Manish Butte

X-Linked Lymphoproliferative Disease in Latvia: A Report of Two Clinically Distinct Cases.

Case Rep Med. 2020;2020:7108657

Authors: Nokalna I, Kreile M, Butane D, Kovalova Z, Daneberga Z, Miklasevics E, Gardovska D, Gailite L

Abstract
X-linked lymphoproliferative disease (XLP) is a rare primary immunodeficiency. Affected individuals usually present with the Epstein-Barr virus infection and have no apparent disease prior to presentation. The most common clinical manifestations are fulminant infectious mononucleosis, dysgammaglobulinaemia, and lymphoma (usually of B-cell origin). XLP is caused by mutations in the SH2D1A gene which encodes the intracellular adaptor molecule SAP (signalling lymphocyte activation molecule- (SLAM-) associated protein). SAP is predominantly expressed in T cells and NK cells and functions to regulate signal transduction pathways downstream of the SLAM family of surface receptors to control CD4+ T cell (and by extension B-cell), CD8+ T cell and NK cell function, and development of NKT cells. Thus, SAP mutations cause dysregulation of the immune system, with defects in both cellular and humoral immunity. Here we report two clinical cases of three patients who presented with different manifestations of XLP, namely, fulminant infectious mononucleosis, Burkitt lymphoma and hypogammaglobulinaemia.

PMID: 32774386 [PubMed – as supplied by publisher]

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Primary Immunodeficiency Diseases in COVID-19 Pandemic: A Predisposing or Protective Factor?

Am J Med Sci. 2020 Jul 29;:

Authors: Babaha F, Rezaei N

PMID: 32773108 [PubMed – as supplied by publisher]

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Phenotypic analysis of T follicular helper and T follicular regulatory cells in primary selective IgM deficiency.

Hum Immunol. 2020 Aug 07;:

Authors: Kasahara TM, Bento CAM, Gupta S

Abstract
Selective IgM deficiency (SIgMD) is a rare immunodeficiency characterized by serum IgM below two standard of mean, and normal IgG and IgA levels. Both in human and mice with selective IgM deficiency, germinal centers cells are decreased. The development of germinal center and humoral immunity are regulated in part by follicular helper T (TFH) and follicular regulatory T (TFR) cells. However, the analysis of circulating TFH (cTFH) and TFR (cTFR) cells in the pathogenesis of SIgMD has not been explored. We observed lower percentage of cTFR cells in SIgMD patients than in control group. However, we did not observe any significant difference in the percentage of cTFH cells and their subsets between both experimental groups. When data were analyzed according to specific antibody response to pneumococcal polysaccharide, we observed a higher percentage of cTFH cells in SIgMD patients with specific antibody deficiency than in SIgMD patients with normal specific antibody response. Our results suggest that cTFH cells and their subsets are preserved in SIgMD patients. However, the role of lower percentage of cTFR cells in the pathogenesis of this immunodeficiency is not clear.

PMID: 32773096 [PubMed – as supplied by publisher]

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Identification of latent core genes and pathways associated with myelodysplastic syndromes based on integrated bioinformatics analysis.

Hematology. 2020 Dec;25(1):299-308

Authors: Zhu Y, Wu L

Abstract
Background: Myelodysplastic syndromes (MDS) are relatively common hematological malignancies characterized by dysplastic hematopoiesis in one or more of the lineages of the bone marrow. This study aimed to identify critical pathogenic biomarkers associated with the carcinogenesis and progression of MDS. Methods: To explore the candidate genes, the expression profiles of GSE2779, GSE4619, and GSE19429 were downloaded from the Gene Expression Omnibus (GEO) database, which contained CD34+ cells isolated from MDS patients and normal controls. The three microarray datasets were integrated to obtain differentially expressed genes (DEGs) and were deeply analyzed by bioinformatics methods. The construction of protein-protein interaction (PPI) network together with module analysis was performed based on Cytoscape software and the Search Tool for the Retrieval of Interacting Genes (STRING) database. Results: Our study identified 114 DEGs, which were highly enriched in various key pathways, including forkhead box protein O (FoxO) signaling pathway, the primary immunodeficiency, and hematopoietic cell lineage. Twelve core genes, such as FOXO1, PAX5 and CXCR4 were identified with a high degree of connectivity. It is plausible that FoxO signaling pathway plays an important role in MDS, and the dysregulation of FOXO1 was significantly associated with TGFβ, IL2/STAT5, Notch signaling and apoptosis pathways. Conclusion: The current study for the first time identified twelve latent indicators and their downstream targets, which might become significant biomarkers for worse clinical characteristics in MDS.

PMID: 32772642 [PubMed – as supplied by publisher]

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Bcl10 is associated with actin dynamics at the T cell immune synapse.

Cell Immunol. 2020 Jul 15;356:104161

Authors: Wagh K, Wheatley BA, Traver MK, Hussain I, Schaefer BC, Upadhyaya A

Abstract
T cell responses to antigen are initiated by engagement of the T cell receptor (TCR)1, leading to activation of diverse signaling cascades, including an incompletely defined pathway that triggers rapid remodeling of the actin cytoskeleton. Defects in the control of actin dynamics and organization are associated with several human immunodeficiency diseases, emphasizing the importance of cytoskeletal remodeling in the functioning of the adaptive immune system. Here, we investigate the role of the adaptor protein Bcl102 in the control of actin dynamics. Although Bcl10 is primarily known as a component of the pathway connecting the TCR to activation of the NF-κB3 transcription factor, a few studies have implicated Bcl10 in antigen receptor-dependent control of actin polymerization and F-actin-dependent functional responses. However, the role of Bcl10 in the regulation of cytoskeletal dynamics remains largely undefined. To investigate the contribution of Bcl10 in the regulation of TCR-dependent cytoskeletal dynamics, we monitored actin dynamics at the immune synapse of primary murine CD8 effector T cells. Quantification of these dynamics reveals two distinct temporal phases distinguished by differences in speed and directionality. Our results indicate that effector CD8 T cells lacking Bcl10 display faster actin flows and more dynamic lamellipodia, compared to wild-type cells. These studies define a role for Bcl10 in TCR-dependent actin dynamics, emphasizing that Bcl10 has important cytoskeleton-directed functions that are likely independent of its role in transmission of NF-κB -activating signals.

PMID: 32768663 [PubMed – as supplied by publisher]

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IgM, IgA and IgG response to conjugate polysaccharides in children with recurrent respiratory infections.

Scand J Immunol. 2020 Aug 07;:e12955

Authors: Cavaliere FM, Graziani S, Del Duca E, Bilotta C, Sgrulletti M, Quinti I, Moschese V

Abstract
Recurrent respiratory tract infections (rRTI) in children represent a challenge in physician’s practice and raise the suspicion of an immunological defect, when allergy and other chronic respiratory diseases are excluded [1]. When major primary antibody deficiencies are excluded [2-4], the diagnosis of Unclassified Primary Antibody Deficiency (UnPAD) or a Specific Antibody Deficiency (SAD) due to a reduced response to purified or conjugate pneumococcal polysaccharide vaccine (PPV-SAD and PCV-SAD, respectively) should be considered [5].

PMID: 32767783 [PubMed – as supplied by publisher]

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A novel SPINK5 mutation and successful subcutaneous immunoglobulin replacement therapy in a child with Netherton syndrome.

Pediatr Dermatol. 2020 Aug 07;:

Authors: Zelieskova M, Banovcin P, Kozar M, Kozarova A, Nudzajova Z, Jesenak M

Abstract
We report a 2-year-old patient with Netherton syndrome presenting with generalized exfoliative erythroderma, ichthyosiform dermatitis, trichorrhexis invaginata, hypernatremic dehydration, failure to thrive, and recurrent respiratory infections. Molecular analysis of SPINK5 identified a novel mutation (c.1530CA). Our case report also verifies and supports the safety and efficacy of subcutaneous immunoglobulin substitution in chronic generalized skin disorders associated with primary immunodeficiencies such as Netherton syndrome.

PMID: 32767583 [PubMed – as supplied by publisher]

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Establishing Simultaneous T Cell Receptor Excision Circles (TREC) and K-Deleting Recombination Excision Circles (KREC) Quantification Assays and Laboratory Reference Intervals in Healthy Individuals of Different Age Groups in Hong Kong.

Front Immunol. 2020;11:1411

Authors: Kwok JSY, Cheung SKF, Ho JCY, Tang IWH, Chu PWK, Leung EYS, Lee PPW, Cheuk DKL, Lee V, Ip P, Lau YL

Abstract
The clinical experience gathered throughout the years has raised awareness of primary immunodeficiency diseases (PIDD). T cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC) assays for thymic and bone marrow outputs measurement have been widely implemented in newborn screening (NBS) programs for Severe Combined Immunodeficiency. The potential applications of combined TREC and KREC assay in PIDD diagnosis and immune reconstitution monitoring in non-neonatal patients have been suggested. Given that ethnicity, gender, and age can contribute to variations in immunity, defining the reference intervals of TREC and KREC levels in the local population is crucial for setting up cut-offs for PIDD diagnosis. In this retrospective study, 479 healthy Chinese sibling donors (240 males and 239 females; age range: 1 month-74 years) from Hong Kong were tested for TREC and KREC levels using a simultaneous quantitative real-time PCR assay. Age-specific 5th-95th percentile reference intervals of TREC and KREC levels (expressed in copies per μL blood and copies per 106 cells) were established in both pediatric and adult age groups. Significant inverse correlations between age and both TREC and KREC levels were observed in the pediatric age group. A significant higher KREC level was observed in females than males after 9-12 years of age but not for TREC. Low TREC or KREC levels were detected in patients diagnosed with mild or severe PIDD. This assay with the established local reference intervals would allow accurate diagnosis of PIDD, and potentially monitoring immune reconstitution following haematopoietic stem cell transplantation or highly active anti-retroviral therapy in the future.

PMID: 32765500 [PubMed – as supplied by publisher]

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Normal fecal calprotectin levels in healthy children are higher than in adults and decrease with age.

Paediatr Child Health. 2020 Aug;25(5):286-292

Authors: Velasco Rodríguez-Belvís M, Viada Bris JF, Plata Fernández C, García-Salido A, Asensio Antón J, Domínguez Ortega G, Muñoz Codoceo RA

Abstract
Background/Objectives: The paediatric reference range of fecal calprotectin (FC) has not been decisively established and previous studies show a wide within-age variability, suggesting that other factors like anthropometric data or type of feeding can influence FC. Our aims were to establish the normal levels of FC in healthy children grouped by age and analyze whether sex, gestational age, birth weight, type of delivery, type of feeding, or anthropometric data influence FC values.
Methods: This multicentre, cross-sectional, and observational study enrolled healthy donors under 18 years of age who attended their Primary Health Care Centre for their routine Healthy Child Program visits. The exclusion criteria were: (i) immunodeficiency, (ii) autoimmune or (iii) gastrointestinal disease; (iv) medication usage; (v) gastrointestinal symptoms; or (vi) positive finding in the microbiological study.
Results: We enrolled 395 subjects, mean age was 4.2 years (range 3 days to 16.9 years), and 204 were male. The median FC was 77.0 mcg/g (interquartile range 246). A negative correlation between age and FC was observed (Spearman’s rho = -0.603, P<0.01), and none of the other factors analyzed were found to influence FC levels.
Conclusions: Normal FC values in healthy children (particularly in infants) are higher than those considered to be altered in adults and show a negative correlation with age. It is necessary to reconsider the upper limits of FC levels for paediatric patients according to age, with further studies required to determine other factors that influence FC during infancy.

PMID: 32765164 [PubMed – as supplied by publisher]

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Characterization of Peripheral Blood Mononuclear Cells Gene Expression Profiles of Pediatric Staphylococcus aureus Persistent and Non-Carriers Using a Targeted Assay.

Microbes Infect. 2020 Aug 03;:

Authors: Israelsson E, Chaussabel D, Fischer RSB, Moore HC, Robinson DA, Dunkle JW, Essigmann HT, Record S, Brown EL

Abstract
Defects in innate immunity affect many different physiologic systems and several studies of patients with primary immunodeficiency disorders demonstrated the importance of innate immune system components in disease prevention or colonization of bacterial pathogens. To assess the role of the innate immune system on nasal colonization with Staphylococcus aureus, innate immune responses in pediatric S. aureus nasal persistent carriers (n=14) and non-carriers (n=15) were profiled by analyzing co-clustered gene sets (modules). We stimulated previously frozen peripheral blood mononuclear cells (PBMCs) from these subjects with i) a panel of TLR ligands, ii) live S. aureus (either a mixture of strains or stimulation with respective carriage isolates), or iii) heat-killed S. aureus. We found no difference in responses between carriers and non-carriers when PBMCs were stimulated with a panel of TLR ligands. However, PBMC gene expression profiles differed between persistent and non-S. aureus carriers following stimulation with either live or dead S. aureus. These observations suggest that individuals susceptible to persistent carriage with S. aureus may possess differences in their live/dead bacteria recognition pathway and that innate pathway signaling is different between persistent and non-carriers of S. aureus.

PMID: 32758644 [PubMed – as supplied by publisher]

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