Manish Butte

Monozygotic Twins Concordant for Common Variable Immunodeficiency: Strikingly Similar Clinical and Immune Profile Associated With a Polygenic Burden.

Front Immunol. 2019;10:2503

Authors: Silva SL, Fonseca M, Pereira MLM, Silva SP, Barbosa RR, Serra-Caetano A, Blanco E, Rosmaninho P, Pérez-Andrés M, Sousa AB, Raposo AASF, Gama-Carvalho M, Victorino RMM, Hammarstrom L, Sousa AE

Abstract
Monozygotic twins provide a unique opportunity to better understand complex genetic diseases and the relative contribution of heritable factors in shaping the immune system throughout life. Common Variable Immunodeficiency Disorders (CVID) are primary antibody defects displaying wide phenotypic and genetic heterogeneity, with monogenic transmission accounting for only a minority of the cases. Here, we report a pair of monozygotic twins concordant for CVID without a family history of primary immunodeficiency. They featured a remarkably similar profile of clinical manifestations and immunological alterations at diagnosis (established at age 37) and along the subsequent 15 years of follow-up. Interestingly, whole-exome sequencing failed to identify a monogenic cause for CVID, but unraveled a combination of heterozygous variants, with a predicted deleterious impact. These variants were found in genes involved in relevant immunological pathways, such as JUN, PTPRC, TLR1, ICAM1, and JAK3. The potential for combinatorial effects translating into the observed disease phenotype is inferred from their roles in immune pathways, namely in T and B cell activation. The combination of these genetic variants is also likely to impose a significant constraint on environmental influences, resulting in a similar immunological phenotype in both twins, despite exposure to different living conditions. Overall, these cases stress the importance of integrating NGS data with clinical and immunological phenotypes at the single-cell level, as provided by multi-dimensional flow-cytometry, in order to understand the complex genetic landscape underlying the vast majority of patients with CVID, as well as those with other immunodeficiencies.

PMID: 31824477 [PubMed – in process]

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Review of Clinical Studies Targeting Inflammatory Pathways for Individuals With Autism.

Front Psychiatry. 2019;10:849

Authors: Hafizi S, Tabatabaei D, Lai MC

Abstract
Immune dysfunction and abnormal immune response may be associated with certain mechanisms underlying autism spectrum disorder (ASD). The early evidence for this link was based on the increased incidence of ASD in children with a history of maternal infection during pregnancy. Observational studies show increased prevalence of immune-related disorders-ranging from atopy, food allergy, viral infections, asthma, primary immunodeficiency, to autoimmune disorders-in individuals with ASD and their families. Evidence of neuroglial activation and focal brain inflammation in individuals with ASD implies that the central nervous system immunity may also be atypical in some individuals with ASD. Also, both peripheral and central inflammatory responses are suggested to be associated with ASD-related behavioral symptoms. Atypical immune responses may be evident in specific ASD subgroups, such as those with significant gastrointestinal symptoms. The present review aimed to evaluate current literature of potential interventions that target inflammatory pathways for individuals with ASD and to summarize whether these interventions were associated with improvement in autism symptoms and adaptation. We found that the current literature on the efficacy of anti-inflammatory interventions in ASD is still limited and large-scale randomized controlled trials are needed to provide robust evidence. We concluded that the role of immune-mediated mechanisms in the emergence of ASD or related challenges may be specific to subsets of individuals (e.g. those with concurrent immunological disorders, developmental regression, or high irritability). These subsets of individuals of ASD might be more likely to benefit from interventions that target immune-mediated mechanisms and with whom next-stage immune-mediated clinical trials could be conducted.

PMID: 31824351 [PubMed]

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Spinal cord toxoplasmosis in a young immunocompetent patient.

Infection. 2019 Dec 09;:

Authors: Martinot M, Greigert V, Farnarier C, Dardé ML, Piperoglou C, Mohseni-Zadeh M, Tarabeux J, Guffroy A, Villard O, Vely F

Abstract
We report a case of spinal cord toxoplasmosis occurring as a primary infection in a 31-year-old immunocompetent man. Exhaustive immunologic and genetic investigations did not identify any immunodeficiency. The causative agent was a typical type 2 strain. In cases of spinal cord lesions, toxoplasmosis should be considered, even in an immunocompetent patient.

PMID: 31820319 [PubMed – as supplied by publisher]

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The clinical phenotype and genotype of NLRP12-autoinflammatory disease: a Chinese case series with literature review.

World J Pediatr. 2019 Dec 09;:

Authors: Wang W, Zhou Y, Zhong LQ, Li Z, Jian S, Tang XY, Song HM

Abstract
BACKGROUND: The nucleotide-binding oligomerization domain-like receptor protein 12 (NLRP12)-autoinflammatory disorder (NLRP12-AD) is a rare autoinflammatory disease characterized by recurrent fever, rash as well as musculoskeletal symptoms, which is rarely reported in Asian populations.
METHODS: Three cases of NLRP12-AD presented to our hospital were studied after parental consents were obtained. Clinical presentations were recorded on a standardized case report form. Mutations of NLRP12 were detected by primary immunodeficiency disease panels and further examined by Sanger sequencing. PubMed literature search for relevant studies of systemic autoinflammatory disorders, especially NLRP12-AD between January, 2000 and January, 2019 was carried and the clinical data were summarized. Comparisons were made between groups in terms of onset age and of ethnicity.
RESULTS: All our patients presented with fever, rash and arthritis/arthralgia, and sensorineural as well as sensorineural deafness (1/3), uveitis (1/3), abdominal pain (1/3), and myalgia (1/3). Two novel mutation variations, p.W581X and p.L558R, are reported here. In addition, we also found that two patients inherited the mutated alleles from their healthy parents, and this may be evidence of haploinsufficiency.
CONCLUSIONS: Although the genotypes are similar, the clinical manifestations between Chinese patients and Western patients vary thus highlighting the possible influence of ethnic and environmental factors. On the other hand, some genetic mutations may lead to specific phenotype, as we have found a high prevalence of sensorineural hearing loss among p.R284X patients.

PMID: 31820221 [PubMed – as supplied by publisher]

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XMEN: welcome to the glycosphere.

J Clin Invest. 2019 Dec 09;:

Authors: Freeze HH

Abstract
XMEN (X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia) is a complex primary immunological deficiency caused by mutations in MAGT1, a putative magnesium transporter. In this issue of the JCI, Ravell et al. greatly expand the clinical picture. The authors investigated patients’ mutations and symptoms and reported distinguishing immunophenotypes. They also showed that MAGT1 is required for N-glycosylation of key T cell and NK cell receptors that can account for some of the clinical features. Notably, transfection of the affected lymphocytes with MAGT1 mRNA restored both N-glycosylation and receptor function. Now we can add XMEN to the ever-growing family of congenital disorders of glycosylation (CDG).

PMID: 31815737 [PubMed – as supplied by publisher]

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Flow Cytometry in the Diagnosis and Follow Up of Human Primary Immunodeficiencies.

EJIFCC. 2019 Nov;30(4):407-422

Authors: Salzer U, Sack U, Fuchs I

Abstract
Primary immunodeficiencies (PID) comprise a group of more than 300 mostly monogenetic disorders of the immune system leading to infection susceptibility and a variety of associated clinical and immunological complications. In a majority of these disorders the absence, disproportions or dysfunction of leucocyte subpopulations or of proteins expressed by these cells are observed. These distinctive features are studied by multicolour flow cytometry and the results are used for diagnosis, follow up, classification and therapy monitoring in patients with PIDs. Although a definite diagnosis almost always relies on genetic analysis in PIDs, the results of flow cytometric diagnostics are pivotal in the initial diagnostic assessment of suspected PID patients and often guide the treating physician to a more selective and efficient genetic diagnostic procedure, even in the era of next generation sequencing technology. Furthermore, phenotypic and functional flow cytometry tests allow to validate novel genetic variants and the mapping of complex disturbances of the immune system in individual patients in a personalized manner. In this review we give an overview on phenotypic, functional as well as disease/protein specific flow cytometric assays in the diagnosis of PID and highlight diagnostic strategies and specialties for several selected PIDs by way of example.

PMID: 31814814 [PubMed]

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Pharmacokinetic Analysis of Weekly Versus Biweekly IgPro20 Dosing in Patients With Primary Immunodeficiency.

Clin Pharmacol Drug Dev. 2019 Dec 08;:

Authors: Rojavin MA, Chapdelaine H, Tortorici MA, Praus M, Baheti G, Zhang Y, Hofmann J, Labrosse R, Dicaire R, Haddad E

Abstract
Flexible dosing of IgPro20 (Hizentra®, CSL Behring, King of Prussia, Pennsylvania) maintains normal serum immunoglobulin G (IgG) levels in patients with primary immunodeficiencies (PID). Until now, clinical trials testing the pharmacokinetic (PK) characteristics of serum IgG of weekly and biweekly subcutaneous IgG therapy were not published. This is the first study assessing PK characteristics following weekly and biweekly IgPro20 in patients with PID. The PK study was conducted in 2 parts: weekly dosing (12 weeks) and biweekly dosing (up to 12 months). Serum IgG concentration-time data were analyzed using noncompartmental methods to generate PK parameters. Fifteen patients provided PK samples for both dosing regimens. For weekly and biweekly regimens, mean doses per infusion were 109 and 213 mg/kg, respectively, and median tmax was 2.0 and 3.02 days, respectively. The mean Ctrough values were similar in weekly and biweekly regimens (10.21 and 10.13 g/dL, respectively). The geometric mean ratios (GMRs) with 90% confidence intervals of biweekly to weekly Cmax and Ctrough were 1.10 (1.06-1.13) and 0.98 (0.95-1.01), respectively. The GMR of dAUC was 1.07 (1.03-1.10). This PK analysis demonstrated similar systemic IgG exposure after weekly and biweekly IgPro20 dosing with an equivalent monthly dose in patients with PID.

PMID: 31814328 [PubMed – as supplied by publisher]

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Inhibitory Effects of Glucosylceramide on Tumorigenesis Induced by a Carcinogen in Mice.

Laryngoscope. 2019 Dec 06;:

Authors: Fujiwara K, Yazama H, Donishi R, Koyama S, Fukuhara T, Takeuchi H

Abstract
OBJECTIVE: Glucosylceramide (Glu-Cer), a glycosylated form of ceramide, has been reported to have cytotoxic effects in the cells of various cancers. We previously reported that dietary Glu-Cer from rice bran had inhibitory effects on human head and neck squamous cell carcinoma (HNSCC) in nonobese diabetes (NOD)/severe combined immunodeficiency (SCID) mice. In HNSCC, preventing recurrence and second primary cancer is required to improve prognosis. The purpose of the present study was to determine whether dietary Glu-Cer had anticarcinogenic and antitumorigenic effects in a mouse model of HNSCC.
METHODS: A total of 40 CB6F1-Tg rasH2@Jcl mice were divided into two groups: control and Glu-Cer. All mice were given 4-nitroquinoline 1-oxide for 24 weeks. Control group mice were fed the normal diet without Glu-Cer. The Glu-Cer group mice were given a mixture of the normal diet plus 0.25% Glu-Cer for 24 weeks. Microscopic examination was performed to identify grossly visible preneoplasms and neoplasms in the mouth, pharynx, and esophagus. Epithelial regions were classified as normal tissue, carcinoma in situ (CIS), or SCC; and the number of each type of region was counted.
RESULTS: Compared with the Glu-Cer group mice, control group mice more frequently developed individual and multiple tumors of each type, including CIS and SCC, in the mouth, pharynx, or esophagus.
CONCLUSION: Tumor development was effectively inhibited by dietary Glu-Cer derived from rice bran, indicating that this and related compounds show promise as prophylactic agents for human HNSCC.
LEVEL OF EVIDENCE: NA Laryngoscope, 2019.

PMID: 31808958 [PubMed – as supplied by publisher]

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Treatment of primary immunodeficiency with allogeneic transplant and gene therapy.

Hematology Am Soc Hematol Educ Program. 2019 Dec 06;2019(1):457-465

Authors: Pai SY

Abstract
The treatment of primary immunodeficiency disorders with allogeneic hematopoietic cell transplantation (HCT) has a history dating back to 1968 with the first successful transplant for a patient with severe combined immunodeficiency (SCID). The omission of conditioning for patients with SCID owing to their inability to reject allogeneic grafts and the increasing use of reduced intensity conditioning regimens often result in a state of mixed or split donor-recipient chimerism. The use of gene therapy (GT) via retroviral or lentiviral transduction of autologous CD34+ hematopoietic stem and progenitor cells is expected to correct only a portion of the hematopoietic stem cell compartment. The consequences of partial correction after either form of cellular therapy differ according to how the genetic deficiency affects immune cell development and function. Moreover, the conditioning regimen or lack thereof impacts the cell lineages at risk of partial correction. Advances in our understanding of immune reconstitution after HCT and GT for SCID, Wiskott-Aldrich syndrome, and chronic granulomatous disease are discussed.

PMID: 31808905 [PubMed – in process]

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Population pharmacokinetic analysis of weekly and biweekly IgPro20 (Hizentra®) dosing in patients with primary immunodeficiency.

Int Immunopharmacol. 2019 Dec 02;:106005

Authors: Zhang Y, Baheti G, Chapdelaine H, Hofmann J, Rojavin M, Tortorici M, Haddad E

Abstract
BACKGROUND: IgPro20 (Hizentra®), a 20% subcutaneous immunoglobulin G (IgG), is an effective treatment for patients with primary immunodeficiencies with impaired IgG production. Flexible dosing regimens of IgPro20 have been supported by pharmacokinetic (PK) modeling and simulation. This study further describes the PK characteristics of serum IgG concentrations after weekly and biweekly administration of IgPro20 and compares predicted and actual serum IgG data using a previously-developed population PK (popPK) model.
METHODS: A popPK model was developed by combining data from a previously-published model with data from a Phase 4 study (IgPro20_4005). An external validation of the original model using dosing, demographics, and historic endogenous serum IgG concentrations from patients enrolled in study IgPro20_4005 was performed. This dataset was then simulated 300 times and predicted serum IgG PK characteristics compared with the observed data.
RESULTS: A total of 173 patients (156 unique patients from original model and 17 patients from study IgPro20_4005) provided 4078 observations of serum IgG concentrations. The popPK estimates obtained demonstrated a clearance (% inter-individual variability) of 0.138 L/day (35%), volume of central compartment of 3.95 L (78.6%), inter-compartmental clearance of 0.260 L/day (56%), and volume of peripheral compartment of 4.44 L. Validation results indicated that observed serum IgG concentration vs time data fell within the 90% prediction intervals for median, 25th, and 75th percentiles of the simulated IgG concentration time courses.
CONCLUSIONS: The present analysis validated the ability of the previously published popPK model to predict serum IgG concentration time profiles after biweekly subcutaneous IgPro20 administration.

PMID: 31806567 [PubMed – as supplied by publisher]

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