Manish Butte

TCR α+ β+ /CD19+ cell-depleted hematopoietic stem cell transplantation for pediatric patients.

Pediatr Transplant. 2019 Jul 04;:e13517

Authors: Mitchell R, Cole T, Shaw PJ, Mechinaud F, O’Brien T, Fraser C

Abstract
TCR α+ β+ /CD19+ cell depletion is an emerging technique for ex vivo graft manipulation in HSCT. We report 20 pediatric patients who underwent TCR α+ β+ /CD19+ cell-depleted HSCT in four Australian centers. Conditioning regimen was dependent on HSCT indication, which included immunodeficiency (n = 14), Fanconi anemia (n = 3), and acute leukemia (n = 3). Donor sources were haploidentical parent (n = 17), haploidentical sibling (n = 2), or matched unrelated donor (n = 1). Mean cell dose was 8.2 × 108 /kg TNC, 12.1 × 106 /kg CD34+ cells, and 0.4 × 105 /kg TCR α+ β+ cells. All patients achieved primary neutrophil and platelet engraftment, with average time to neutrophil engraftment 11 days (range 8-22) and platelet engraftment 24 days (range 12-69). TRM at 1 year was 15%. Rate of grade II-IV aGVHD at 1 year was 20% with no grade III-IV aGVHD seen. CMV reactivation occurred in 81% of CMV-positive recipients, with one patient developing CMV disease. Average time to CD4 recovery (>400 × 106 /L) was 258 days. Overall survival for the cohort at 5 years was 80%. This report highlights the initial experience of TCR α+ β+ /CD19+ cell-depleted HSCT in Australian centers, with high rates of engraftment, low rates of aGVHD, and acceptable TRM.

PMID: 31271477 [PubMed – as supplied by publisher]

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Safety and tolerability of subcutaneous immunoglobulin 20% in primary immunodeficiency diseases from two continents.

Immunotherapy. 2019 Jul 03;:

Authors: Suez D, Kriván G, Jolles S, Stein M, Gupta S, Paris K, van Hagen PM, Brodszki N, Engl W, Leibl H, McCoy B, Yel L

Abstract
Aim: This pooled analysis evaluated the safety and tolerability of the subcutaneous immunoglobulin 20% product, Ig20Gly, in primary immunodeficiency diseases using data from two Phase II/III studies conducted in North America and Europe. Patients & materials/methods: Patients received Ig20Gly (volumes, ≤60 ml/site; rates, ≤60 ml/h/site). Adverse events (AEs), tolerability and infusion parameters were assessed. Results: Patients (2-83 years; N = 122) received 6676 Ig20Gly infusions. No causally related serious or severe AEs were reported. Thirty-five patients (28.7%) reported 232 causally related local AEs. Twenty-seven patients (22.1%) reported 165 causally related systemic AEs. There was no association between the infusion volume or rate and causally related local AEs. Conclusion: Ig20Gly was well tolerated in a broad population of patients with primary immunodeficiency diseases.

PMID: 31268374 [PubMed – as supplied by publisher]

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The Next Generation of Diagnostic Tests for Primary Immunodeficiency Disorders.

J Infect Dis. 2019 Jul 02;:

Authors: French MA, Tangye SG

PMID: 31268150 [PubMed – as supplied by publisher]

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Recurrent Herpes Zoster Ophthalmicus in a Patient With a Novel Toll-Like Receptor 3 Variant Linked to Compromised Activation Capacity in Fibroblasts.

J Infect Dis. 2019 Jul 02;:

Authors: Liang F, Glans H, Enoksson SL, Kolios AGA, Loré K, Nilsson J

Abstract
BACKGROUND: Herpes zoster ophthalmicus occurs primarily in elderly or immunocompromised individuals after reactivation of varicella zoster virus (VZV). Recurrences of zoster ophthalmicus are uncommon because the reactivation efficiently boosts anti-VZV immunity. A 28-year-old female presented to our clinic with a history of multiple recurrences of zoster ophthalmicus.
METHODS: Whole-exome sequencing (WES), analyses of VZV T-cell immunity, and pathogen recognition receptor function in primary antigen-presenting cells (APCs) and fibroblasts were performed.
RESULTS: Normal VZV-specific T-cell immunity and antibody response were detected. Whole-exome sequencing identified a heterozygous nonsynonymous variant (c.2324C > T) in the Toll-like receptor 3 (TLR3) gene resulting in formation of a premature stop-codon. This alteration could potentially undermine TLR3 signaling in a dominant-negative fashion. Therefore, we investigated TLR3 signaling responses in APCs and fibroblasts from the patient. The APCs responded efficiently to stimulation with TLR3 ligands, whereas the responses from the fibroblasts were compromised.
CONCLUSIONS: We report a novel TLR3 variant associated with recurrent zoster ophthalmicus. Toll-like receptor 3 responses that were unaffected in APCs but diminished in fibroblasts are in line with previous reports linking TLR3 deficiency with herpes simplex virus encephalitis. Mechanisms involving compromised viral sensing in infected cells may thus be central to the described immunodeficiency.

PMID: 31268141 [PubMed – as supplied by publisher]

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Fecal microbial dysbiosis in children with Wiskott-Aldrich syndrome.

Scand J Immunol. 2019 Jul 03;:e12805

Authors: Zhang L, Li Y, Tang X, Zhao X

Abstract
Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease caused by a mutation in the WAS gene that encodes the WAS protein (WASp); up to 5-10% of these patients develop inflammatory bowel disease (IBD). The mechanisms by which WASp deficiency causes IBD are unclear. Intestinal microbial dysbiosis and imbalances in host immune responses play important roles in the pathogenesis of polygenetic IBD; however, few studies have conducted detailed examination of the microbial alterations, and their relationship with IBD in WAS. Here, we collected fecal samples from 19 children (all less than 2 years old) with WAS and samples from WASp-KO mice with IBD and subjected them to 16S ribosomal RNA sequencing. We found that microbial community richness and structure in WAS children were different from those in controls; WAS children revealed reduced microbial community richness and diversity. Relative abundance of Bacteroidetes and Verrucomicrobiain in WAS children was significantly lower, while that of Proteobacteria was markedly higher. WASp-KO mice revealed a significant decreased abundance of Firmicutes.Fecal microbial dysbiosis caused by WASp deficiency is similar to that observed for polygenetic IBD,suggesting that WASp may play crucial function in microbial homeostasis and that microbial dysbiosis may contribute to IBD in WAS. These microbial alterations may be useful targets for monitoring and therapeutically managing intestinal inflammation in WAS. This article is protected by copyright. All rights reserved.

PMID: 31267543 [PubMed – as supplied by publisher]

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The Epidemiology and Clinical Manifestations of Autoimmunity in Selective IgA Deficiency.

Clin Rev Allergy Immunol. 2019 Jul 02;:

Authors: Odineal DD, Gershwin ME

Abstract
Selective immunoglobulin A deficiency (SIgAD) is the most common primary immunodeficiency, defined as an isolated deficiency of IgA (less than 0.07 g/L). Although the majority of people born with IgA deficiency lead normal lives without significant pathology, there is nonetheless a significant association of IgA deficiency with mucosal infection, increased risks of atopic disease, and a higher prevalence of autoimmune disease. To explain these phenomena, we have performed an extensive literature review to define the geoepidemiology of IgA deficiency and particularly the relative risks for developing systemic lupus erythematosus, hyperthyroidism, hypothyroidism, type 1 diabetes mellitus, Crohn’s disease, ulcerative colitis, rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, and vitiligo; these diseases have strong data to support an association. We also note weaker associations with scleroderma, celiac disease, autoimmune hepatitis, immune thrombocytopenic purpura, and autoimmune hemolytic anemia. Minimal if any associations are noted with myasthenia gravis, lichen planus, and multiple sclerosis. Finally, more recent data provide clues on the possible immunologic mechanisms that lead to the association of IgA deficiency and autoimmunity; these lessons are important for understanding the etiology of autoimmune disease.

PMID: 31267472 [PubMed – as supplied by publisher]

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Defining B cell defects and correlation with complications in Common Variable Immune Deficiency patients.

J Allergy Clin Immunol. 2019 Jun 29;:

Authors: Chapel H, Patel S

PMID: 31265844 [PubMed – as supplied by publisher]

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The NEW ESID Online Database Network.

Bioinformatics. 2019 Jul 02;:

Authors: Scheible R, Rusch S, Guzman D, Mahlaoui N, Ehl S, Kindle G

Abstract
SUMMARY: Primary Immunodeficiencies (PIDs) belong to the group of rare diseases. The European Society for Immunodeficiencies (ESID) operates an international research database application for continuous long-term documentation of patient data. The system is a web application which runs in a standard browser. Therefore, the system is easy to access from any location. Technically, the system is based on Gails backed by MariaDB with high standard security features to comply with the demands of a modern research platform.
AVAILABILITY: The ESID Online Database is accessible via the official website: https://esid.org/Working-Parties/Registry-Working-Party/ESID-Registry.A demo system is available via: https://cci-esid-reg-demo-app.uniklinik-freiburg.de/EERS with user demouser and password Demo-2019.

PMID: 31263866 [PubMed – as supplied by publisher]

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EuroFlow-Based Flowcytometric Diagnostic Screening and Classification of Primary Immunodeficiencies of the Lymphoid System.

Front Immunol. 2019;10:1271

Authors: van Dongen JJM, van der Burg M, Kalina T, Perez-Andres M, Mejstrikova E, Vlkova M, Lopez-Granados E, Wentink M, Kienzler AK, Philippé J, Sousa AE, van Zelm MC, Blanco E, Orfao A

Abstract
Guidelines for screening for primary immunodeficiencies (PID) are well-defined and several consensus diagnostic strategies have been proposed. These consensus proposals have only partially been implemented due to lack of standardization in laboratory procedures, particularly in flow cytometry. The main objectives of the EuroFlow Consortium were to innovate and thoroughly standardize the flowcytometric techniques and strategies for reliable and reproducible diagnosis and classification of PID of the lymphoid system. The proposed EuroFlow antibody panels comprise one orientation tube and seven classification tubes and corresponding databases of normal and PID samples. The 8-color 12-antibody PID Orientation tube (PIDOT) aims at identification and enumeration of the main lymphocyte and leukocyte subsets; this includes naïve pre-germinal center (GC) and antigen-experienced post-GC memory B-cells and plasmablasts. The seven additional 8(-12)-color tubes can be used according to the EuroFlow PID algorithm in parallel or subsequently to the PIDOT for more detailed analysis of B-cell and T-cell subsets to further classify PID of the lymphoid system. The Pre-GC, Post-GC, and immunoglobulin heavy chain (IgH)-isotype B-cell tubes aim at identification and enumeration of B-cell subsets for evaluation of B-cell maturation blocks and specific defects in IgH-subclass production. The severe combined immunodeficiency (SCID) tube and T-cell memory/effector subset tube aim at identification and enumeration of T-cell subsets for assessment of T-cell defects, such as SCID. In case of suspicion of antibody deficiency, PIDOT is preferably directly combined with the IgH isotype tube(s) and in case of SCID suspicion (e.g., in newborn screening programs) the PIDOT is preferably directly combined with the SCID T-cell tube. The proposed ≥8-color antibody panels and corresponding reference databases combined with the EuroFlow PID algorithm are designed to provide fast, sensitive and cost-effective flowcytometric diagnosis of PID of the lymphoid system, easily applicable in multicenter diagnostic settings world-wide.

PMID: 31263462 [PubMed – in process]

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Impaired HDL Function Amplifies Systemic Inflammation in Common Variable Immunodeficiency.

Sci Rep. 2019 Jul 01;9(1):9427

Authors: Macpherson ME, Halvorsen B, Yndestad A, Ueland T, Mollnes TE, Berge RK, Rashidi A, Otterdal K, Gregersen I, Kong XY, Holven KB, Aukrust P, Fevang B, Jørgensen SF

Abstract
Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency, characterized by inadequate antibody responses and recurrent bacterial infections. Paradoxically, a majority of CVID patients have non-infectious inflammatory and autoimmune complications, associated with systemic immune activation. Our aim was to explore if HDL, known to have anti-inflammatory properties, had impaired function in CVID patients and thereby contributed to their inflammatory phenotype. We found reduced HDL cholesterol levels in plasma of CVID patients compared to healthy controls, particularly in patients with inflammatory and autoimmune complications, correlating negatively with inflammatory markers CRP and sCD25. Reverse cholesterol transport capacity testing showed reduced serum acceptance capacity for cholesterol in CVID patients with inflammatory and autoimmune complications. They also had reduced cholesterol efflux capacity from macrophages to serum and decreased expression of ATP-binding cassette transporter ABCA1. Human HDL suppressed TLR2-induced TNF release less in blood mononuclear cells from CVID patients, associated with decreased expression of transcriptional factor ATF3. Our data suggest a link between impaired HDL function and systemic inflammation in CVID patients, particularly in those with autoimmune and inflammatory complications. This identifies HDL as a novel therapeutic target in CVID as well as other more common conditions characterized by sterile inflammation or autoimmunity.

PMID: 31263122 [PubMed – in process]

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