Manish Butte

Benefit of Howell-Jolly bodies detection: finding of an acquired hyposplenism in a patient with Goodpasture syndrome.

September 24, 2020 By Manish Butte

Benefit of Howell-Jolly bodies detection: finding of an acquired hyposplenism in a patient with Goodpasture syndrome.

Ann Biol Clin (Paris). 2020 Apr 01;78(2):191-194

Authors: Leroux T, Daliphard S, Etienne I, Gellé M, Bobée V

Abstract
Howell-Jolly bodies are intraerythrocytic inclusions corresponding to a small portion of chromatin. Red blood cells that contain these nuclear remnants are removed from the circulation by the spleen. In most cases, presence of Howell-Jolly bodies on a blood smear is the result of functional asplenia and splenectomy. Observation. We report incidental finding of numerous Howell-Jolly bodies in a patient followed by the nephrology department. This microscopic observation of blood smear led to a diagnostic imaging and to the evidence of a reduced spleen, possibly favoured by a history of Goodpasture syndrome in this renal transplant patient without splenectomy. Vaccination and antibioprophylaxy were proposed to prevent infectious risk linked to this splenic hypoplasia. Conclusion. Seeking of Howell-Jolly bodies could be made in every condition associated with a risk of splenic hypoplasia to prevent infectious risk.

PMID: 32319948 [PubMed – indexed for MEDLINE]

A research-driven approach to the identification of novel natural killer cell deficiencies affecting cytotoxic function.

September 24, 2020 By Manish Butte

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A research-driven approach to the identification of novel natural killer cell deficiencies affecting cytotoxic function.

Blood. 2020 02 27;135(9):629-637

Authors: Lam MT, Mace EM, Orange JS

Abstract
Natural killer cell deficiencies (NKDs) are an emerging phenotypic subtype of primary immune deficiency. NK cells provide a defense against virally infected cells using a variety of cytotoxic mechanisms, and patients who have defective NK cell development or function can present with atypical, recurrent, or severe herpesviral infections. The current pipeline for investigating NKDs involves the acquisition and clinical assessment of patients with a suspected NKD followed by subsequent in silico, in vitro, and in vivo laboratory research. Evaluation involves initially quantifying NK cells and measuring NK cell cytotoxicity and expression of certain NK cell receptors involved in NK cell development and function. Subsequent studies using genomic methods to identify the potential causative variant are conducted along with variant impact testing to make genotype-phenotype connections. Identification of novel genes contributing to the NKD phenotype can also be facilitated by applying the expanding knowledge of NK cell biology. In this review, we discuss how NKDs that affect NK cell cytotoxicity can be approached in the clinic and laboratory for the discovery of novel gene variants.

PMID: 31945148 [PubMed – indexed for MEDLINE]

Immune dysregulation in patients with RAG deficiency and other forms of combined immune deficiency.

September 24, 2020 By Manish Butte

Immune dysregulation in patients with RAG deficiency and other forms of combined immune deficiency.

Blood. 2020 02 27;135(9):610-619

Authors: Delmonte OM, Villa A, Notarangelo LD

Abstract
Traditionally, primary immune deficiencies have been defined based on increased susceptibility to recurrent and/or severe infections. However, immune dysregulation, manifesting with autoimmunity or hyperinflammatory disease, has emerged as a common feature. This is especially true in patients affected by combined immune deficiency (CID), a group of disorders caused by genetic defects that impair, but do not completely abolish, T-cell function. Hypomorphic mutations in the recombination activating genes RAG1 and RAG2 represent the prototype of the broad spectrum of clinical and immunological phenotypes associated with CID. The study of patients with RAG deficiency and with other forms of CID has revealed distinct abnormalities in central and peripheral T- and B-cell tolerance as the key mechanisms involved in immune dysregulation. Understanding the pathophysiology of autoimmunity and hyperinflammation in these disorders may also permit more targeted therapeutic interventions.

PMID: 31942628 [PubMed – indexed for MEDLINE]

Primary immunodeficiencies reveal the molecular requirements for effective host defense against EBV infection.

September 24, 2020 By Manish Butte

Primary immunodeficiencies reveal the molecular requirements for effective host defense against EBV infection.

Blood. 2020 02 27;135(9):644-655

Authors: Tangye SG, Latour S

Abstract
Epstein-Barr virus (EBV) is an enigma; on one hand, it infects and persists in latent form in the vast majority of the global population, causing relatively benign disease in otherwise healthy individuals. On the other hand, EBV represents the first identified oncogenic virus, capable of causing ≥7 different types of malignancies, usually in immunocompromised individuals. Furthermore, some individuals with defined inborn errors of immunity exhibit extreme susceptibility to EBV-induced disease, developing severe and often fatal infectious mononucleosis, hemophagocytic lymphohistiocytosis, lymphoproliferative disease, and/or EBV+ B-cell lymphoma. Thus, host and pathogen have coevolved to enable viral persistence and survival with minimal collateral damage to the healthy host. However, acquired or genetic disruptions to host defense that tip the balance in favor of EBV can have catastrophic effects. The study of primary immunodeficiencies has provided opportunities to define nonredundant requirements for host defense against EBV infection. This has not only revealed mechanisms underlying EBV-induced disease in these primary immunodeficiencies but also identified molecules and pathways that could be targeted to enhance the efficacy of an EBV-specific vaccine or treat severe EBV infection and pathological consequences in immunodeficient hosts.

PMID: 31942615 [PubMed – indexed for MEDLINE]

Regulation of the Notch-ATM-abl axis by geranylgeranyl diphosphate synthase inhibition.

September 24, 2020 By Manish Butte

Regulation of the Notch-ATM-abl axis by geranylgeranyl diphosphate synthase inhibition.

Cell Death Dis. 2019 09 30;10(10):733

Authors: Agabiti SS, Li J, Dong W, Poe MM, Wiemer AJ

Abstract
Notch proteins drive oncogenesis of many cancers, most prominently T-cell acute lymphoblastic leukemia (T-ALL). Because geranylgeranylated Rab proteins regulate Notch processing, we hypothesized that inhibition of geranylgeranyl diphosphate synthase (GGDPS) would impair Notch processing and reduce viability of T-ALL cells that express Notch. Here, we show that GGDPS inhibition reduces Notch1 expression and impairs the proliferation of T-ALL cells. GGDPS inhibition also reduces Rab7 membrane association and depletes Notch1 mRNA. GGDPS inhibition increases phosphorylation of histone H2A.X, and inhibitors of ataxia telangiectasia-mutated kinase (ATM) mitigate GGDPS inhibitor-induced apoptosis. GGDPS inhibition also influences c-abl activity downstream of caspases, and inhibitors of these enzymes prevent GGDPS inhibitor-induced apoptosis. Surprisingly, induction of apoptosis by GGDPS inhibition is reduced by co-treatment with γ-secretase inhibitors. While inhibitors of γ-secretase deplete one specific form of the Notch1 intracellular domain (NICD), they also increase Notch1 mRNA expression and increase alternate forms of Notch1 protein expression in cells treated with a GGDPS inhibitor. Furthermore, inhibitors of γ-secretase and ATM increase Notch1 mRNA stability independent of GGDPS inhibition. These results provide a model by which T-ALL cells use Notch1 to avoid DNA-damage-induced apoptosis, and can be overcome by inhibition of GGDPS through effects on Notch1 expression and its subsequent response.

PMID: 31570763 [PubMed – indexed for MEDLINE]

“Defective Bcl-2 expression in memory B cells from CVID patients”.

September 23, 2020 By Manish Butte

“Defective Bcl-2 expression in memory B cells from CVID patients”.

Clin Exp Immunol. 2020 Sep 22;:

Authors: Del Pino Molina L, Torres Canizales JM, Pernía O, Rodríguez Pena R, Ibanez de Caceres I, López Granados E

Abstract
Common Variable Immunodeficiency (CVID) is a primary immunodeficiency characterized by hypogammaglobulinemia and different degrees of B-cell compartment alteration. Memory B-cell differentiation requires the orchestrated activation of several intracellular signalling pathways that lead to the activation of a number of factors, such as NFκB, which in turn promote transcriptional programs required for long-term survival. The aim of this study was to determine if disrupted B-cell differentiation, survival and activation in B cells in CVID patients could be related to defects in intracellular signalling pathways. For this purpose, we selected intracellular readouts that reflected the strength of homeostatic signalling pathways in resting cells, as the protein expression levels of the Bcl-2 family which transcription is promoted by NFκB. We found reduced Bcl-2 protein levels in memory B cells from CVID patients. We further explored the possible alteration of this crucial pro-survival signalling pathway in CVID patients, by analysing the expression levels of mRNAs from antiapoptotic proteins in naïve B cells, mimicking T-cell dependent activation in vitro with CD40L and IL-21. BCL-XL mRNA levels were decreased, together with reduced levels of AICDA, after naïve B-cell activation in CVID patients. The data suggested a molecular mechanism for this tendency toward apoptosis in B cells from CVID patients. Lower Bcl-2 protein levels in memory B cells could compromise their long-term survival and cause less activation of NFκB in naïve B cells, which might be unable to increase BCL-XL mRNA levels, thus not promoting survival in the germinal centers.

PMID: 32961586 [PubMed – as supplied by publisher]

Evaluation of B-cell intracellular signaling by monitoring the PI3K-Akt axis in patients with common variable immunodeficiency and activated phosphoinositide 3-kinase delta syndrome.

September 23, 2020 By Manish Butte

Evaluation of B-cell intracellular signaling by monitoring the PI3K-Akt axis in patients with common variable immunodeficiency and activated phosphoinositide 3-kinase delta syndrome.

Cytometry B Clin Cytom. 2020 Sep 22;:

Authors: Del Pino-Molina L, Torres Canizales JM, Rodríguez-Pena R, López-Granados E

Abstract
BACKGROUND: Primary antibody deficiencies (PADs) are characterized by hypogammaglobulinemia and impaired B-cell differentiation. Patients with common variable immunodeficiency (CVID) present severe reductions in at least 2 serum immunoglobulins and impaired terminal differentiation of B cells. Most patients with CVID do not appear to present monogenic defects. Activated phosphoinositide 3-kinase delta syndrome (APDS), caused by gain-of-function mutations in the PIK3CD gene (p110δ), can present in patients with a CVID-like phenotype. Memory B-cell differentiation requires the orchestrated activation of numerous intracellular signaling pathways, which promote transcriptional programs required for long-term B-cell survival. The aim of this study was to develop a flow cytometry assay to trace the PI3K-Akt-mTOR pathway, a critical component of B-cell homeostasis, and analyze its status in PADs.
METHODS: We analyzed the intracellular expression of Akt and S6 by flow cytometry and their phosphorylation status in both baseline conditions and upon B-cell receptor activation with anti-IgM in various primary B-cell subsets of patients with CVID and APDS.
RESULTS: B cells from CVID patients showed reduced phosphorylation in Akt and S6 proteins after anti-IgM stimulation. Constitutive high baseline B-cell levels of Akt and S6 phosphorylation in a patient with APDS were reduced once m-TOR inhibition therapy was initiated.
CONCLUSIONS: Intracellular flow cytometry can be routinely employed to explore alterations in the PI3K-Akt-mTOR pathway in B cells from patients with PADs. AKT and S6 phosphorylation levels are informative biomarkers that could be employed as mTOR inhibitors for monitoring therapies targeting this pathway.

PMID: 32961022 [PubMed – as supplied by publisher]

Job’s Syndrome: A Rare Case Report.

September 23, 2020 By Manish Butte

Job’s Syndrome: A Rare Case Report.

Clin Pediatr (Phila). 2020 05;59(4-5):505-507

Authors: Richa S, Bhasin H, Sahoo B, Abrol P, Sharma S

PMID: 32019325 [PubMed – indexed for MEDLINE]

Global Distribution of Common Variable Immunodeficiency (CVID) in the Light of the UNDP Human Development Index (HDI): A Preliminary Perspective of a Rare Disease.

September 22, 2020 By Manish Butte

Global Distribution of Common Variable Immunodeficiency (CVID) in the Light of the UNDP Human Development Index (HDI): A Preliminary Perspective of a Rare Disease.

J Immunol Res. 2020;2020:8416124

Authors: Weifenbach N, Schneckenburger AAC, Lötters S

Abstract
Common variable immunodeficiency (CVID), although the most common primary immunodeficiency in humans, is a rare disease. We explored the spatial global distribution and country-wise prevalence of CVID, based on published data and those available from databases. As a country’s medical progress is linked to its technological and socio-economic developmental status, we expected that observed CVID prevalence was linked to human wellbeing. To assess this, we examined the correlation of observed CVID prevalence and the UNDP Human Development Index (HDI), which is a key measure of human development. Seventy-four data sets from 47 countries were available (most of them no older than 10 years). Analyses revealed that observed CVID prevalence ranged from 0.001 to 3.374 per 100,000 (mean 0.676 ± 0.83) and was highest in “high” HDI countries (Spearman’s rho = 0.757). Observed prevalence was particularly high in countries where immunodeficiencies are systematically documented in registers. In “low” and “middle” HDI countries, CVID awareness is extremely poor. Assuming that true CVID prevalence does not differ among countries, this study, though preliminary, provides evidence that the discrepancy between observed and (unknown) true prevalence can be clearly linked to the countries’ developmental status. As a potential alternative explanation, we briefly discuss the possibility that variation in CVID prevalence is related to human genetic lineage.

PMID: 32953893 [PubMed – in process]

Novel deletion mutation in Bruton’s tyrosine kinase results in X-linked agammaglobulinemia: A case report.

September 22, 2020 By Manish Butte

Novel deletion mutation in Bruton’s tyrosine kinase results in X-linked agammaglobulinemia: A case report.

World J Clin Cases. 2020 Sep 06;8(17):3859-3866

Authors: Hu XM, Yuan K, Chen H, Chen C, Fang YL, Zhu JF, Liang L, Wang CL

Abstract
BACKGROUND: X-linked agammaglobulinemia is a primary immunodeficiency disease caused by gene mutations of Bruton’s tyrosine kinase (BTK). We found a new mutation point and summarized the correlation analysis and performed a literature review.
CASE SUMMARY: The proband was a 5-year-old boy. He was admitted to our hospital due to a recurrent cough and a fever that had persisted for a month. He had a history of multiple respiratory infections and sinusitis. There was no immunodeficiency or recurrent infection history among his family members. Agammaglobulinemia was characterized as follows: Immunoglobulin (Ig) A, 90.0 mg/dL (90-450 mg/dL); IgG, 20.0 mg/dL (800-1800 mg/dL); and IgM, 18.0 mg/dL (60-280 mg/dL). Notably, the assessment of IgG subtypes revealed the following very low levels: Subtype 1, 0.26 g/L (3.62-12.28 g/L); subtype 2, 0.10 g/L (0.57-2.9 g/L); subtype 3, 0.009 g/L (0.129-0.789 g/L); and subtype 4, 0.003 g/L (0.013-1.446 g/L). Cellular immunological test results were as follows: CD3, 74.6% (50%-84.0%); CD4, 47.3% (27.0%-51.0%); and CD8, 24.9% (15.0%-44.0%). A de novo hemizygous deletion in BTK was detected: c.902_c.904delAAG/p.E301del. Transcript levels of the mutant BTK were similar to those of the wild-type gene, though overexpression resulted in markedly reduced levels of mutant BTK (9.49% ± 1.58%), relative to the wild-type BTK (75.8% ± 2.98%, P < 0.01).
CONCLUSION: This case of X-linked agammaglobulinemia was attributed to a de novo hemizygous deletion mutation in BTK (c.902_c.904delAAG/p.E301del). The mutation resulted in markedly reduced BTK protein stability in vitro.

PMID: 32953865 [PubMed]