine autoinflammation with defects of the adaptive and/or innate immune system, resulting in the occurrence of infection, autoimmunity, and/or uncontrolled hyperinflammation in addition to autoinflammation. Further, there are strong indications that classical IL-1-driven autoinflammatory diseases are associated with activation of adaptive immunity. As suggested by this development, we are of the opinion that an all-encompassing definition of autoinflammatory diseases should regard autoinflammatory conditions and innate dysregulation as inseparable and integral parts of the immune system as a whole. Hence, in this article, we try to advance the conceptual understanding of autoinflammatory disease by, proposing a modification of the definition by Daniel Kastner et al., which allows for a congruent and precise description of conditions that expand the immunological spectrum of autoinflammatory disease.

PMID: 28496446 [PubMed – in process]

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Evaluation of pulmonary complications in patients with primary immunodeficiency disorders.

Eur Ann Allergy Clin Immunol. 2017 May;49(3):122-128

Authors: Reisi M, Azizi G, Kiaee F, Masiha F, Shirzadi R, Momen T, Rafiemanesh H, Tavakolinia N, Modaresi M, Aghamohammadi A

Abstract
Summary: Background. Primary immunodeficiencies (PIDs) are inherited disorders in which one or several components of immune system are defected. Moreover, affected patients are at high risk for developing recurrent infections, particularly pulmonary infections. The spectrum of pulmonary manifestations in PIDs is broad, and includes acute and chronic infection, structural abnormalities (eg, bronchiectasis), malignancy and dysregulated inflammation resulting in tissue damage. In this study, our aims are to evaluate pulmonary complications in PID patients. Patients and Methods. We studied 204 cases with confirmed PID. To evaluate pulmonary complications in these patients, we used pulmonary function test (PFT), high resolution computed tomography (HRCT) scan and bronchoalveolar lavage (BAL). Results. Our results showed that pneumonia was the most frequent clinical manifestations in all PID patients. There were significantly greater numbers of episodes of pneumonia in HIgM, XLA and CVID patients with delayed diagnoses < 6 years. Moreover, of 57.4% CVID patients, 55% XLA patients and 33.3% HIgM patients had abnormal PFT results, and bronchiectasis was showed in 9 (42.9%) of XLA, 6 (11.8%) of HIES, 3 (21.4%) of HIgM and 38 (62.3%) of CVID patients. Conclusion. Pulmonary complications should be considered in cases with PIDs especially in CVID cases.

PMID: 28497675 [PubMed – in process]

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Screening of 181 patients with antibody deficiency for Deficiency of Adenosine Deaminase 2 sheds new light on the disease in adulthood.

Arthritis Rheumatol. 2017 May 10;:

Authors: Schepp J, Proietti M, Frede N, Buchta M, Hübscher K, Rojas Restrepo J, Goldacker S, Warnatz K, Pachlopnik Schmid J, Duppenthaler A, Lougaris V, Uriarte I, Kelly S, Hershfield M, Grimbacher B

Abstract
OBJECTIVE: We aimed to test the relevance of Deficiency of Adenosine Deaminase 2 in patients with antibody deficiency and describe the clinical picture of the disease in adulthood.
METHODS: We screened for DADA2 in a cohort of 181 patients with antibody deficiency with and without vascular lesions by the means of Next-Generation-Sequencing and targeted Sanger Sequencing. All mutations were confirmed by determining the ADA2 enzymatic activity levels in dried plasma spots. Clinical data and laboratory values were collected in a standardized format.
RESULTS: Following the diagnosis of two siblings of the index family, we identified nine additional affected patients with compound heterozygous or homozygous CECR1 mutations, containing six novel and four previously published mutations. The patients’ age at evaluation ranged from 14 to 51 years with a median age of 22 years. Clinically, we saw a broad phenotype ranging from isolated antibody deficiency to recurrent strokes. All but one patient had low memory B-cells. Moreover, the B-cell function seemed to correlate with inflammation.
CONCLUSIONS: Taken together, we found that DADA2 presents not only with vasculopathy but also with an immunodeficiency of the B-cell compartment. Therefore, patients with antibody deficiency should be screened for DADA2. Anti-TNF-alpha treatment might improve the immunological features over time and might be considered in patients without vascular manifestations but elevated inflammation markers. Conservative management of the less severely affected patients has so far proven to be the choice for our adolescent and adult DADA2-patients; however, in patients with severe cytopenias and bone marrow failure, HSCT should be considered. This article is protected by copyright. All rights reserved.

PMID: 28493328 [PubMed – as supplied by publisher]

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Common Variable Immunodeficiency Caused by FANC Mutations.

J Clin Immunol. 2017 May 11;:

Authors: Sekinaka Y, Mitsuiki N, Imai K, Yabe M, Yabe H, Mitsui-Sekinaka K, Honma K, Takagi M, Arai A, Yoshida K, Okuno Y, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Muramatsu H, Kojima S, Hira A, Takata M, Ohara O, Ogawa S, Morio T, Nonoyama S

Abstract
Common variable immunodeficiency (CVID) is the most common adult-onset primary antibody deficiency disease due to various causative genes. Several genes, which are known to be the cause of different diseases, have recently been reported as the cause of CVID in patients by performing whole exome sequencing (WES) analysis. Here, we found FANC gene mutations as a cause of adult-onset CVID in two patients. B cells were absent and CD4(+) T cells were skewed toward CD45RO(+) memory T cells. T-cell receptor excision circles (TRECs) and signal joint kappa-deleting recombination excision circles (sjKRECs) were undetectable in both patients. Both patients had no anemia, neutropenia, or thrombocytopenia. Using WES, we identified compound heterozygous mutations of FANCE in one patient and homozygous mutation of FANCA in another patient. The impaired function of FANC protein complex was confirmed by a monoubiquitination assay and by chromosome fragility test. We then performed several immunological evaluations including quantitative lymphocyte analysis and TRECs/sjKRECs analysis for 32 individuals with Fanconi anemia (FA). In total, 22 FA patients (68.8%) were found to have immunological abnormalities, suggesting that such immunological findings may be common in FA patients. These data indicate that FANC mutations are involved in impaired lymphogenesis probably by the accumulation of DNA replication stress, leading to CVID. It is important to diagnose FA because it drastically changes clinical management. We propose that FANC mutations can cause isolated immunodeficiency in addition to bone marrow failure and malignancy.

PMID: 28493158 [PubMed – as supplied by publisher]

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PLA2R-positive (primary) membranous nephropathy in a child with IPEX syndrome.

Pediatr Nephrol. 2017 May 09;:

Authors: Chuva T, Pfister F, Beringer O, Felgentreff K, Büttner-Herold M, Amann K

Abstract
BACKGROUND: Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare primary immunodeficiency syndrome characterized by the development of multiple autoimmune disorders in affected individuals. Different forms of renal injury have been reported in IPEX syndrome, and membranous nephropathy (MN) is among the most common glomerulopathies found. However, the exact pathogenesis of MN in this setting has not been elucidated, and it is not clear whether it is part of the clinical spectrum of the disease or secondary to medications, infections or other concomitant insults.
DIAGNOSIS/TREATMENT: We describe a child diagnosed with IPEX syndrome shortly after birth who presented with nephrotic syndrome at the age of 11 weeks. Renal biopsy revealed a MN with enhanced immunohistochemical staining for phospholipase A2 receptor (PLA2R).
CONCLUSION: This is the first report of a PLA2R-positive MN in a patient with IPEX syndrome. We suggest that, in this context, MN results from an autoimmune process against podocytic antigens, namely PLA2R.

PMID: 28488220 [PubMed – as supplied by publisher]

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