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Involvement of miR-142 and miR-155 in Non-Infectious Complications of CVID.

October 22, 2020 By Manish Butte

Involvement of miR-142 and miR-155 in Non-Infectious Complications of CVID.

Molecules. 2020 Oct 16;25(20):

Authors: Amato G, Vita F, Quattrocchi P, Minciullo PL, Pioggia G, Gangemi S

Abstract
BACKGROUND AND OBJECTIVES: Common variable immunodeficiency (CVID) is the most prevalent antibody impairment. It is characterized by failure in immunoglobulin and protective antibody generation and defined by an increased tendency toward bacterial infections, autoimmunity, and malignancy. Most CVID diagnoses do not follow a classical Mendelian pattern of inheritance. In recent years, CVID has been considered an epigenetic phenomenon in the majority of cases, overtaking previous monogenetic and/or polygenetic theories. The aim of this study was to review the role of microRNAs (miRNAs) in CVID, focusing on the involvement of the same miRNAs in various non-infectious clinical complications of CVID, mainly autoimmunity and/or cancer.
MATERIALS AND METHODS: A bibliographic search of the scientific literature was carried out independently by two researchers in scientific databases and search engines. The MeSH terms “microRNAs” and “common variable immunodeficiency” were used. All research articles from inception to May 2020 were considered.
RESULTS: The literature data showed the involvement of two miRNAs in primary immunodeficiency: miR-142 and miR-155. Both of these miRNAs have been investigated through mice models, in which miR-142 and miR-155 were deleted. These knock-out (KO) mice models showed phenotypic analogies to CVID patients with hypogammaglobulinemia, adaptive immunodeficiency, polyclonal proliferation, lung disease, and enteric inflammation. miR-142 and miR-155 have been found to be involved in the following autoimmune and neoplastic clinical complications of CVID: Gastric cancer, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, natural killer/Tcell lymphoma (NKTCL), and immune thrombocytopenia.
CONCLUSIONS: miR-142 and miR-155 deregulation leads to similar CVID phenotypesin KO mice models. Although no data are available on the involvement of these miRNAs in human CVID, their dysregulation has been detected in human CVID comorbidities. The literature data show that miRNA sequences in murine models are comparable to those in humans; therefore, miR-142 and miR-155 involvement in human CVID could be hypothesized.

PMID: 33081305 [PubMed – in process]

Flow Cytometry for Diagnosis of Primary Immune Deficiencies-A Tertiary Center Experience From North India.

October 22, 2020 By Manish Butte

Flow Cytometry for Diagnosis of Primary Immune Deficiencies-A Tertiary Center Experience From North India.

Front Immunol. 2019;10:2111

Authors: Rawat A, Arora K, Shandilya J, Vignesh P, Suri D, Kaur G, Rikhi R, Joshi V, Das J, Mathew B, Singh S

Abstract
Flow cytometry has emerged as a useful technology that has facilitated our understanding of the human immune system. Primary immune deficiency disorders (PIDDs) are a heterogeneous group of inherited disorders affecting the immune system. More than 350 genes causing various PIDDs have been identified. While the initial suspicion and recognition of PIDDs is clinical, laboratory tools such as flow cytometry and genetic sequencing are essential for confirmation and categorization. Genetic sequencing, however, are prohibitively expensive and not readily available in resource constrained settings. Flow cytometry remains a simple, yet powerful, tool for multi-parametric analysis of cells. While it is confirmatory of diagnosis in certain conditions, in others it helps in narrowing the list of putative genes to be analyzed. The utility of flow cytometry in diagnosis of PIDDs can be divided into four major categories: (a) Enumeration of lymphocyte subsets in peripheral blood. (b) Detection of intracellular signaling molecules, transcription factors, and cytokines. (c) Functional assessment of adaptive and innate immune cells (e.g., T cell function in severe combined immune deficiency and natural killer cell function in familial hemophagocytic lymphohistiocytosis). (d) Evaluation of normal biological processes (e.g., class switching in B cells by B cell immunophenotyping). This review focuses on use of flow cytometry in disease-specific diagnosis of PIDDs in the context of a developing country.

PMID: 31572360 [PubMed – indexed for MEDLINE]

Hemophagocytic syndrome associated with Mycobacterium bovis in a patient with X-SCID: a case report.

October 21, 2020 By Manish Butte

Hemophagocytic syndrome associated with Mycobacterium bovis in a patient with X-SCID: a case report.

BMC Infect Dis. 2020 Sep 29;20(1):711

Authors: Shi B, Chen M, Xia Z, Xiao S, Tang W, Qin C, Cheng Y, Huang T, Huang C, Li Y, Xu H

Abstract
BACKGROUND: Mycobacterium bovis could infect patients with immunodeficiency or immunosuppressive conditions via Bacillus Calmette-Guérin (BCG) vaccination. Tuberculosis-related hemophagocytic syndrome (HPS) is reported, but not HPS caused by Mycobacterium bovis in children.
CASE PRESENTATION: A 4-month Chinese boy presented fever and cough. The initial laboratory investigation showed the lymphocyte count of 0.97 × 109/L, which decreased gradually. HPS was diagnosed based on the test results that fulfilled the HLH-2004 criteria. In addition, Mycobacterium tuberculosis complex was detected from his peripheral blood via metagenomic next-generation sequencing (mNGS) and M. bovis was identified by polymerase chain reaction-reverse dot blot (PCR-RDB). Thus, the patient was treated with Isoniazid, Rifampin, and Pyrazinamide, but not improved. However, parents refused to accept further therapy, and was discharged on the day 12 of admission. To confirm the pathogenesis, genetic analysis was performed. Mutation in the interleukin-2 receptor subunit gamma gene: Exon 6: c.854G > A; p. Arg285Gln was detected in the patient and the mother, which could underlie X-linked severe combined immunodeficiency.
CONCLUSIONS: A boy with X-SCID was diagnosed with M. bovis-associated HPS, emphasizing that X-SCID should be considered when M. bovis is detected in a male infant with low lymphocyte counts.

PMID: 32993535 [PubMed – indexed for MEDLINE]

Antisense Inhibition of Prekallikrein to Control Hereditary Angioedema.

October 21, 2020 By Manish Butte

Antisense Inhibition of Prekallikrein to Control Hereditary Angioedema.

N Engl J Med. 2020 09 24;383(13):1242-1247

Authors: Cohn DM, Viney NJ, Fijen LM, Schneider E, Alexander VJ, Xia S, Kaeser GE, Nanavati C, Baker BF, Geary RS, Levi M, Meijers JCM, Stroes ESG

Abstract
Hereditary angioedema is characterized by recurrent and unpredictable episodes of subcutaneous and mucosal swelling that can be life threatening. IONIS-PKK-LRx is a ligand-conjugated antisense oligonucleotide designed for receptor-mediated delivery to hepatocytes. In a compassionate-use pilot study, two patients with severe bradykinin-mediated angioedema were initially administered weekly subcutaneous injections of the unconjugated parent drug, IONIS-PKKRx, for 12 to 16 weeks, after which they received IONIS-PKK-LRx at a dose of 80 mg every 3 to 4 weeks for 7 to 8 months. Treatment was accompanied by a reduction in the angioedema attack rate. (Funded by Amsterdam UMC.).

PMID: 32877578 [PubMed – indexed for MEDLINE]

GeneReviews®

October 21, 2020 By Manish Butte

GeneReviews®

Book. 1993

Authors: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A

Abstract
CLINICAL CHARACTERISTICS: Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is characterized by varying combinations of steroid-resistant nephrotic syndrome (ranging from non-immune fetal hydrops to adolescent onset), primary adrenal insufficiency (with or without mineralocorticoid deficiency), testicular insufficiency, hypothyroidism, ichthyosis, lymphopenia/immunodeficiency, and neurologic abnormalities that can include developmental delay, regression / progressive neurologic involvement, cranial nerve deficits, and peripheral motor and sensory neuropathy.
DIAGNOSIS/TESTING: The diagnosis of SPLIS is established in a proband with at least one suggestive finding and biallelic pathogenic variants in SGPL1 identified by molecular genetic testing.
MANAGEMENT: Treatment of manifestations: Multidisciplinary management of steroid-resistant nephrotic syndrome, endocrine involvement, immunodeficiency, poor weight gain / feeding issues, developmental delay / intellectual disability, neurologic involvement, hearing loss, ichthyosis. Surveillance: Routine follow up as requested by specialty care providers and routine monitoring of development progress and educational needs. Agents/circumstances to avoid: Nephrotoxic medications; medications that require renal excretion (individuals with renal insufficiency); live vaccines, exposure to infectious agents, and transfusion products that have not been irradiated. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and awareness of agents/circumstances to avoid.
GENETIC COUNSELING: SPLIS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SGPL1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SGPL1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

PMID: 33074640

primary immunodeficiency NOT human immunodeficiency virus; +22 new citations

October 19, 2020 By Manish Butte

22 new pubmed citations were retrieved for your search.
Click on the search hyperlink below to display the complete search results:

primary immunodeficiency NOT human immunodeficiency virus

These pubmed results were generated on 2020/10/19

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books.
Citations may include links to full-text content from PubMed Central and publisher web sites.

Immunocompromised Seroprevalence and Course of Illness of SARS-CoV-2 in One Pediatric Quaternary Care Center.

October 14, 2020 By Manish Butte

Immunocompromised Seroprevalence and Course of Illness of SARS-CoV-2 in One Pediatric Quaternary Care Center.

J Pediatric Infect Dis Soc. 2020 Oct 13;:

Authors: Freeman MC, Rapsinski GJ, Zilla ML, Wheeler SE

Abstract
BACKGROUND: The burden of COVID-19 is poorly understood in pediatric patients due to frequent asymptomatic and mild presentations. Additionally, the disease prevalence in pediatric immunocompromised patients remains unknown.
METHODS: This cross-sectional study tested convenience samples from pediatric patients who had clinically indicated lab work collected and an immunocompromising condition, including oncologic diagnoses, solid organ transplant, bone marrow transplant, primary immunodeficiency, and rheumatologic conditions or inflammatory bowel disease on systemic immunosuppression, for the presence of antibodies to SARS-CoV-2.
RESULTS: We tested sera from 485 children and observed SARS-CoV-2 seroprevalence of 1.0% (CI 95%: 0.3-2.4%). Two patients were positive by NP swab RT-PCR, but only one seroconverted. Patients with oncologic diagnoses or solid organ transplant were most likely to be tested for COVID-19 when presenting with respiratory illness as compared to other groups.
CONCLUSIONS: Seroprevalence of antibodies to SARS-CoV-2 in immunocompromised children was similar to that of an immunocompetent pediatric population (0.6%, CI 95%: 0.3-1.1%), suggesting an adequate antibody response. However, none of the patients who tested positive for antibodies or via NP RT-PCR had more than a mild illness course and two patients did not have any reported illness, suggesting that SARS-CoV-2 may not cause a worse clinical outcome in immunosuppressed children, in contrast to immunocompromised adults.

PMID: 33049042 [PubMed – as supplied by publisher]

Protein Kinase C-Delta Defect in Autoimmune Lymphoproliferative Syndrome-Like Disease: First Case from the National Iranian Registry and Review of the Literature.

October 14, 2020 By Manish Butte

Protein Kinase C-Delta Defect in Autoimmune Lymphoproliferative Syndrome-Like Disease: First Case from the National Iranian Registry and Review of the Literature.

Immunol Invest. 2020 Oct 13;:1-12

Authors: Sharifinejad N, Azizi G, Behniafard N, Zaki-Dizaji M, Jamee M, Yazdani R, Abolhassani H, Aghamohammadi A

Abstract
BACKGROUND: Protein kinase C is a family of serine/threonine kinases that play a key role in the adaptive immune cell signaling, as well as regulation of growth, apoptosis, and differentiation of a variety of cell types. Patients homozygous for a null mutation of the Protein Kinase C Delta (PRKCD) gene, present clinical feature of immune dysregulation with susceptibility to Epstein-Barr virus infection. However, a minority of patients present the autoimmune lymphoproliferative syndrome (ALPS).
METHODS: The data were collected by direct interview and examining the patient’s clinical record. Whole-exome sequencing was performed to detect the underlying genetic mutation in the patient. We also conducted electronic searches for ALPS-like reported patients in PubMed, Web of Science, and Scopus databases.
RESULTS: In this study, we reported a 13-year-old boy who presented with autoimmunity, lymphoproliferation, recurrent pneumonia, cardiomyopathy, and dermatological manifestations. An elevation of double-negative T cells, CD8+ T cells, serum IgG level, as well as a reduction in NK cells, was observed in the patient. A homozygous frameshift mutation (c.1293_1294insA) in exon 13 of the PRKCD gene was confirmed. The literature search showed 39 ALPS-like patients with monogenic defects which only six (15.3%) of them were due to PRKCD genes.
CONCLUSION: PRKCD should be considered in the context of ALPS clinical manifestations with prominent dermatological involvements.

PMID: 33047643 [PubMed – as supplied by publisher]

High frequency of variants in genes associated with primary immunodeficiencies in patients with rheumatic diseases with secondary hypogammaglobulinaemia.

October 14, 2020 By Manish Butte

High frequency of variants in genes associated with primary immunodeficiencies in patients with rheumatic diseases with secondary hypogammaglobulinaemia.

Ann Rheum Dis. 2020 Oct 12;:

Authors: Sogkas G, Dubrowinskaja N, Adriawan IR, Anim M, Witte T, Schmidt RE, Atschekzei F

Abstract
OBJECTIVES: Treatment of rheumatic diseases requires immunomodulatory agents which can compromise antibody production. However, even in case of agents directly targeting B cells, a minority of patients develop hypogammaglobulinaemia, suggesting a genetic predisposition, which has not been investigated so far. The phenotypic overlap between primary immunodeficiency disorders (PIDs) and rheumatic diseases suggests a shared genetic basis, especially in case of patients with rheumatic diseases with hypogammaglobulinaemia.
METHODS: 1008 patients with rheumatic diseases visiting the outpatient clinics of the Hannover University Hospital were screened for hypogammaglobulinaemia. Those with persistent hypogammaglobulinaemia and an equal number of patients without it underwent targeted next-generation sequencing, searching for variations in genes linked with hypogammaglobulinaemia in the context of PIDs.
RESULTS: We identified 33 predicted pathogenic variants in 30/64 (46.9%) patients with persistent secondary hypogammaglobulinaemia. All 33 variants were monoallelic and 10 of them in 10/64 (15.6%) patients were found in genes associated with autosomal dominant PIDs. 2/64 (3.1%) patients harboured variants which were previously reported to cause PIDs. In the group without hypogammaglobulinaemia we identified seven monoallelic variants in 7/64 (10.9%), including a variant in a gene associated with an autosomal dominant PID.
CONCLUSIONS: Approximately half of patients with persistent secondary hypogammaglobulinaemia harboured at least a variant in a PID gene. Despite the fact that previous immunomodulatory treatment is an exclusion criterion in the diagnosis of PIDs, we identified genetic variants that can account for PID in patients with clear rheumatic phenotypes who developed hypogammaglobulinaemia after the introduction of immunomodulatory treatment. Our data suggest the common genetic causes of primary and secondary hypogammaglobulinaemia.

PMID: 33046446 [PubMed – as supplied by publisher]

Comparison of elapegademase and pegademase in ADA-deficient patients and mice.

October 14, 2020 By Manish Butte

Comparison of elapegademase and pegademase in ADA-deficient patients and mice.

Clin Exp Immunol. 2020 05;200(2):176-184

Authors: Murguia-Favela L, Min W, Loves R, Leon-Ponte M, Grunebaum E

Abstract
The absence of adenosine deaminase (ADA) causes severe combined immune deficiency (SCID), which has been treated with PEGylated bovine-extracted ADA (ADAGEN). ADAGEN was recently replaced by a PEGylated recombinant bovine ADA, expressed in Escherichia coli (elapegademase, ELA-ADA). Limited information on ELA-ADA is available. ADA enzymatic activity of ELA-ADA and ADAGEN was assessed in vitro at diverse dilutions. ADA activity and immune reconstitution in an ADA-SCID patient treated with ELA-ADA were compared with age-matched patients previously treated with ADAGEN. ADA activity and thymus reconstitution were evaluated in ADA-deficient mice following ELA-ADA or ADAGEN administered from 7 days postpartum. In vitro, ADA activity of ELA-ADA and ADAGEN were similar at all dilutions. In an ADA-SCID patient, ELA-ADA treatment led to a marked increase in trough plasma ADA activity, which was 20% higher than in a patient previously treated with ADAGEN. A marked increase in T cell numbers and generation of naive T cells was evident following 3 months of ELA-ADA treatment, while T cell numbers increased following 4 months in 3 patients previously treated with ADAGEN. T cell proliferations stimulation normalized and thymus shadow became evident following ELA-ADA treatment. ADA activity was significantly increased in the blood of ADA-deficient mice following ELA-ADA compared to ADAGEN, while both treatments improved the mice weights, the weight, number of cells in their thymus and thymocyte subpopulations. ELA-ADA has similar in- vitro and possibly better in-vivo activity than ADAGEN. Future studies will determine whether ELA-ADA results in improved long-term immune reconstitution.

PMID: 31989577 [PubMed – indexed for MEDLINE]