Stanford Alliance for Primary Immunodeficiency

Stanford University

You are here: Home / Archives for Manish Butte

Manish Butte

Application of Flow Cytometry in Predominantly Antibody Deficiencies.

By

Related Articles

Application of Flow Cytometry in Predominantly Antibody Deficiencies.

Endocr Metab Immune Disord Drug Targets. 2020 Jul 20;:

Authors: Yazdani R, Aghamohammadi A, Rezaei N

Abstract
Predominantly antibody deficiencies (PADs) are a heterogeneous group of primary immunodeficiency disorders (PIDs), consisting of recurrent infections, autoimmunity, inflammation, and other immune complications. In the recent years, several immunological and genetic defects have been recognized in PADs. Currently, 45 distinct PAD disorders with 40 different genetic defects have been identified based on the 2019 IUIS classification. Genetic analysis is helpful for diagnosing PIDs; however, genetic studies are expensive, time-consuming, and unavailable in everywhere. Flow cytometry is a highly sensitive tool for evaluating the immune system and diagnosing PADs. In addition to cell populations and subpopulations assay, flow cytometry can measure cell surface, intracellular and intranuclear proteins, biological changes associated with specific immune defects, and certain functional immune abnormalities. These capabilities help in rapid diagnostic and prognostic assessment as well as in evaluating the pathogenesis of PADs. For the first time, this review particularly provides an overview of the application of flow cytometry for diagnosis, immunophenotyping, and determining the pathogenesis of PADs.

PMID: 32693771 [PubMed – as supplied by publisher]

Powered by WPeMatico

IONIS-PKKRx a Novel Antisense Inhibitor of Prekallikrein and Bradykinin Production.

By

Icon for PubMed Central Related Articles

IONIS-PKKRx a Novel Antisense Inhibitor of Prekallikrein and Bradykinin Production.

Nucleic Acid Ther. 2019 04;29(2):82-91

Authors: Ferrone JD, Bhattacharjee G, Revenko AS, Zanardi TA, Warren MS, Derosier FJ, Viney NJ, Pham NC, Kaeser GE, Baker BF, Schneider E, Hughes SG, Monia BP, MacLeod AR

Abstract
Kallikrein is the key contact system mediator responsible for the conversion of high-molecular-weight kininogen into the inflammatory vasodilator peptide bradykinin, a process regulated by C1-esterase inhibitor (C1-INH). In hereditary angioedema (HAE), genetic mutations result in deficient or dysfunctional C1-INH and dysregulation of the contact system leading to recurrent, sometimes fatal, angioedema attacks. IONIS-PKKRx is a second-generation 2′-O-(2-methoxyethyl)-modified chimeric antisense oligonucleotide, designed to bind and selectively reduce prekallikrein (PKK) mRNA in the liver. IONIS-PKKRx demonstrated dose-dependent reduction of human prekallikrein hepatic mRNA and plasma protein in transgenic mice and dose- and time-dependent reductions of plasma PKK in Cynomolgus monkeys. Similar dose-dependent reductions of plasma PKK levels were observed in healthy human volunteers accompanied by decreases in bradykinin generation capacity with an acceptable safety and tolerability profile. These results highlight a novel and specific approach to target PKK for the treatment of HAE and other diseases involving contact system activation and overproduction of bradykinin.

PMID: 30817230 [PubMed – indexed for MEDLINE]

Powered by WPeMatico

TREC and KREC profiling as a representative of thymus and bone marrow output in patients with various inborn errors of immunity.

By

Related Articles

TREC and KREC profiling as a representative of thymus and bone marrow output in patients with various inborn errors of immunity.

Clin Exp Immunol. 2020 Jun 26;:

Authors: Dasouki M, Jabr A, AlDakheel G, Elbadaoui F, Alazami AM, Al-Saud B, Arnaout R, Aldhekri H, Alotaibi I, Al-Mousa H, Hawwari A

Abstract
Primary immune deficiency (PID) disorders are clinically and molecularly heterogeneous diseases. T cell receptor excision circles (TRECs) and κ (kappa)-deleting excision circles (KRECs) are markers of T and B cell development, respectively. They are useful tools to assess T and B cell function and immune reconstitution and have been used for newborn screening for severe combined immunodeficiency disease (SCID) and agammaglobulinemia, respectively. Their profiles in several genetically confirmed PIDs are still lacking. The objective of this study was to determine TREC and KREC genomic profiling among various molecularly confirmed PIDs. We used real-time-quantitative polymerase chain reaction (RT-qPCR)-based triplex analysis of TRECs, KRECs and β-actin (ACTB) in whole blood genomic DNA isolated from 108 patients with molecularly confirmed PIDs. All agammaglobulinemia patients had low KREC counts. All SCIDs and Omenn syndrome patients secondary to mutations in RAG1, RAG2, DCLRE1C and NHEJ1 had low TREC and KREC counts. JAK3-deficient patients had normal KREC and the TREC count was influenced by the type of mutation. Early-onset ADA patients had low TREC and KREC counts. Four patients with zeta-chain-associated protein kinase 70 (ZAP70) had low TREC. All purine nucleoside phosphorylase (PNP) patients had low TREC. Combined immunodeficiency (CID) patients secondary to AK2, PTPRC, CD247, DCLREC1 and STAT1 had normal TREC and KREC counts. Most patients with ataxia-telangiectasia (AT) patients had low TREC and KREC, while most DOCK8-deficient patients had low TRECs only. Two of five patients with Wiskott-Aldrich syndrome (WAS) had low TREC counts as well as one patient each with bare lymphocyte syndrome (BLS) and chronic granulomatous disease. All patients with Griscelli disease, Chediak-Higashi syndrome, hyper-immunoglobulin (Ig)M syndrome and IFNGR2 had normal TREC and KREC counts. These data suggest that, in addition to classical SCID and agammaglobulinemia, TREC/KREC assay may identify ZAP70 patients and secondary target PIDs, including dedicator of cytokinesis 8 (DOCK8) deficiency, AT and some individuals with WAS and BLS.

PMID: 32691468 [PubMed – as supplied by publisher]

Powered by WPeMatico

The Value of Chromosome Analysis to Interrogate Variants in DNMT3B Causing Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome Type I (ICF1).

By

Icon for Springer Related Articles

The Value of Chromosome Analysis to Interrogate Variants in DNMT3B Causing Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome Type I (ICF1).

J Clin Immunol. 2019 11;39(8):857-859

Authors: Kellner ES, Rathbun PA, Marshall GS, Tolusso LK, Smolarek TA, Sun M, Chandra S, Bleesing J, Marsh RA

PMID: 31686314 [PubMed – indexed for MEDLINE]

Powered by WPeMatico

Quality of Life of Patients with Wiskott Aldrich Syndrome and X-Linked Thrombocytopenia: a Study of the Primary Immune Deficiency Consortium (PIDTC), Immune Deficiency Foundation, and the Wiskott-Aldrich Foundation.

By

Icon for Springer Related Articles

Quality of Life of Patients with Wiskott Aldrich Syndrome and X-Linked Thrombocytopenia: a Study of the Primary Immune Deficiency Consortium (PIDTC), Immune Deficiency Foundation, and the Wiskott-Aldrich Foundation.

J Clin Immunol. 2019 11;39(8):786-794

Authors: Shah AJ, Sokolic R, Logan B, Yin Z, Iyengar S, Scalchunes C, Mangurian C, Albert M, Cowan MJ

Abstract
BACKGROUND: We undertook a study to determine the impact of Wiskott Aldrich Syndrome (WAS) and X-linked thrombocytopenia (XLT) and their therapies upon the health-related quality of life (HRQOL) of patients and their families.
MATERIALS AND METHODS: We undertook a survey of patients and their families, who self-identified as having either WAS or XLT. We assessed the PedsQL™ 4.0, the parent proxy form, and the family impact module. These results were compared with normative data from previously published reports.
RESULTS: Sixty-eight patients (29 patients completed both the PedsQL™ 4.0 and the parent proxy form; 21 completed only the PedsQL™ 4.0; and 18 completed only the parent proxy form) were included. In contrast to patient-reported outcomes, parents of patients who had a bone marrow transplant (BMT) reported that their children had better QOL scores compared with those who did not (82.6 vs. 73.3, p = 0.023). The QOL of patients vs. previously published normative data showed decreases in patient scores for psychosocial health (72.62 vs. 86.58, p = < 0.001), emotional functioning (69.91 vs. 82.64, p = < 0.001), social functioning (77.55 vs. 91.56, p = < 0.001), and school functioning (70.46 vs. 85.67, p = < 0.001). The family impact study revealed deficits in emotional, social, and cognitive functioning, communication, and worry.
CONCLUSION: These results show that patients with WAS/XLT are significantly impacted with respect to QOL. BMT offered a better QOL for patients according to parents, but not as reported by the patients. Future studies should incorporate QOL to provide more data and a better understanding of outcomes for long-term survivors and decision-making regarding BMT.

PMID: 31620947 [PubMed – indexed for MEDLINE]

Powered by WPeMatico

Novel Gain-of-Function Mutation in Stat1 Sumoylation Site Leads to CMC/CID Phenotype Responsive to Ruxolitinib.

By

Icon for Springer Related Articles

Novel Gain-of-Function Mutation in Stat1 Sumoylation Site Leads to CMC/CID Phenotype Responsive to Ruxolitinib.

J Clin Immunol. 2019 11;39(8):776-785

Authors: Al Shehri T, Gilmour K, Gothe F, Loughlin S, Bibi S, Rowan AD, Grainger A, Mohanadas T, Cant AJ, Slatter MA, Hambleton S, Lilic D, Leahy TR

Abstract
Mutations in the coiled-coil and DNA-binding domains of STAT1 lead to delayed STAT1 dephosphorylation and subsequently gain-of-function. The associated clinical phenotype is broad and can include chronic mucocutaneous candidiasis (CMC) and/or combined immunodeficiency (CID). We report a case of CMC/CID in a 10-year-old boy due to a novel mutation in the small ubiquitin molecule (SUMO) consensus site at the C-terminal region of STAT1 leading to gain-of-function by impaired sumoylation. Immunodysregulatory features of disease improved after Janus kinase inhibitor (jakinib) treatment. Functional testing after treatment confirmed reversal of the STAT1 hyper-phosphorylation and downstream transcriptional activity. IL-17 and IL-22 production was, however, not restored with jakinib therapy (ruxolitinib), and the patient remained susceptible to opportunistic infection. In conclusion, a mutation in the SUMO consensus site of STAT1 can lead to gain-of-function that is reversible with jakinib treatment. However, full immunocompetence was not restored, suggesting that this treatment strategy might serve well as a bridge to definitive therapy such as hematopoietic stem cell transplant rather than a long-term treatment option.

PMID: 31512162 [PubMed – indexed for MEDLINE]

Powered by WPeMatico