Manish Butte

Effect of Class Switch Recombination Defect on the Phenotype of Ataxia-Telangiectasia Patients.

Immunol Invest. 2020 Mar 02;:1-15

Authors: Amirifar P, Mozdarani H, Yazdani R, Kiaei F, Moeini Shad T, Shahkarami S, Abolhassani H, Delavari S, Sohani M, Rezaei A, Hassanpour G, Akrami SM, Aghamohammadi A

Abstract
Objectives: Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder with multisystem involvement caused by homozygous or compound heterozygous mutations in the ataxia telangiectasia mutated (ATM) gene which encodes a serine/threonine protein kinase. The aims of this study were to investigate class switch recombination (CSR) and to review the clinical and immunologic phenotypes of 3 groups of A-T patients, including A-T patients with CSR defects (CSR-D), A-T patients with selective immunoglobulin A deficiency (IgA-D) and A-T patients with normal Ig level.Methods: In this study, 41 patients with confirmed diagnosis of A-T (16 A-T patients with HIgM, 15 A-T patients with IgA-D, and 10 A-T patients with normal Ig levels) from Iranian immunodeficiency registry center were enrolled. B-cell proliferation, in vitro CSR toward IgE and IgA were compared between three groups as well as G2 radiosensitivity assay.Results: Earliest presentation of telangiectasia was a significant hallmark in A-T patients with CSR-D (p = .036). In this investigation, we found that the frequency of respiratory infection (p = .002), pneumonia (p = .02), otitis media (p = .008), chronic fever (p < .001), autoimmunity (p = .02) and hepatosplenomegaly (p = .03) in A-T patients with HIgM phenotype were significantly higher than the other groups. As expected IgE production stimulation and IgA CSR were perturbed in HIgM patients that were aligned with the higher readiosenstivity scores in this group.Conclusion: A-T patients with HIgM compared to other A-T patients presenting more infections and noninfectious complications, therefore, early detection and careful management of these patients is necessary.

PMID: 32116070 [PubMed – as supplied by publisher]

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Complete clinical remission of invasive Candida infection with CARD9 deficiency after G-CSF treatment.

Comp Immunol Microbiol Infect Dis. 2020 Jan 08;70:101417

Authors: Du B, Shen N, Hu J, Tao Y, Mo X, Cao Q

Abstract
Caspase-associated recruitment domain-containing protein 9 (CARD9) deficiency is an autosomal-recessive primary immunodeficiency characterized by susceptibility to recurrent Candida infections, and its diagnosis and treatment is challenging. The present study aims to investigate the genetic characteristic and treatment strategy of a Chinese pediatric patient with CARD9 deficiency. In the present study, whole-exome sequencing (WES) was performed to screen the causal variants in a Chinese pediatric patient who exhibited an invasive Candida infection in the abdominal cavity and central nervous system. After the disease-causing gene being confirmed, the patient was treated with a combination of G-CSF and antifungal agents. DNA sequencing revealed a homozygous insertion mutation (c.819-820insG) in exon 6 of the CARD9 gene, which led to downstream amino acids conversion on codon 274 (p.D274fsX60). Th17 cell populations and cytokine levels showed decreased levels. The treatment regimen successfully resolved the patient’s symptoms, and he remained symptom-free after more than 1 year of follow-up. This study described an invasive Candida infection in a pediatric patient and WES identified an insertion variant of the CARD9 gene. A combination of G-CSF and antifungal agents was highly effective in treating the invasive fungal infection accompanied by CARD9-induced immunodeficiency.

PMID: 32113042 [PubMed – as supplied by publisher]

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Pathobiology and Treatment of Lymphomatoid Granulomatosis; A Rare EBV-Driven Disorder.

Blood. 2020 Feb 27;:

Authors: Melani C, Jaffe ES, Wilson WH

Abstract
Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disease (LPD). This disease is hypothesized to result from defective immune surveillance of EBV with most patients showing evidence of immune dysfunction despite no known primary immunodeficiency. Pathologically, LYG is graded by the number and density of EBV+ atypical B-cells and other characteristic findings include an angioinvasive/angiodestructive reactive T-cell infiltrate and varying degree of necrosis. Clinically, LYG universally involves the lungs with other common extranodal sites including skin, central nervous system (CNS), liver, and kidneys. Nodal and/or bone marrow involvement is extremely rare and if present suggests an alternative diagnosis. Treatment selection is based on histologic grade and underlying pathobiology with low-grade disease hypothesized to be immune-dependent and typically polyclonal, and high-grade disease to be immune-independent and typically oligoclonal or monoclonal. Methods of augmenting the immune-response to EBV in low-grade LYG include treatment with interferon alpha-2b (IFN-a) while high-grade disease requires immuno-chemotherapy. Given the underlying defective immune surveillance of EBV, patients with high-grade disease may recur with low-grade disease following immuno-chemotherapy and those with low-grade disease may progress to high-grade disease following immune-modulation, which can be effectively managed with cross-over treatment. In primary refractory or multiply relapsed patients, hematopoietic stem cell transplantation (HSCT) may be considered but its efficacy is not well established. This review discusses the pathogenesis of LYG and highlights distinct histopathologic and clinical features that distinguish this disorder from other EBV+ B-cell LPDs and lymphomas. Treatment options, including immune-modulation and combination immuno-chemotherapy are discussed.

PMID: 32107539 [PubMed – as supplied by publisher]

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[Clinical manifestations and late diagnosis of common variable immunodeficiency].

Rev Alerg Mex. 2019 Oct-Dec;66(4):488-492

Authors: Carvalho-Neves Forte W, Morad H, Oliveira É, Reis A, Mosca T, Leite L, Santos de-Menezes MC

Abstract
BACKGROUND: Common Variable Immunodeficiency (CVID) is the most frequent type of severe primary immunodeficiency (PID). Clinical manifestations of CVID occur at any age; nevertheless, they are more frequent between the age of 6 and 10 years, and between the age of 20 and 40 years. In medical literature, there are hardly any diagnostic reports on CVID after 50 years of age.
CLINICAL CASE: A 58-year-old man with a clinical history of repeated infections since the age of 35. The tests showed a decrease in IgG, IgA, and specific antibodies, without any other causes of hypogammaglobulinemia. The CVID diagnosis was made and the patient received treatment with human immunoglobulin replacement and a reinforcement of personal and environmental hygiene. The patient stopped presenting repeated infections.
CONCLUSION: Diagnoses made after the age of 50, although they’re late, they are fundamental to the recovery of the patient. In the referred case, replacement with human immunoglobulin allowed an improvement in the quality of life.

PMID: 32105430 [PubMed – as supplied by publisher]

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miR-101, miR-548b, miR-554, and miR-1202 are reliable prognosis predictors of the miRNAs associated with cancer immunity in primary central nervous system lymphoma.

PLoS One. 2020;15(2):e0229577

Authors: Takashima Y, Kawaguchi A, Iwadate Y, Hondoh H, Fukai J, Kajiwara K, Hayano A, Yamanaka R

Abstract
MicroRNAs (miRNAs) inhibit protein function by silencing the translation of target mRNAs. However, in primary central nervous system lymphoma (PCNSL), the expression and functions of miRNAs are inadequately known. Here, we examined the expression of 847 miRNAs in 40 PCNSL patients with a microarray and investigated for the miRNA predictors associated with cancer immunity-related genes such as T helper cell type 1/2 (Th-1/Th-2) and regulatory T cell (T-reg) status, and stimulatory and inhibitory checkpoint genes, for prognosis prediction in PCNSL. The aim of this study is to find promising prognosis markers based on the miRNA expression in PCNSL. We detected 334 miRNAs related to 66 cancer immunity-related genes in the microarray profiling. Variable importance measured by the random survival forest analysis and Cox proportional hazards regression model elucidated that 11 miRNAs successfully constitute the survival formulae dividing the Kaplan-Meier curve of the respective PCNSL subgroups. On the other hand, univariate analysis shortlisted 23 miRNAs for overall survival times, with four miRNAs clearly dividing the survival curves-miR-101/548b/554/1202. These miRNAs regulated Th-1/Th-2 status, T-reg cell status, and immune checkpoints. The miRNAs were also associated with gene ontology terms as Ras/MAP-kinase, ubiquitin ligase, PRC2 and acetylation, CDK, and phosphorylation, and several diseases including acquired immunodeficiency syndrome, glioma, and those related to blood and hippocampus with statistical significance. In conclusion, the results demonstrated that the four miRNAs comprising miR-101/548b/554/1202 associated with cancer immunity can be a useful prognostic marker in PCNSL and would help us understand target pathways for PCNSL treatments.

PMID: 32101576 [PubMed – as supplied by publisher]

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Hyperactive PI3Kδ predisposes naive T cells to activation via aerobic glycolysis programs.

Cell Mol Immunol. 2020 Feb 25;:

Authors: Jia Y, Yang Q, Wang Y, Li W, Chen X, Xu T, Tian Z, Feng M, Zhang L, Tang W, Tian N, Zhou L, Song W, Zhao X

Abstract
Activated phosphoinositide 3-kinase δ syndrome (APDS) is an autosomal-dominant combined immunodeficiency disorder resulting from pathogenic gain-of-function (GOF) mutations in the PIK3CD gene. Patients with APDS display abnormal T cell homeostasis. However, the mechanisms by which PIK3CD GOF contributes to this feature remain unknown. Here, with a cohort of children with PIK3CD GOF mutations from multiple regions of China and a corresponding CRISPR/Cas9 gene-edited mouse model, we reported that hyperactive PI3Kδ disrupted TNaive cell homeostasis in the periphery by intrinsically promoting the growth, proliferation, and activation of TNaive cells. Our results showed that PIK3CD GOF resulted in loss of the quiescence-associated gene expression profile in naive T cells and promoted naive T cells to overgrow, hyperproliferate and acquire an activated functional status. Naive PIK3CD GOF T cells exhibited an enhanced glycolytic capacity and reduced mitochondrial respiration in the resting or activated state. Blocking glycolysis abrogated the abnormal splenic T cell pool and reversed the overactivated phenotype induced by PIK3CD GOF in vivo and in vitro. These results suggest that enhanced aerobic glycolysis is required for PIK3CD GOF-induced overactivation of naive T cells and provide a potential therapeutic approach for targeting glycolysis to treat patients with APDS as well as other immune disorders.

PMID: 32099075 [PubMed – as supplied by publisher]

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