Research

Targeted sequencing identifies a novel SH2D1A pathogenic variant in a Chinese family: Carrier screening and prenatal genetic testing.

PLoS One. 2017;12(2):e0172173

Authors: Zhang JY, Chen SC, Chen YY, Li SY, Zhang LL, Shen YH, Chang CX, Xiang YQ, Huang HF, Xu CM

Abstract
X-linked lymphoproliferative disease type 1 (XLP1) is a rare primary immunodeficiency characterized by a clinical triad consisting of severe EBV-induced hemophagocytic lymphohistiocytosis, B-cell lymphoma, and dysgammaglobulinemia. Mutations in SH2D1A gene have been revealed as the cause of XLP1. In this study, a pregnant woman with recurrence history of birthing immunodeficiency was screened for pathogenic variant because the proband sample was unavailable. We aimed to clarify the genetic diagnosis and provide prenatal testing for the family. Next-generation sequencing (NGS)-based multigene panel was used in carrier screening of the pregnant woman. Variants of immunodeficiency related genes were analyzed and prioritized. Candidate variant was verified by using Sanger sequencing. The possible influence of the identified variant was evaluated through RNA assay. Amniocentesis, karyotyping, and Sanger sequencing were performed for prenatal testing. We identified a novel de novo frameshift SH2D1A pathogenic variant (c.251_255delTTTCA) in the pregnant carrier. Peripheral blood RNA assay indicated that the mutant transcript could escape nonsense-mediated mRNA decay (NMD) and might encode a C-terminal truncated protein. Information of the variant led to success prenatal diagnosis of the fetus. In conclusion, our study clarified the genetic diagnosis and altered disease prevention for a pregnant carrier of XLP1.

PMID: 28231257 [PubMed – in process]

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Modeling strategy to identify patients with primary immunodeficiency utilizing risk management and outcome measurement.

Immunol Res. 2017 Feb 21;:

Authors: Modell V, Quinn J, Ginsberg G, Gladue R, Orange J, Modell F

Abstract
This study seeks to generate analytic insights into risk management and probability of an identifiable primary immunodeficiency defect. The Jeffrey Modell Centers Network database, Jeffrey Modell Foundation’s 10 Warning Signs, the 4 Stages of Testing Algorithm, physician-reported clinical outcomes, programs of physician education and public awareness, the SPIRIT® Analyzer, and newborn screening, taken together, generates P values of less than 0.05%. This indicates that the data results do not occur by chance, and that there is a better than 95% probability that the data are valid. The objectives are to improve patients’ quality of life, while generating significant reduction of costs. The advances of the world’s experts aligned with these JMF programs can generate analytic insights as to risk management and probability of an identifiable primary immunodeficiency defect. This strategy reduces the uncertainties related to primary immunodeficiency risks, as we can screen, test, identify, and treat undiagnosed patients. We can also address regional differences and prevalence, age, gender, treatment modalities, and sites of care, as well as economic benefits. These tools support high net benefits, substantial financial savings, and significant reduction of costs. All stakeholders, including patients, clinicians, pharmaceutical companies, third party payers, and government healthcare agencies, must address the earliest possible precise diagnosis, appropriate intervention and treatment, as well as stringent control of healthcare costs through risk assessment and outcome measurement. An affected patient is entitled to nothing less, and stakeholders are responsible to utilize tools currently available. Implementation offers a significant challenge to the entire primary immunodeficiency community.

PMID: 28224361 [PubMed – as supplied by publisher]

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Acute Rejection of a Kidney Transplant in a Patient With Common Variable Immunodeficiency: A Case Report.

Transplant Proc. 2017 Mar;49(2):380-385

Authors: Al Nimri O, Rajput A, Martinez E, Fahrenholz JM, Paueksakon P, Langone A, Concepcion BP

Abstract
Common variable immunodeficiency is a primary immunodeficiency characterized by hypogammaglobulinemia and recurrent bacterial infections. We report a case of a 44-year-old male patient with end-stage renal disease and an established diagnosis of common variable immunodeficiency who underwent a living unrelated kidney transplant. He remained nearly infection free on maintenance immunoglobulin replacement. However, his posttransplant course was complicated by acute rejection that ultimately led to allograft loss. This case illustrates the challenge of transplantation in this patient population because of the delicate balance that must be achieved between maintaining adequate immunosuppression and minimizing the risk of infection.

PMID: 28219603 [PubMed – in process]

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Unexplained cyanosis caused by hepatopulmonary syndrome in a girl with APECED syndrome.

J Pediatr Endocrinol Metab. 2017 Feb 21;:

Authors: Celmeli F, Kocabas A, Isik IA, Parlak M, Kisand K, Ceylaner S, Turkkahraman D

Abstract
Autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED) is a rare but devastating primary immunodeficiency disease caused by loss-of-function mutations in autoimmune regulator (AIRE) gene on chromosome 21q22.3. The clinical spectrum of the disease is characterized by a wide heterogeneity because of autoimmune reactions toward different endocrine and non-endocrine organs. Here, we report a 17-year-old Turkish girl diagnosed with APECED at 9 years in whom a novel homozygote mutation in AIRE gene p.R15H (c.44G>A) was found. In the clinical course of the patient, chronic liver disease due to autoimmune hepatitis has evolved resulting in hepatopulmonary syndrome (HPS) which has not been reported before in patients with APECED.

PMID: 28222032 [PubMed – as supplied by publisher]

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Human NLRP3 inflammasome activity is regulated by and potentially targetable via BTK.

J Allergy Clin Immunol. 2017 Feb 16;:

Authors: Liu X, Pichulik T, Wolz OO, Dang TM, Stutz A, Dillen C, Delmiro Garcia M, Kraus H, Dickhöfer S, Daiber E, Münzenmayer L, Wahl S, Rieber N, Kümmerle-Deschner J, Yazdi A, Franz-Wachtel M, Macek B, Radsak M, Vogel S, Schulte B, Walz JS, Hartl D, Latz E, Stilgenbauer S, Grimbacher B, Miller L, Brunner C, Wolz C, Weber AN

Abstract
BACKGROUND: The Nod-like receptor, NACHT, LRR and PYD domains-containing protein 3 (NLRP3), and Bruton’s tyrosine kinase (BTK) are protagonists in innate and adaptive immunity, respectively: NLRP3 senses exogenous and endogenous insults leading to inflammasome activation, which occurs spontaneously in Muckle-Wells Syndrome (MWS); BTK mutations cause the genetic immunodeficiency X-linked agammaglobulinemia (XLA). However, to date few proteins that regulate NLRP3 inflammasome activity in human primary immune cells have been identified and clinically promising pharmacological targeting strategies remain elusive.
OBJECTIVE: We therefore sought to identify novel regulators of the NLRP3 inflammasome in human cells with a view to exploring interference with inflammasome activity at the level of such regulators.
METHODS: Following proteome-wide phospho-proteomics, an identified novel regulator, BTK, was studied in human and murine cells using pharmacological and genetic BTK ablation.
RESULTS: We here show that BTK is a critical regulator of NLRP3 inflammasome activation: Pharmacological (using the Food and Drug Administration (FDA)-approved inhibitor, ibrutinib) and genetic (in XLA patients and Btk-knockout mice) BTK ablation in primary immune cells led to reduced Interleukin (IL)-1β processing and secretion in response to Nigericin and the Staphylococcus aureus toxin, Leukocidin (Luk) AB. BTK affected Apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and caspase-1 cleavage and interacted with NLRP3 and ASC. S. aureus infection control in vivo and IL-1β release from MWS patient cells were impaired by ibrutinib. Notably, IL-1β processing and release from immune cells isolated from cancer patients on ibrutinib therapy was reduced.
CONCLUSION: Our data suggest that XLA may partially result from genetic inflammasome deficiency and that NLRP3 inflammasome-linked inflammation could potentially be targeted pharmacologically via BTK.

PMID: 28216434 [PubMed – as supplied by publisher]

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Antibody deficiency in patients with frequent exacerbations of Chronic Obstructive Pulmonary Disease (COPD).

PLoS One. 2017;12(2):e0172437

Authors: McCullagh BN, Comellas AP, Ballas ZK, Newell JD, Zimmerman MB, Azar AE

Abstract
Chronic Obstructive Pulmonary Disease is the third leading cause of death in the US, and is associated with periodic exacerbations, which account for the largest proportion of health care utilization, and lead to significant morbidity, mortality, and worsening lung function. A subset of patients with COPD have frequent exacerbations, occurring 2 or more times per year. Despite many interventions to reduce COPD exacerbations, there is a significant lack of knowledge in regards to their mechanisms and predisposing factors. We describe here an important observation that defines antibody deficiency as a potential risk factor for frequent COPD exacerbations. We report a case series of patients who have frequent COPD exacerbations, and who were found to have an underlying primary antibody deficiency syndrome. We also report on the outcome of COPD exacerbations following treatment in a subset with of these patients with antibody deficiency. We identified patients with COPD who had 2 or more moderate to severe exacerbations per year; immune evaluation including serum immunoglobulin levels and pneumococcal IgG titers was performed. Patients diagnosed with an antibody deficiency syndrome were treated with either immunoglobulin replacement therapy or prophylactic antibiotics, and their COPD exacerbations were monitored over time. A total of 42 patients were identified who had 2 or more moderate to severe COPD exacerbations per year. Twenty-nine patients had an underlying antibody deficiency syndrome: common variable immunodeficiency (8), specific antibody deficiency (20), and selective IgA deficiency (1). Twenty-two patients had a follow-up for at least 1 year after treatment of their antibody deficiency, which resulted in a significant reduction of COPD exacerbations, courses of oral corticosteroid use and cumulative annual dose of oral corticosteroid use, rescue antibiotic use, and hospitalizations for COPD exacerbations. This case series identifies antibody deficiency as a potentially treatable risk factor for frequent COPD exacerbations; testing for antibody deficiency should be considered in difficult to manage frequently exacerbating COPD patients. Further prospective studies are warranted to further test this hypothesis.

PMID: 28212436 [PubMed – in process]

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Clinical Manifestations and Genetic Analysis of 17 Patients with Autosomal Dominant Hyper-IgE Syndrome in Mainland China: New Reports and a Literature Review.

J Clin Immunol. 2017 Feb 14;:

Authors: Wu J, Chen J, Tian ZQ, Zhang H, Gong RL, Chen TX, Hong L

Abstract
PURPOSE: Autosomal dominant hyper-IgE syndrome (AD-HIES) is a rare complicated primary immunodeficiency disease (PID). Signal transducer and activator of transcription 3 (STAT3) gene mutation is found to cause AD-HIES. The distribution of AD-HIES patients with STAT3 deficiency in the Chinese population is not clear. Herein, we retrospectively report 17 AD-HIES patients with STAT3 deficiency and demonstrate their clinical, immunological, and genetic features.
METHODS: Patients’ clinical data were collected from their medical records. Routine laboratory testing results included lymphocyte subset analysis and immunoglobulin quantification. STAT3 mutations were investigated by sequencing of genomic DNA.
RESULTS: Among 575 patients with PID, 28 (4.87%) were clinically diagnosed as HIES. Among them, 17 (2.96%) were confirmed as STAT3 mutant AD-HIES. The ratio of male to female patients was 8:9. All of the 17 patients had NIH scores over 40 points. The mean ages at onset and diagnosis were 1.05 and 10.35 years, respectively. Three patients (17.65%, 3/17) died with a mean age of 13.33 years. Eczema, recurrent skin infection, and respiratory tract infection were the most common clinical symptoms and are present in all of the 17 patients in this study. Six patients (37.5%, 6/16) suffered complication from BCG vaccination. Noninfection symptoms are characteristic facial features in 17 patients (100%, 17/17), retention of primary teeth in 10 patients (90.91%, 10/11), and abnormal bone fractures in 7 patients (41.18%, 7/17). Eleven types of STAT3 mutations were identified in 17 patients, including 1 novel mutation.
CONCLUSIONS: We here retrospectively report the largest Chinese cohort of AD-HIES patients with STAT3 mutation. Unique features, when compared to existing literature reports, include (1) later age of diagnosis, (2) significantly higher rate of BCG complications, and (3) lower rate of candidiasis and chronic otitis media.

PMID: 28197791 [PubMed – as supplied by publisher]

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Treatment of Infantile Inflammatory Bowel Disease and Autoimmunity by Allogeneic Stem Cell Transplantation in LPS-Responsive Beige-Like Anchor Deficiency.

Front Immunol. 2017;8:52

Authors: Bakhtiar S, Gámez-Díaz L, Jarisch A, Soerensen J, Grimbacher B, Belohradsky B, Keller KM, Rietschel C, Klingebiel T, Koletzko S, Albert MH, Bader P

Abstract
Inflammatory bowel disease (IBD) in young children can be a clinical manifestation of various primary immunodeficiency syndromes. Poor clinical outcome is associated with poor quality of life and high morbidity from the complications of prolonged immunosuppressive treatment and malabsorption. In 2012, mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) gene were identified as the cause of an autoimmunity and immunodeficiency syndrome. Since then, several LRBA-deficient patients have been reported with a broad spectrum of clinical manifestations without reliable predictive prognostic markers. Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been performed in a few severely affected patients with complete or partial response. Herein, we present a detailed course of the disease and the transplantation procedure used in a LRBA-deficient patient suffering primarily from infantile IBD with immune enteropathy since the age of 6 weeks, and progressive autoimmunity with major complications following long-term immunosuppressive treatment. At 12 years of age, alloHSCT using bone marrow of a fully matched sibling donor-a healthy heterozygous LRBA mutant carrier-was performed after conditioning with a reduced-intensity regimen. During the 6-year follow-up, we observed a complete remission of enteropathy, autoimmunity, and skin vitiligo, with complete donor chimerism. The genetic diagnosis of LRBA deficiency was made post-alloHSCT by detection of two compound heterozygous mutations, using targeted sequencing of DNA samples extracted from peripheral blood before the transplantation.

PMID: 28197149 [PubMed – in process]

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